Pharmacokinetics is a section of clinical pharmacology that studies routes of administration, biotransformation, binding to blood proteins, distribution and excretion of drugs (JIC).
One of the main indicators that determine the pharmacological effect is the concentration of drugs in the receptor region, however, it cannot be established under the conditions of a whole organism. It has been experimentally proven that in most cases there is a correlation between the concentration of the drug in the blood and its content in other biological fluids and tissues (Fig. 1-1).
Therefore, to determine the pharmacokinetic parameters of a drug, its content in the blood is studied. To get the appropriate idea of the drug entering the blood and removing it from the body, the drug content in the blood plasma is determined for a long time using liquid or gas-liquid chromatography, radioimmunoassay and enzyme-linked immunosorbent assays, and a spectrophotometric method. Based on the data obtained, a graph (pharmacokinetic curve) is plotted, noting the study time on the abscissa axis, and the drug concentration in the blood plasma on the ordinate axis.
Due to the complexity of describing the details of the drug distribution process in all organs and tissues, the body is conventionally represented as one or several parts (chambers) isolated by a permeable membrane, in which the drug is distributed. This type of modeling is called chamber modeling. Blood and well-supplied organs (heart, lungs, liver, kidneys, endocrine glands) are usually taken for the central chamber, for the peripheral - less intensively supplied organs and tissues (muscles, skin, adipose tissue). In these chambers, the drug is distributed at different rates: faster - in the central, slower - in the peripheral. The simplest is the single-chamber model, when it is assumed that after the administration of the drug, its concentration decreases according to the mono-exponential law. In accordance with the laws of linear kinetics, the rate of change in the amount of a drug in a chamber is proportional to its amount in this chamber.
Apparent volume of distribution (V d) is a hypothetical volume of body fluid required to evenly distribute the entire amount of drugs (injected dose) in a concentration similar to that in blood plasma. This indicator is measured in l / kg. When administered intravenously, the volume of distribution is equal to the ratio of the drug dose to its initial concentration in the blood.
High values of the volume of distribution indicate that JIC actively penetrates into biological fluids and tissues. Moreover, if JIC is actively bound, for example, by adipose tissue, its concentration in the blood can almost instantly become very low, and the volume of distribution will reach several hundred liters, exceeding the real volume of body fluids. Therefore, this indicator is called the apparent volume of distribution.
The volume of distribution depends on various factors.
· Physicochemical properties of drugs (molecular weight, degree of ionization and polarity, solubility in water and fats) affect its passage through membranes.
· Physiological factors (age, gender, total amount of adipose tissue in the body). For example, in the elderly and newborns, V d is reduced.
· Pathological conditions, especially diseases of the liver, kidneys, cardiovascular system (CVS).
Maximum concentration (C max) and the time of the onset of maximum concentration (T max). When a drug enters the systemic circulation (in the case of extravascular injection), its concentration gradually increases, reaching the value (C max) at the moment T max, and then begins to decrease.
If the absorption process is linear (the rate of the process is directly proportional to the amount of drugs in the system), the rate of this process is characterized by the absorption constant (k abs), measured in hours and is calculated through the half-absorption period (T 1/2) - the time during which 1 / 2 administered dose of the drug.
Bioavailability (F) is the part of the drug dose (in%) that reached the systemic circulation after extravascular administration (in this case, not all of the drug reaches the systemic circulation).
The absolute bioavailability is determined by the ratio of the area under curve (AUC) values for extravascular and intravenous drug administration.
Bioequivalence (relative bioavailability) is the ratio of the amount of drugs that entered the systemic circulation when used in various dosage forms or drugs produced by different companies. If the compared drugs are similar (active substance, dose, dosage form), but manufactured by different manufacturers, they are called generics, and in this case, a study of their bioequivalence is necessary. Two drugs are bioequivalent if they provide the same drug bioavailability.
The rate constant of elimination (k e) is the percentage of the decrease in the concentration of a substance in the blood per unit time (reflects the fraction of the drug excreted from the body per unit of time). Elimination consists of the processes of biotransformation and excretion. The rate constant of elimination characterizes elimination within the framework of a single-chamber model with a linear nature of the elimination process.
The half-life (T 1/2) is the time required to reduce the concentration of the drug in the blood by 50% as a result of elimination. Within the framework of the linear model, T 1/2 is calculated by the formula:
G 1/2 = 0.693 / *.
Almost in one T 1/2, 50% of JIC is excreted from the body, in two periods - 75%, in 3 periods - approximately 90%, etc.
The relationship between T 1/2 and k e1 is important for the selection of the dosage regimen and especially for determining the interval between doses.
Clearance (CI) - the volume of plasma or blood completely freed from J1C per unit of time. This indicator quantitatively characterizes the elimination of the drug and is expressed in ml / min or l / h. Within the linear model, the clearance is calculated using the formula:
Cl = V d -k el = D / AUC,
where C / is the clearance, V d is the volume of distribution, K e1 is the rate constant of elimination, D is the dose, AUC is the area under the kinetic curve.
Total clearance is the sum of renal and hepatic clearance (since these organs are the main routes of drug excretion). (Other routes of elimination or extrahepatic metabolism are usually not considered when calculating total clearance.)
Hepatic clearance characterizes the biotransformation of drugs in the liver (metabolic clearance) and excretion in the bile (bile clearance).
Renal clearance reflects the elimination of the drug in the urine. For example, the renal clearance of cimetidine is approximately 600 ml / min, the metabolic clearance is 200 ml / min, and the bile clearance is 10 ml / min, so the total clearance is 810 ml / min.
The main physiological factors that determine clearance are the functional state of the main physiological systems of the body, the volume of inflowing blood and the blood flow rate in the organ. Hepatic clearance depends on the rate of hepatic blood flow or the functional capacity of the metabolizing enzymes. For example, the clearance of lidocaine, which is extensively metabolized by hepatic enzymes, depends primarily on the rate of its delivery to the liver (i.e., on the volume of inflowing blood and blood flow rate), therefore, for example, in congestive heart failure, it is reduced. The clearance of phenothiazines depends mainly on the activity of metabolizing enzymes, therefore, when hepatocytes are damaged, the clearance of drugs of this group decreases sharply, as a result of which their concentration in the blood increases significantly.
Equilibrium (or stationary) concentration (C ss) - the concentration achieved in a state when in each interval between taking regular doses, the amount of absorbed drug is equal to the amount of eliminated [i.e. ie, at a steady state, or equilibrium, state]. That is, if a drug is administered in a constant dose at fixed time intervals, the duration of which is less than the elimination time, its concentration in the blood increases and then fluctuates within the average value between the maximum and minimum values.
When C ss is reached, the clinical effect of drugs is manifested in full. The less T 1/2 LS, the sooner C is reached and the more pronounced its fluctuations will be. For example, T 1/2 of novocainamide is 2-3 hours, and when administered every 6 hours, its C ss is characterized by a large scatter of values. Therefore, to prevent and reduce fluctuations in C ss in the blood, dosage forms with a sustained release of the active substance are becoming more widespread.
In practice, the C s of a substance can be calculated from its concentration in the blood after a single injection:
s _ 1, 44 F D- T and 2 V d -t
where F is bioavailability, D is the dose, T 1/2 is the half-life, V d is the volume of distribution, t is the time interval between doses.
In clinical practice, pharmacokinetic parameters are used, in particular, to calculate the prescribed doses of drugs.
The volume of distribution is used to calculate the loading dose required to achieve the required effective blood concentration of JIC:
C, where D Haep is the loading dose, V D is the volume of distribution, C is the concentration of JIC in the blood plasma.
To calculate the maintenance dose, i.e. the dose required to maintain the required concentration of J1C in the blood, the clearance value is used:
Under ss, where D nod is the maintenance dose, C is the total clearance, C m is the equilibrium concentration.
| Table 1-1. Clinical significance of basic pharmacokinetic parameters |
The clinical significance of the main pharmacokinetic parameters is given in table. 1-1.
The main pharmacokinetic processes include absorption, metabolism (biotransformation), distribution and excretion of JIC.
Absorption of drugs
Suction (absorption) - the process of drug intake from the injection site into the circulatory and / or lymphatic system. Absorption depends on the route of administration, the solubility of the drug in the tissues at the injection site and blood flow in these tissues, the dosage form and the physicochemical properties of the drug.
The rate of development, the severity and duration of the effect, and in some cases the nature of the action of the drug, depend on the route of drug administration. Allocate enteral [through the gastrointestinal tract (GIT)] and parenteral (bypassing the GIT) routes of administration, the absorption of which is different (with intravenous and intra-arterial administration of drugs immediately and completely enters the general bloodstream).
Oral absorption
The most common and accessible route of drug administration is through the mouth (oral).
Suction mechanisms
When administered enterally, absorption is realized through passive diffusion, active transport, filtration through the pores, and pinocytosis (Fig. 1-2). When a drug is absorbed, one of the listed mechanisms usually predominates, depending on the route of administration and the physicochemical properties of the drug. So, in the mouth, stomach,
in the colon and rectum, as well as from the skin surface, absorption occurs mainly by passive diffusion and, to a lesser extent, by filtration.
Passive diffusion is the most common mechanism for drug absorption. It does not require energy consumption, the amount of absorbed substance is directly proportional to the concentration gradient and the distribution coefficient in the "lipid-water" media. Fat-soluble drugs are absorbed faster than water-soluble drugs; there is no competition for absorption between two JICs of similar chemical composition. When absorbed, the drug first penetrates into the liquid on the surface of the cell membrane, then dissolves in its lipid layer and, finally, penetrates into the aqueous phase on the inner side of the membrane. The absorption of drugs depends on its physicochemical properties, especially the degree of ionization in the lumen of the gastrointestinal tract. Electrolytes that are in a non-dissociated state are subject to diffusion. The solubility and degree of ionization of drugs are determined by the pH of the contents of the stomach and intestines. With a decrease in pH, weak acids are better absorbed (in an acidic medium, they are in a less ionized state), and an increase in pH facilitates the absorption of weak bases and delays the absorption of weak acids. In theory, acids are better absorbed in the stomach (at a low pH of the gastric content, they are in a less ionized state) than in the intestine, however, their short residence time in the stomach and the absorbing surface area limited in comparison with the intestine practically eliminate the pH value. It should be emphasized that drugs by passive diffusion are well absorbed not only in the small intestine, but also in the colon and rectum, which serves as the basis for the development of many JICs with delayed release of the active substance, as well as the administration of drugs by the rectal route.
Active transport implies energy expenditures for the movement of drugs across the cell membrane, often against a concentration gradient. This mechanism is highly specific and characteristic for the absorption of natural substances (for example, amino acids, sugars and some vitamins), as well as drugs that have structural similarities with them (for example, methyldopa). The degree of absorption of drugs depends on the dose of the drug, since the phenomenon of "saturation of carrier proteins" is possible.
Filtration through the pores. Previously, it was believed that only drugs with a molecular weight of less than 100 Da can be absorbed in this way, but recent studies indicate its greater importance.
Pinocytosis is absorption, which consists in the absorption of particles of a substance by the cell membrane. This mechanism is of little importance in drug absorption.
Factors affecting absorption
The absorption of drugs depends on the physicochemical properties of the drug and the dosage form, the state of the patient's gastrointestinal tract, the interaction of the drug with the contents of the stomach and intestines, and the parameters of the pharmacokinetics of the drug.
Physicochemical properties of drugs and dosage forms:
Duration of disintegration of the tablet or capsule;
Dissolution time in the contents of the stomach and intestines;
The presence of excipients (drying substances) in a tablet or capsule;
Stability in the gastrointestinal tract;
Physicochemical properties of drugs (fat solubility, hydrophilicity, pK a).
The patient's gastrointestinal tract:
PH of the contents of the gastrointestinal tract;
Gastric emptying rate;
Time of drug passage through the small intestine;
The presence of gastrointestinal diseases;
The intensity of the blood supply to the gastrointestinal tract;
Enzyme activity.
Interaction of drugs with the contents of the stomach and intestines:
Interaction with other drugs;
Interaction with food.
Pharmacokinetic characteristics of the drug:
Intestinal wall metabolism;
Metabolism under the influence of intestinal microflora.
The form of drug release can determine its solubility and further absorption. The presence of excipients (drying agents) that were previously considered inert can also alter the absorption of the drug. For example, bentonite - a component of some granular forms of para-aminosalicylic acid - can adsorb rifampicin and impair its absorption when used in combination.
The rate of gastric emptying determines the rate at which drugs enter the small intestine, where most drugs are absorbed. Usually drugs that slow down gastric emptying help to reduce the rate of absorption of most drugs. However, the absorption of some drugs, for example, poorly soluble or unevenly absorbed, may increase with a slowdown in gastric emptying or peristalsis of the small intestine.
Deterioration of absorption of some drugs may be the result of a syndrome of insufficient absorption (malabsorption), caused by impaired absorption through the mucous membrane of the small intestine of one or more nutrients, followed by impaired metabolic processes. There are primary (hereditary) and secondary (acquired) malabsorption syndromes. The effect of gastrointestinal tract pathology on JIC absorption is shown in table. 1-2.
Table 1-2. Influence of diseases and pathological conditions of the gastrointestinal tract on the absorption of drugs
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The absorption of drugs can be influenced by other drugs, as well as food (see the chapter "Drug interactions").
The effect of drugs on the absorption of nutrients (nutrients)
Many drugs can impair the absorption of nutrients (proteins, fats, carbohydrates, vitamins, microelements, etc.), and, with prolonged use, lead to their deficiency (Tables 1-3).
Some drugs (for example, biguanides, acarbose) reduce the absorption of carbohydrates. Biguanides also increase the utilization of glucose in peripheral tissues, inhibit gluconeogenesis in the liver and reduce the increased insulin content in type II diabetes mellitus and obese patients. Acarbose inhibits intestinal α-glucosidases and reduces enzymatic degradation of di
Table 1-3. The effect of drugs on the absorption of nutrients (nutrients)
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oligo- and polysaccharides to monosaccharides, thereby reducing the absorption of glucose from the intestine and afternoon hyperglycemia. Acarbose reduces the absorption of most carbohydrates, such as starch, maltose, sucrose, while the drug itself is not absorbed.
There are drugs that reduce the absorption of fats, for example, orlistat, a specific inhibitor of gastrointestinal lipases. It forms a covalent bond with the active serine site of gastric and pancreatic lipases. The inactivated enzyme loses its ability to break down food fats in the form of triglycerides (TG). Undivided TGs are not absorbed.
Controlled release oral drug delivery systems
Some drugs with a short T 2 (for example, procainamide) must be taken at short intervals to maintain a stable concentration in the blood. When other J1Cs are taken orally (for example, indomethacin, carbamazepine), the active substance is rapidly released in the gastrointestinal tract and, therefore, its high plasma concentration is quickly reached, which can cause unwanted drug reactions. The main solution to these problems is the development of dosage forms with a sustained release of the active substance.
The system is based on a semipermeable membrane that surrounds the osmotically active core of the drug. One hole is drilled in each capsule using laser technology. After the capsule enters the gastrointestinal tract, water from the small intestine through a semipermeable membrane enters the capsule nucleus, dissolving the drug on its surface. Thus, a stable osmotic pressure is created inside the device, pushing the drug solution out through the hole. The delivery speed of drugs is mainly controlled by the size of the opening. The release rate remains constant until the contents of the capsule are completely dissolved, and then, as the concentration of drugs in the core decreases, it will gradually decrease. For the first time, this system began to be widely used in prolonged dosage forms of indomethacin, then - (3-blockers.
Various systems of controlled drug release have been developed. Their purpose is as follows:
intake of the optimal amount of drugs into the body;
ensuring good control of drug therapy acceptable to the patient.
Systems for the controlled release of hormonal contraceptives (subcutaneous implants) have been developed, from which the required amount of the hormone is released at a relatively constant rate over several years.
Suction from the mouth and nose
Buccal and sublingual administration of drugs promotes its rapid absorption, while there is no "first pass" effect (observed when a number of drugs are absorbed from the small intestine). The disadvantages of these routes of administration include the unpleasant taste of the drug and the need to keep it in the mouth without chewing or swallowing. Sublingual nitrates are traditionally used, but other drugs are often used, for example, captopril, pentazocine. With the sublingual use of buprenorphine and morphine, the analgesic effect develops faster than with oral administration at the same dose.
Curve - dependence of drug concentration in blood plasma on time after drug administration.
Maximum concentration - characterizes the effectiveness and safety of drugs, its value should not go beyond the therapeutic range.
First-line kinetics - the rate of drug elimination is proportional to its concentration (the higher the concentration, the faster the excretion)
Kinetics of the second line - the rate of elimination does not depend on the concentration (NSAIDs in high doses)
Control of drug concentration is needed:
When the effectiveness of drugs is difficult to assess clinically (prevention of epilepsy)
When it is difficult to assess the clinical and undesirable effects of the same drug (digoxin prescribed for arrhythmias can itself cause arrhythmias)
If the drug has potentially dangerous side effects
In case of poisoning and overdose
For metabolic or elimination disorders (CRF)
144 - 147. List the main pharmacokinetic parameters. Total clearance: determination of factors influencing the parameter, value for optimization of pharmacotherapy.
Total clearance is the volume of plasma or blood that is completely cleared of the drug per unit of time.
The volume of distribution is a hypothetical volume of fluid of the organism for even distribution of the entire administered dose of drugs in a concentration similar to the concentration in blood plasma. If the values are high, then the drug penetrates as much as possible into biological fluids and tissues. The molecular weight of the drug, its solubility in water, age, sex, pregnancy affect the volume of distribution.
The half-life is the time during which the concentration of drugs in the body is halved.
Equilibrium concentration is a state when the entry of drugs into the body is equal to its elimination. It takes approximately 5 half-lives to reach it.
Bioavailability - shows what part (%) of the drug reaches the systemic circulation.
Bioequivalence is the degree of similarity of a drug analogue (generic) to the original drug.
Phase I metabolism is a change in the structure of a drug through its oxidation, hydrolysis, etc. Aimed at achieving drug activity
Routes of drug administration. Factors influencing the choice of routes of administration. Examples.
I. Enteral administration
The advantages are simplicity and convenience. AB is prescribed before meals, because absorption of many of them depends on food. NSAIDs after meals, because they irritate the gastric mucosa. The disadvantages are that the absorption of many drugs depends on the state of the gastrointestinal tract, some drugs (insulin) are destroyed in the stomach, some drugs (NSAIDs) have a negative effect on the stomach and intestines.
2. Sublingual
The drug begins to take effect quickly. The absorption rate does not depend on food intake. For example nitroglycerin.
3. Rectal
Used for drugs with a high metabolism. Prescribe drugs that irritate the gastric mucosa (NSAIDs).
II. Parenteral administration
1. Intravascular (usually IV)
Provides fast creation of high concentration. In this way, you can prescribe drugs that are destroyed in the gastrointestinal tract (insulin), irritating the gastrointestinal tract or not absorbed in it (aminoglycosides). The disadvantages include various technical difficulties, the risk of developing infections at the injection site.
2. Intramuscular injection
Absorption into the blood takes 10-30 minutes. There are no principal advantages
3. Subcutaneously
Insulin or heparin can be administered.
4. Inhalation
Drugs for the treatment of lungs and bronchi
5. Endotracheal
In intensive care practice.
Drug absorption: definition, mechanisms. Factors affecting the absorption of parenteral drugs. Examples.
Absorption (absorption) - the process of drug intake from the injection site into the blood and / or lymphatic system. Drugs are able to overcome cell membranes, without violating their integrity, using a number of mechanisms: passive diffusion, active transport, filtration, pinocytosis.
For the absorption of drugs in the body, the solubility, chemical structure and molecular weight of drugs are important. Solubility in water increases with the presence of an alcohol group in the drug. The rate of absorption of drugs after i / m injection also depends on the intensity of blood circulation at the injection site.
Factors affecting the absorption of drugs when taken orally. Examples.
Gastrointestinal motility. PH of stomach contents.
Food intake. For example, the absorption of penicillins after a meal slows down, while the absorption of metoprolol, on the contrary, is accelerated.
Dosage form. Solutions, suspensions, capsules, simple tablets are better absorbed.
Distribution of drugs in the body. Factors affecting distribution. Examples.
Lipid solubility
The degree of binding to blood plasma proteins
Regional blood flow intensity
Presence of biological barriers (blood-enphalic barrier, histohematological, plasma membranes, capillary wall)
Binding of drugs to blood proteins. Factors affecting binding. Examples.
Proteins: albumins, lipoproetins, acidic a-glycoprotein, y-globulins.
Older age, high fat intake, kidney and liver disease.
Drug metabolism. Biotransformation reactions. Factors affecting metabolism. Examples.
The biological role of this process is to create a substrate that is convenient for further utilization or in accelerating elimination from the body.
Phase I metabolism - a change in the structure of a drug by oxidation, reduction or hydrolysis, etc. Aimed at achieving drug activity
Phase II metabolism - binding of drug molecules. For example methylation, acetylation. Aimed at removing drugs.
Biotransformation is influenced by: age, gender, diet, concomitant diseases, environmental factors. The most important organs for biotransformation are the liver and intestines.
Presystemic elimination of drugs. Examples, implications for the optimization of pharmacotherapy.
These are the processes of biotransformation before the drug enters the systemic circulation. If, as a result of active first-pass metabolism, substances with less pharmacological activity than the original drug are formed, then parenteral administration is preferable.
An example of a drug with a high first-pass metabolism is nitroglycerin, which is active when taken sublingually and intravenously, but when taken orally completely loses its effect.
Excretion of drugs from the body: main pathways, mechanisms. Factors affecting the excretion of drugs by the kidneys. Examples, implications for the optimization of pharmacotherapy.
Most drugs are excreted from the body by the kidneys, to a lesser extent by the lungs through the sweat glands, salivary glands, with breast milk, and the liver.
Elimination of drugs occurs through: glomerular filtration, passive reabsorption in the tubules.
Pharmacological effects of drugs. Affinity concept. Agonists, antagonists, partial receptor agonists, antagonists with their own activity. Drugs that have a nonspecific, specific, selective effect. Examples.
1. Physiological effects - changes in blood pressure, heart rate.
2. Biochemical - an increase in the level of enzymes in the blood
Affinity - the strength of the binding of a substance to receptors.
Internal activity is the ability of a substance, after their interaction with receptors, to cause physiological or biochemical reactions corresponding to the functional significance of these receptors.
Agonists are substances with both affinity and intrinsic activity. Drugs with pronounced intrinsic activity are full agonists, and those with less pronounced activity are partial.
Antagonists are substances that have affinity and do not have internal activity.
Drugs providing non-specific the action causes a wide range of pharmacological effects. This group includes, for example, vitamins, glucose, amino acids. They have broad indications for use.
If a drug acts as an agonist or antagonist on the receptors of certain systems, then its action is called specific.
Selectivity is manifested in the event that drugs change the activity of one of the components of the systems. For example, propranolol blocks all B-adrenergic receptors, while atenolol only blocks B1.
157. Minimum therapeutic concentration, therapeutic range, therapeutic breadth, average therapeutic concentration, therapeutic index of a drug: definitions, value for optimizing pharmacotherapy.
The minimum therapeutic concentration is the concentration of the drug in the blood causing an effect equal to 50% of the maximum.
Therapeutic range - the range of concentrations from the minimum therapeutic to causing the first signs of side effects.
Therapeutic latitude - the ratio of the upper limit of the therapeutic range to the lower
The average therapeutic concentration is an intermediate concentration in the therapeutic range.
Therapeutic index is an indicator reflecting the ratio of the average lethal dose to the average therapeutic dose.
Details
General pharmacology. Pharmacokinetics
Pharmacokinetics- a section of pharmacology devoted to the study of the kinetic laws of the distribution of medicinal substances. Studies the release of medicinal substances, absorption, distribution, deposition, transformation and excretion of medicinal substances.
Routes of drug administration
The rate of development of the effect, its severity and duration depend on the route of administration. In some cases, the route of administration determines the nature of the action of the substances.
Distinguish:
1) enteral routes of administration (through the digestive tract)
With these routes of administration, substances are well absorbed, mainly by passive diffusion through the membrane. Therefore, lipophilic non-polar compounds are well absorbed and hydrophilic polar compounds are poorly absorbed.
Under the tongue (sublingual)
Absorption occurs very quickly, substances enter the bloodstream, bypassing the liver. However, the absorption surface is small, and in this way only highly active substances administered in small doses can be administered.
Example: nitroglycerin tablets containing 0.0005 g of nitroglycerin. The action occurs in 1-2 minutes.
Through the mouth (per os)
Medicinal substances are simply swallowed. Absorption occurs partly from the stomach, but mostly from the small intestine (this is facilitated by the significant absorbing surface of the intestine and its intense blood supply). The main mechanism of intestinal absorption is passive diffusion. Absorption from the small intestine is relatively slow. It depends on intestinal motility, pH of the environment, quantity and quality of intestinal contents.
From the small intestine, the substance through the portal vein of the liver enters the liver and only then into the general bloodstream.
The absorption of substances is also regulated by a special membrane transporter - P-glycoprotein. It promotes the removal of substances into the intestinal lumen and prevents their absorption. There are known inhibitors of this substance - cyclosporin A, quinidine, verapamil, itraknazole, etc.
It should be remembered that it is impractical to prescribe some medicinal substances by mouth, since they are destroyed in the gastrointestinal tract under the action of gastric juice and enzymes. In this case (or if the drug has an irritating effect on the gastric mucosa), it is prescribed in capsules or pills, which dissolve only in the small intestine.
Rectally (per rectum)
A significant part of the substance (about 50%) enters the bloodstream, bypassing the liver. In addition, with this route of administration, the substance is not affected by the enzymes of the gastrointestinal tract. Absorption takes place by simple diffusion. Rectally, substances are prescribed in the form of suppositories or enemas.
Medicinal substances with the structure of proteins, fats and polysaccharides are not absorbed in the colon.
A similar route of administration is also used for local exposure.
2) parenteral routes of administration
The introduction of substances bypassing the digestive tract.
Subcutaneous
Substances can be absorbed by passive diffusion and filtration through the intercellular spaces. In this way, both lipophilic non-polar and hydrophilic polar substances can be injected under the skin.
Usually, solutions of medicinal substances are injected subcutaneously. Sometimes - oil solutions or suspensions.
Intramuscular
Substances are absorbed in the same way as with subcutaneous administration, but more quickly, since vascularization of skeletal muscles is more pronounced compared to subcutaneous fat.
Hypertonic solutions, irritating substances should not be injected into the muscles.
At the same time, oil solutions, suspensions are injected into the muscles in order to create a drug depot, in which the drug can be absorbed into the blood for a long time.
Intravenously
The drug immediately enters the bloodstream, so its action develops very quickly - in 1-2 minutes. In order not to create too high a concentration of the substance in the blood, it is usually diluted in 10-20 ml of isotonic sodium chloride solution and injected slowly over several minutes.
Do not inject oil solutions or suspensions into a vein due to the danger of vascular blockage!
Intra-arterial
Allows you to create a high concentration of the substance in the area that is supplied with blood by this artery. Anticancer drugs are sometimes administered in this way. To reduce the general toxic effect, the outflow of blood can be artificially impeded by applying a tourniquet.
Intrasternal
Usually used when intravenous administration is technically impossible. The medicine is injected into the spongy substance of the sternum. The method is used for children and the elderly.
Intraperitoneal
It is rarely used, as a rule, in operations. The action occurs very quickly, since most drugs are well absorbed through the sheets of the peritoneum.
Inhalation
Administration of drugs by inhalation. This is how gaseous substances, vapors of volatile liquids, aerosols are introduced.
The lungs are well supplied with blood, so absorption is very fast.
Transdermal
If necessary, long-acting highly lipophilic medicinal substances that easily penetrate through intact skin.
Intranasal
For introduction into the nasal cavity in the form of drops or spray based on local or resorptive action.
Penetration of medicinal substances through the membrane. Lipophilic non-polar substances. Hydrophilic polar substances.
The main methods of penetration are passive diffusion, active transport, facilitated diffusion, pinocytosis.
The plasma membrane consists mainly of lipids, which means that only lipophilic non-polar substances can penetrate by passive diffusion through the membrane. On the contrary, hydrophilic polar substances (HPV) practically do not penetrate through the membrane in this way.
Many drugs are weak electrolytes. In solution, some of these substances are in non-ionized form, i.e. in non-polar, and some - in the form of ions carrying electric charges.
The non-ionized part of the weak electrolyte penetrates through the membrane by passive diffusion
To assess ionization, use the value of pK a - the negative logarithm of the ionization constant. Numerically, pK a is equal to the pH at which half of the molecules of the compound are ionized.
To determine the degree of ionization, use the Henderson-Hasselbach formula:
pH = pKa + - for bases
Base ionization occurs by protonation
The degree of ionization is determined as follows
pH = pK a + - for acids
Ionization of acids occurs by protonation.
HA = H + + A -
For acetylsalicylic acid pKa = 3.5. At pH = 4.5:
Therefore, at pH = 4.5, acetylsalicylic acid will be almost completely dissociated.
Substance absorption mechanisms
Medicinal substances can enter the cell by:
Passive diffusion
The membrane contains aquaporins, through which water enters the cell and can pass by passive diffusion along the concentration gradient hydrophilic polar substances with very small molecular sizes dissolved in water (these aquaporins are very narrow). However, this type of drug intake into the cell is very rare, since most of the drug molecules are larger than the diameter of the aquaporins.
Lipophilic non-polar substances also penetrate by simple diffusion.
Active transport
Transport of a medicinal hydrophilic polar substance across the membrane against a concentration gradient using a special carrier. Such transport is selective, saturable and energy-intensive.
The drug, which has an affinity for the transport protein, binds to the binding sites of this carrier on one side of the membrane, then a conformational change of the carrier occurs, and, finally, the substance is released from the other side of the membrane.
Facilitated diffusion
Transport of a hydrophilic polar substance through a membrane by a special transport system along a concentration gradient, without energy consumption.
Pinocytosis
The invaginations of the cell membrane that surround the molecules of the substance and form vesicles that pass through the cytoplasm of the cell and release the substance from the other side of the cell.
Filtration
Through the pores of the membranes.
Also matters filtration of medicinal substances through the intercellular spaces.
Filtration of HPV through the intercellular spaces is important for absorption, distribution and excretion and depends on:
a) the size of the intercellular spaces
b) the size of the molecules of substances
1) through the gaps between the endothelial cells in the capillaries of the renal glomeruli, most of the medicinal substances in the blood plasma easily pass by filtration if they are not bound to plasma proteins.
2) in the capillaries and venules of the subcutaneous fat, skeletal muscles, the gaps between the endothelial cells are sufficient for the passage of most medicinal substances. Therefore, when injected under the skin or into the muscles, both lipophilic non-polar substances (by passive diffusion in the lipid phase) and hydrophilic polar substances (by filtration and passive diffusion in the aqueous phase through the gaps between endothelial cells) are well absorbed and penetrate into the blood.
3) with the introduction of HPV into the blood, substances quickly penetrate into most tissues through the gaps between the endothelial cells of the capillaries. Exceptions are substances for which there are active transport systems (antiparkinsonian drug levadopa) and tissues separated from the blood by histohematogenous barriers. Hydrophilic polar substances can penetrate such barriers only in some places in which the barrier is poorly expressed (in the area postrema of the medulla oblongata, HPV penetrates into the trigger zone of the vomiting center).
Lipophilic non-polar substances easily penetrate into the central nervous system through the blood-brain barrier by passive diffusion.
4) In the epithelium of the gastrointestinal tract, the intercellular spaces are small, so HPV is poorly absorbed in it. Thus, the hydrophilic polar substance neostigmine is prescribed under the skin at a dose of 0.0005 g, and to obtain a similar effect when administered orally, a dose of 0.015 g is required.
Lipophilic non-polar substances are easily absorbed in the gastrointestinal tract by passive diffusion.
Bioavailability. Pre-systemic elimination.
Due to the fact that the systemic effect of a substance develops only when it enters the bloodstream, from where it enters the tissues, the term “bioavailability” has been proposed.
In the liver, many substances undergo biotransformation. Part of the substance can be excreted in the intestine with bile. That is why only part of the injected substance can enter the bloodstream, the rest is exposed to elimination during the first passage through the liver.
Elimination- biotransformation + excretion
In addition, drugs may not be completely absorbed in the intestine, metabolized in the intestinal wall, and partially excreted from it. All this, together with elimination during the first passage through the liver, is called presystemic elimination.
Bioavailability- the amount of unchanged substance that has entered the general bloodstream, as a percentage of the injected amount.
As a rule, reference books indicate the bioavailability values when they are administered orally. For example, the bioavailability of propranolol is 30%. This means that when administered orally at a dose of 0.01 (10 mg), only 0.003 (3 mg) of unchanged propranolol enters the bloodstream.
To determine the bioavailability, the drug is injected into a vein (with the intravenous route of administration, the bioavailability of the substance is 100%). At certain time intervals, the concentration of the substance in the blood plasma is determined, then a curve of the change in the concentration of the substance over time is plotted. Then the same dose of the substance is administered orally, the concentration of the substance in the blood is determined and a curve is also built. Measure the area under the curves - AUC. Bioavailability - F - is defined as the ratio of AUC when administered orally to AUC when administered intravenously and is expressed as a percentage.
Bioequivalence
With the same bioavailability of two substances, the rate of their entry into the general bloodstream can be different! Accordingly, different will be:
Time to Peak Concentration
Maximum plasma concentration
The magnitude of the pharmacological effect
That is why the concept of bioequivalence is introduced.
Bioequivalence means similar bioavailability, peak action, nature and magnitude of the pharmacological effect.
Distribution of medicinal substances.
When lipophilic substances enter the bloodstream, as a rule, they are distributed relatively evenly in the body, while hydrophilic polar substances are unevenly distributed.
A significant influence on the nature of the distribution of substances is exerted by biological barriers that are encountered on their way: capillary walls, cell and plasma membranes, hemato-encephalic and placental barriers (it is pertinent to see the section "Filtration through the intercellular spaces").
The endothelium of the capillaries of the brain has no pores, there is practically no pinocytosis. Also, astroglia play a role, which increase the barrier strength.
Blood-ophthalmic barrier
Prevents the penetration of hydrophilic polar substances from the blood into the eye tissue.
Placental
Prevents the penetration of hydrophilic polar substances from the mother's body into the fetus.
To characterize the distribution of a drug in the system of a single-chamber pharmacokinetic model (the body is conventionally represented as a single space filled with liquid. When administered, the drug is instantly and evenly distributed) use such an indicator as the apparent volume of distribution - V d
Apparent volume of distribution reflects the estimated volume of fluid in which the substance is distributed.
If for a medicinal substance V d = 3 l (blood plasma volume), then this means that the substance is in the blood plasma, does not penetrate into the blood cells and does not leave the bloodstream. Perhaps this is a high molecular weight substance (V d for heparin = 4 l).
V d = 15 L means that the substance is in the blood plasma (3 L), in the intercellular fluid (12 L) and does not penetrate into the tissue cells. This is probably a hydrophilic polar substance.
V d = 400 - 600 - 1000 l means that the substance is still deposited in peripheral tissues and its concentration in the blood is low. For example, for imipramine - a tricyclic antidepressant - V d = 23 l / kg, that is, approximately 1600 l. This means that the concentration of imipramine in the blood is very low and hemodialysis is ineffective in case of imipramine poisoning.
Escrow
When the drug is distributed in the body, a part can be retained (deposited) in various tissues. From the depot, the substance is released into the blood and has a pharmacological effect.
1) Lipophilic substances can be deposited in adipose tissue. Anesthesia agent thiopental sodium causes anesthesia for 15-20 minutes, since 90% of thiopental sodium is deposited in adipose tissue. After the cessation of anesthesia, post-anesthetic sleep occurs for 2-3 hours due to the release of sodium thiopental.
2) Tetracyclines are deposited in bone tissue for a long time. Therefore, it is not prescribed for children under 8 years of age, as it can disrupt the development of bones.
3) Deposition associated with blood plasma. In combination with plasma proteins, the substances do not show pharmacological activity.
Biotransformation
Only highly hydrophilic ionized compounds, means for inhalation anesthesia, are released unchanged.
Biotransformation of most substances occurs in the liver, where high concentrations of substances are usually created. In addition, biotransformation can occur in the lungs, kidneys, intestinal wall, skin, etc.
Distinguish two main types biotransformation:
1) metabolic transformation
The transformation of substances through oxidation, reduction and hydrolysis. Oxidation occurs mainly due to mixed microsomal oxidases with the participation of NADPH, oxygen and cytochrome P-450. Recovery occurs under the influence of the system of nitro- and azo-reductases, etc. Usually, esters, carboxylesterases, amidases, phosphatases, etc. are hydrolyzed.
Metabolites are usually less active than the starting substances, but sometimes more active than them. For example: enalapril is metabolized to enaprilat, which has a pronounced hypotensive effect. However, it is poorly absorbed in the gastrointestinal tract, so they try to inject it into / in.
Metabolites can be more toxic than the starting materials. Paracetamol metabolite - N-acetyl-para-benzoquinone imine in overdose causes liver necrosis.
2) conjugation
A biosynthetic process, accompanied by the addition of a number of chemical groups or molecules of endogenous compounds to a drug or its metabolites.
The processes either go one after the other, or they go separately!
Distinguish also:
-specific biotransformation
A separate enzyme acts on one or more compounds, while exhibiting high substrate activity. Example: Methyl alcohol is oxidized by alcohol dehydrogenase to form formaldehyde and formic acid. Ethanol is also oxidized by aclogol dehydrogenase, but the affinity of ethanol for the enzyme is much higher than that of methanol. Therefore, ethanol can slow down the biotransformation of methanol and reduce its toxicity.
-nonspecific biotransformation
Under the influence of microsomal liver enzymes (mainly oxidase of mixed functions), localized in the smooth-surface areas of the endoplasmic reticulum of liver cells.
As a result of biotransformation, lipophilic uncharged substances are usually converted into hydrophilic charged ones, therefore they are easily excreted from the body.
Excretion (excretion)
Medicinal substances, metabolites and conjugates, are mainly excreted in the urine and bile.
-with urine
In the kidneys, low molecular weight compounds dissolved in plasma (not bound to proteins) are filtered through the capillary membranes of the glomeruli and capsules.
The active secretion of substances in the proximal tubule with the participation of transport systems also plays an active role. In this way, organic acids, salicylates, penicillins are released.
Substances can slow down each other's elimination.
Lipophilic uncharged substances are reabsorbed by passive diffusion. The hydrophilic polar ones are not reabsorbed and are excreted in the urine.
PH is of great importance. For the accelerated elimination of acidic compounds, the reaction of urine should be changed to the alkaline side, and for the removal of bases - to the acidic one.
- with bile
This is how tetracyclines, penicillins, colchicine, etc. are excreted. These drugs are significantly excreted in the bile, then partially excreted in excrement, or are reabsorbed ( intestinal-hepatic recirculation).
- with the secrets of different glands
Particular attention should be paid to the fact that during lactation, the mammary glands secrete many substances that a nursing mother receives.
Elimination
Biotransformation + excretion
A number of parameters are used to quantitatively characterize the process: elimination rate constant (K elim), elimination half-life (t 1/2), total clearance (Cl T).
Elimination rate constant - K elim- reflects the rate of removal of a substance from the body.
Half-life - t 1/2- reflects the time required to reduce the concentration of a substance in plasma by 50%
Example: substance A was injected into a vein at a dose of 10 mg. Elimination rate constant = 0.1 / h. After an hour, 9 mg will remain in the plasma, and after two hours - 8.1 mg.
Clearance - Cl T- the amount of blood plasma purified from the substance per unit of time.
Distinguish between renal, hepatic and total clearance.
With a constant concentration of the substance in the blood plasma, the renal clearance - Cl r is determined as follows:
Cl = (V u x C u) / C p [ml / min]
Where C u and C p are the concentration of the substance in urine and blood plasma, respectively.
V u - urinary flow rate.
Total ground clearance Cl T is determined by the formula: Cl T = V d x K el
The total clearance shows how much of the volume of distribution is released from the substance per unit of time.
MOXIFLOXACIN
PHARMACOKINETICS
The pharmacokinetic properties of moxifloxacin have been studied in detail and described in a number of publications by Stass H.H. with coauthors (1996-2001). The pharmacokinetics of moxifloxacin are discussed in a number of reviews.
Suction. Concentrations in the blood
Moxifloxacin is well absorbed from the gastrointestinal tract. After taking the drug orally at a dose of 400 mg, the maximum plasma concentrations (1.6 - 3.8 mg / l, on average 2.5 mg / l) are reached after 0.5 - 6 hours (on average after 2 hours). After oral administration, 86% of the dose taken is absorbed. The kinetics of plasma concentrations of moxifloxacin after oral administration is shown in Fig. 9, and the pharmacokinetic parameters are in table. 29.
Rice. nine.
Plasma concentrations of moxifloxacin in healthy subjects after a single oral administration (V) or intravenous infusion () 400 mg
After a single dose of moxifloxacin in doses of 50, 100, 200, 400, 600 or 800 mg, the maximum plasma concentrations and AUC increased in proportion to the dose taken and were determined after 0.75-3 hours, regardless of the dose; other pharmacokinetic parameters of moxifloxacin (T) / 2, total and renal clearance, volume of distribution) did not depend on the dose (Table 30). The pharmacokinetics of moxifloxacin are linear after a single dose of 50 to 800 mg.
The absolute bioavailability of moxifloxacin after oral administration is almost complete (86-89%) and does not depend on the dose: when taking 100 mg, it is 92%, when taking 400 mg - 86%.
Table 29.
Pharmacokinetic parameters of moxifloxacin (geometric means) in 12 healthy young people after a single oral administration or 1-hour intravenous infusion of 400 mg / 57, in modification]
Legend:
C max - maximum plasma concentrations;
T max is the time to reach maximum plasma concentrations;
T 1/2 - the time for a decrease in plasma concentrations by a factor of 2;
MRT is the mean retention time;
AUC is the area under the pharmacokinetic curve.
Table 30.
Pharmacokinetic parameters of moxifloxacin after a single oral or intravenous administration
Method of application, vine (mg) | С max, mg / l | T max, h | T l / 2, h | AUC, mg x h / l | OK, ml / min / kg | PC, ml / min / kg | OR, l / kg |
||
Ingestion |
|||||||||
Intravenous administration |
|||||||||
Legend:
C max - the maximum concentration in the blood;
T max - time to reach C max;
T 1/2 - half-elimination period;
MRT - retention time;
OK - total ground clearance;
PC - renal clearance;
VM - excretion in the urine;
OR is the volume of distribution.
* At the end of the intravenous infusion.
Eating a high-calorie breakfast with a high fat content slows down the absorption of moxifloxacin (Fig. 10): Cmax decreases by about 16% (from 1.22 to 1.04 mg / L), and Tmax - lengthens (from 1.4 -1 , 5 to 3.5 - 3.6 h), but the value of bioavailability does not change. Yogurt has little effect on the absorption of moxifloxacin: the relative bioavailability (absorption after taking yogurt compared to absorption on an empty stomach) when assessing the AUC indices is 85%, and when comparing the C max indices - 85%; T max when taking yoghurt lengthens from 0.88 to 2.75 hours.
Rice. ten.
Effect of high-calorie, high-fat meals on moxifloxacin absorption 163]
After repeated application of moxifloxacin, steady-state plasma concentrations were created within 2-3 days.
After many days (5-10 days) application of moxifloxacin in different doses, no accumulation of the drug in the blood was observed. After 5-10 days of application of moxifloxacin at doses of 400 and 600 mg 1 time per day, there is a tendency to an increase in C max or AUC. After repeated use of moxifloxacin 400 mg once a day, the AUC increased in some cases by 31%, and after 600 mg once a day - by 20%; when applied at 100 or 200 mg 2 times a day, the AUC indicator did not change significantly. These data indicate the absence of clinically significant accumulation of the drug in the plasma under various modes of oral administration of the drug (Table 31).
After a single 30-min intravenous infusion of moxifloxacin at doses of 100, 200, and 400 mg, plasma concentrations were created in proportion to the administered dose. Plasma drug concentrations decreased linearly regardless of dose. The kinetics of moxifloxacin plasma concentrations is well described by a three-chamber model: a rapid initial decrease in concentrations (T 1/2 in the alpha phase about 10-15 minutes) followed by a biphasic decrease in concentrations (T 1/2 in the beta phase about 4-5 hours, gamma phase - about 20 hours). Most of the pharmacokinetic parameters of moxifloxacin (T 1/2, volume of distribution, total and renal clearance, and some others) did not depend on the administered dose.
Table 31.
Pharmacokinetic parameters of moxifloxacin in healthy people after repeated oral administration of the drug in different doses
|
Dosing regimen, mg |
Research time |
С max, mg / l |
T max, h |
C min, mg / l |
AUC, mg x h / l |
Renal clearance, l / h |
|
100 (2 times a day) |
1st dose |
|||||
|
200 (2 times a day) |
1st dose |
|||||
|
400 (once a day) |
1st dose |
|||||
|
400 (once a day) |
1st dose |
|||||
|
400 (once a day) |
1st dose |
|||||
|
600 (once a day) |
1st dose |
Legend: See table. 29;
With min - the minimum detectable concentration in the blood.
After intravenous administration of 400 mg, Cmax of moxifloxacin in the blood of healthy people averaged 4.48 mg / l, AUC - 34 mg / l, stationary volume of distribution - 1.9 l / kg, T 1/2 - 11.9 h, total ground clearance 11.8 l / h. After intravenous administration, the maximum plasma concentrations of moxifloxacin were higher (by 31%) than after oral administration, and the AUC value for both modes of administration was the same.
Distribution
Moxifloxacin binds to serum proteins (mainly albumin) by 39%, while the amount of binding does not depend on the concentration of the drug in plasma in the range of 0.07 - 3.3 mg / l (Table 32); accordingly, the free (not bound by proteins) fraction is about 60%.
The rapid decrease in plasma concentrations of moxifloxacin after the end of the intravenous infusion indicates its rapid distribution in the body. A high indicator of the volume of distribution of the drug (see Tables 29, 30) indicates its good penetration into organs, tissues and cells.
Moxifloxacin after a single oral or intravenous administration of 400 mg quickly penetrates into the interstitial fluid: after intravenous administration, C max in the interstitial fluid in the subcutaneous tissues was 0.47 mg / l, in the muscle tissue - 0.62 mg / l; the T 1/2 value in the interstitial fluid and in plasma was the same and was approximately 14 hours. After 24 hours, the drug concentration in the interstitial fluid was approximately 2 times higher than in plasma.
Table 32.
Binding (%) of moxifloxacin and its metabolites by human plasma proteins
* Two definitions are given.
Moxifloxacin quickly penetrates into the inflammatory fluid of a skin blister obtained by applying a cantharidin patch to the skin. After oral administration of 400 mg of the drug, the maximum concentrations in the blister fluid (2.8 mg / l) were lower than in plasma (4.9 mg / l) and were reached later (T max, 3.1 and 1 h, respectively); the T 1/2 in the blister fluid was slightly higher (10 h) than in plasma (8.3 h), and the AUC value was less (32.5 and 39 mg-h / l, respectively). Approximately the same tendencies were observed with intravenous administration of the drug. The rate of penetration of moxifloxacin into the inflammatory fluid after oral administration was 83.5%, and after intravenous administration - 93.7%.
After intravenous administration of 400 mg of moxifloxacin C max in saliva averaged 4.95 mg / l, and in plasma - 4.19 mg / l. With an increase in the dose of moxifloxacin, its concentration in saliva increased. The pharmacokinetic parameters of the drug in saliva were generally close to the parameters established for plasma - after intravenous administration at doses of 100, 200, and 400 mg, C max was 1.09, respectively; 2.88 and 6.3 mg / l, AUC - 6.6; 15.8 and 40.9 mg-h / l, T 1/2 - 16.9; 12.3 and 12.6 hours, MRT 17.4; 14.6 and 14.5 h, stationary volume of distribution - 3.1; 2.0 and 1.6 l / kg, total ground clearance -254, 210 and 163 ml / min.
In 18 patients who underwent diagnostic bronchoscopy, plasma concentrations of moxifloxacin 3, 12 and 24 hours after a single dose of 400 mg were 3.28, respectively; 1.27 and 0.5 mg / l, in the mucous membrane of the bronchi - 5.5; 2.2 and 1 mg / kg, in the epithelial lining fluid - 24.4; 8.4 and 3.5 mg / l. The concentrations of moxifloxacin in the bronchial mucosa (5.5 mg / kg after taking 400 mg) were the same as after taking 600 mg of grepafloxacin (5.3 mg / kg), exceeding the concentrations of trovafloxacin (1.5 mg / kg after taking 200 mg ), sparfloxacin (1.3 mg / kg after taking 400 mg) and were slightly lower than levofloxacin (8.3 mg / kg) after taking 500 mg.
Table 33.
Concentrations of moxifloxacin (mg / L, mg / kg) in various human tissues after a single oral administration of 400 mg
* - data 10 hours after application;
** - concentration of unbound drug;
*** - concentration after 3 - 36 hours.
Summary data on the content of moxifloxacin in various fluids and human tissues are presented in table. 33.
Penetration into cells of a macroorganism
Moxifloxacin penetrates well and is contained in large quantities in the cells of the macroorganism. In experiments with human polymorphonuclear neutrophils, it was shown that moxifloxacin quickly penetrates into cells, creating concentrations almost 10 times higher than in the extracellular environment (Fig. 11). The penetration of fluoroquinolone into neutrophils is influenced by the temperature and pH of the incubation medium, the presence of metabolic inhibitors (sodium fluoride, sodium cyanide, carbonyl cyanide-m-chlorophenylhydrazone and 2,4-dinitrophenol) and membrane activators; the uptake of moxifloxacin by killed cells was the same as that of living cells (Table 34). After washing the neutrophils from the drug, it is rapidly released from the cells (Fig. 10). Similar results were obtained with cultured epithelial cells (McCoy). At therapeutic extracellular concentrations, moxifloxacin showed pronounced intracellular activity against S. aureus in human neutrophils. Moxifloxacin inhibited intracellular reproduction of L. maltophila in human monocytes of the THP-1 line and alveolar epithelial cells of the A549 line at a concentration of 0.008 mg / l; ciprofloxacin inhibited intracellular legionella in these cells at concentrations of 0.016 and 0.064 mg / l, respectively.
Bibliography
MOXIFLOXACIN
New antimicrobial drug from the fluoroquinolone group
| Further -
Introduction
One of the most important preclinical trials of new drugs is the study of their pharmacokinetic properties. These studies allow us to study the processes of absorption, distribution, metabolism and excretion of medicinal substances. Knowledge of distribution processes makes it possible to identify organs and tissues into which they penetrate most intensively and / or in which they are retained for the longest time, which can contribute to a more detailed study of the mechanisms of action of medicinal substances.
The purpose of this study was the study of the distribution in the body and tissue bioavailability of a new derivative of GABA - citrocard, which has cardio and cerebroprotective properties. A preclinical study of the pharmacological properties and drug safety of the drug was carried out at the Department of Pharmacology and Biopharmacy of the FUV and in the laboratory of pharmacology of cardiovascular drugs of the Volgograd State Medical University.
Research methods
The experiments were carried out on 150 white outbred male rats weighing 180-220 g, which were kept in a vivarium on a standard diet in compliance with all the rules and International Recommendations of the European Convention for the Protection of Vertebrate Animals used in experimental research (1997).
For the quantitative determination of compounds, we have developed an HPLC method for the determination of phenibut and its derivatives. We used a Shimadzu liquid chromatograph (Japan) with a diode array detector and a C18 4.6 × 100 mm, 5μm column. To prepare the mobile phase, acetonitrile (UF 210) (Russia) and a buffer system consisting of monosubstituted potassium phosphate 50 mM, pH 2.7 (Russia) and sodium salt of heptanesulfonic acid (0.12%) were used. The ratio of the aqueous and organic phase is 88: 12% v / v. The substance of the citrocard was fixed at a wavelength of 205 nm. The sensitivity of the method is 1 mg / ml. Extraction of citrocard, as well as simultaneous precipitation of proteins from biological samples, was performed from rat plasma with 10% TCA in a ratio of 1: 0.5.
The distribution of compounds in the body of rats was studied in organs of potential action: heart and brain; in tissues with strong vascularization - lungs and spleen; with moderate vascularization - the muscle (musculus quadriceps femoris) and weak vascularization - the omentum, as well as in the organs providing elimination - the liver and kidneys. 20% homogenates were prepared from organs in distilled water.
Citrocard was administered to rats intravenously and orally at a therapeutic dose of 50 mg / kg. Intravenous blood and organ samples were taken after 5, 10, 20, 40 minutes and after 1, 2, 4, 8 and 12 hours, and after oral administration - after 15, 30 minutes and after 1, 2, 4, 8 and 12 hours after administration.
To assess the intensity of drug penetration into tissues, the tissue availability index (ft) was used, determined by the ratio of the AUC value (area under the pharmacokinetic curve) in the tissue to the corresponding AUC value in the blood. The apparent distribution coefficient (Kd) of the drug between blood and tissue, determined by the ratio of the corresponding concentrations at the same time point on the final (monoexponential) portions of the curves, was also estimated.
Calculations were performed using the non-model method, statistical processing was carried out in Excel.
Research results
As a result of the study, averaged pharmacokinetic profiles of the dependence of the concentration of the compound in the blood plasma of rats on time were obtained. As can be seen from the data presented, the maximum concentration of citrocard (134.01 μg / ml) is observed in the fifth minute after administration. Then there is a rapid decrease in concentration and after 12 hours of the study, the content of the compound in the plasma becomes below the detection threshold. The decrease is biexponential, suggesting a fast first phase of distribution followed by a slower phase of elimination. For two hours of the study, the concentration of citrocard decreases almost 10 times (in the second hour, 14.8 μg / ml of blood plasma is determined). This indicates that the citrocard is undergoing intense elimination in the rat organism.
The main pharmacokinetic parameters (Table 1) show low values of the half-life (T1 / 2 = 1.85 hours) and the average retention time in the body of one drug molecule (MRT = 2.36 hours). The rate-average decrease in the concentration of citrocard in blood plasma causes a small value of the area under the pharmacokinetic curve (AUC = 134.018 μg * hour / ml). The value of the stationary volume of distribution (Vss) is 0.88 l / kg, the indicator slightly exceeds the volume of extracellular fluid in the rat's body, which indicates the low ability of the drug to be distributed and accumulated in tissues. This, apparently, is associated with a low value of the systemic clearance indicator (Cl = 0.37 l / h * kg), despite the severity of the processes of elimination of the compound.
When administered orally, citrocard is found in organs and tissues 15 minutes after administration, reaching a maximum after 2 hours and after 12 hours the concentration level drops to the threshold for determining this drug. Pharmacokinetic parameters are presented in table. 1.
table 1. Pharmacokinetic parameters of the citrocard compound in the blood plasma of rats after intravenous and oral administration at a dose of 50 mg / kg
With oral administration of citrocard, the distribution pattern becomes different. The half-life and the volume of distribution of the studied substance significantly increase.
In the heart, an organ of potential action when administered intravenously, the compound is found at a maximum concentration (24.69 μg / g) 5 minutes after administration, for 20 minutes the indicator is kept at the same level, and then slightly decreases by 40 minutes, being determined to 8 hours. The pharmacokinetic profile of the citrocard in the heart coincides with that in the blood plasma. The tissue availability is 0.671; distribution coefficient - 1 (Table 2). With oral administration, tissue bioavailability increases by 30% and is 0.978, the distribution coefficient remains at the same level as with intravenous administration (Table 3).
The drug in low concentrations penetrates the blood-brain barrier into the brain. The maximum amount (6.31 μg / g) of citrocard in the brain is determined at the fifth minute and remains above the detection threshold for 4 hours. Tissue availability is 0.089; distribution coefficient - 0.134. When administered orally, the level of citrocard in the brain is below the threshold for determining the table. 2 and 3).
In the spleen and lungs, a similar trend is noted with both routes of administration. Tissue accessibility is 0.75 for the lungs and 1.09 for the spleen; distribution coefficient - 1.097 and 1.493, respectively, with intravenous administration (Table 2). Oral tissue bioavailability in these organs is the same (1.35 and 1.37), the partition coefficient is 0.759 for the spleen and 0.885 for the lungs (Table 3).
In muscle tissue, the citrocard is determined at the level of organs with a high degree of vascularization for both routes of administration. The maximum concentration (58.1 μg / g) is observed at 10 minutes, tissue availability is 1.143 distribution coefficient - 1.755 with intravenous administration (Table 2) and with oral administration, tissue availability - 0.943, distribution coefficient - 0.677 (Table 3).
In the omentum, citrocard is found in rather high concentrations when administered intravenously (52.7 μg / g) and in very low concentrations when administered orally (6 μg / g). Tissue accessibility is equal to 0.43 for intravenous administration and 0.86 for oral administration; the distribution coefficient is 0.664 and 0.621, respectively (Tables 2 and 3).
The tissue availability of the citrocard for the liver and kidneys is 1.341 and 4.053, the distribution coefficient is 1.041 and 4.486, respectively (Table 2). These values do not actually differ from those for oral administration (Table 3), which indicates the presence of high concentrations of the drug in the elimination organs. The decrease in the amount of the substance in the liver and kidneys is similar to that in the blood plasma.
Table 2. Pharmacokinetic parameters of the distribution of citrocard compounds in organs and tissues after intravenous administration to rats at a dose of 50 mg / kg
Table 3.Pharmacokinetic parameters of the distribution of citrocard compounds in organs and tissues after oral administration to rats at a dose of 50 mg / kg
Thus, the distribution of citrocardi over organs and tissues is carried out according to the following scheme: the highest content is noted in the kidneys, both for oral and intravenous administration. This is confirmed by the high values of renal clearance, which is 80% for intravenous administration, and 60% for oral administration of the total clearance. The citrocard is well distributed to organs with a high degree of vascularization, where its tissue availability is higher than unity. The content of citrocard in the heart is comparable to its content in the blood, while tissue bioavailability for the heart is approximately 1.5 times higher after oral administration, compared with intravenous administration. The content of the citrocard in the omentum also depends on the route of administration. With oral administration, tissue bioavailability is 2 times higher than with intravenous administration, and amounts to 86 and 43% of its content in the blood, respectively. The smallest content of citrocard is observed in the brain. Tissue bioavailability after intravenous administration is 8.9% of its content in the bloodstream. When administered orally, the concentration of the compound in the brain is below the detection threshold. Whereas in the analogue of citrocard, phenibut, the concentration in the brain with intravenous administration is 9%, with oral administration - 100%.
Main conclusions
- As a result of the studies carried out, it was found that the distribution of the citrocard in organs and tissues is heterogeneous. The studied compound has the greatest tropism towards organs with a high degree of vascularization and organs of elimination.
- In the rat brain, the compound is determined at low concentrations, which is most likely associated with transport across the blood-brain barrier and is not associated with lipophilicity of the citrocard and a high degree of cerebral vascularization.
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