PHARMACOKINETICS (Greek phar-makon medicine + kinetikos relating to the movement) — the component of pharmacology studying patterns of absorption, distribution, metabolism and release of medicines. The research of these patterns is based on mathematical modeling of the specified processes.
As independent section of pharmacology F. it was created in the 30th 20 century, but was considered as especially academic discipline up to the middle of the 60th when on the basis of the pharmacokinetic principles the mathematical model of the optimum mode of use of streptocides (was developed see. Sulfanamide drugs). From now on F. began to develop intensively in several directions (development of new pharmacokinetic models, the analysis of communication between pharmacokinetic parameters: studying of patterns
of distribution of the pharmaceuticals existing and implemented in practice and definition of the odtimal-ny modes of their appointment; research of problems biol. availability, etc.) - In modern conditions the opreredeleniye of pharmacokinetic characteristics of new medicinal substances is an important part of their preclinical and clinical testing.
Basic pharmacokinetic processes. Each medicinal substance is exposed in an organism to absorption, distribution and allocation. The vast majority of medicinal substances is exposed in an organism to also metabolic transformations.
Absorption of medicinal substances is carried out at the expense of different mechanisms. So, lipophilic substances are soaked up by hl. obr. by passive diffusion through membranes (see Membranes biological). Hydrophilic substances with a low molecular weight (weight) get by filtering through a time biol. membranes. Many substances are soaked up at the expense of active transport of their molecules by means of transport systems of cellular membranes. Substances of the proteinaceous nature are soaked up, obviously, by a pinocytic (see).
Distribution of medicinal substances is estimated by pharmacokinetic methods preferential on the extracellular liquid including a blood plasma, cerebrospinal liquid, intraocular liquid and liquid contents went. - kish. path. Normal the volume of extracellular liquid at the person weighing 70 kg is accepted equal 15 l at total quantity of water in an organism apprx. 40 l. The total amount of extracellular liquid increases at exudates in belly and chest cavities, hypostases, etc. that can affect distribution of drugs in an organism.
Distribution of pharmaceuticals in an organism is provided with the blood circulatory system. Hypodispersion of drugs is interfered by membranes of bodies, cells and cellular organellas. At transfer of medicine through membranes its partial linkng with ingredients biol is possible. liquids on both sides of a membrane. There are different types of binding of pharmaceuticals differing on degree of specificity. Binding of drugs on a surface of proteinaceous molecules, hl is the most universal. obr. albumine (see) blood. It occurs due to hydrophobic interaction and is characterized by bystry reversibility. In a picture of the general distribution of drugs their linkng with blood proteins has double value. On the one hand, it can be followed by decrease in concentration of active drug and according to this easing of effect; on the other hand, binding promotes deposition of drug and by that prolongs its stay in an organism. So, slow removal and considerable duration of effect of streptocides of long action and doxycycline is in many respects caused by high extent of linkng of these drugs with blood proteins.
Also specific binding of drugs nek-ry fabrics is known. So, well soluble substances in lipids, napr, barbiturates (see), are deposited in fatty tissue. During the escaping of an anesthesia or at dialysis concerning a poisoning with barbiturates the phenomenon of a so-called secondary dream developing owing to mobilization of these substances from fat depos is shown. Other example of specific deposition of drugs at the person is accumulation of tetracyclines (see) in the growing bone tissue and dentine of teeth.
The most important binding site of medicinal substances are specific receptors (see Receptors, cellular receptors). In a specific receptor concentration of medicine considerably exceeds its concentration in surrounding biol. liquids, but in view of rather small size of a receptor this binding usually is practically not reflected in an overall picture of distribution of drug in an organism.
Pharmaceuticals can be allocated from an organism in not changed look or in the form of metabolites. Drugs, poorly soluble in lipids, are emitted preferential with kidneys in not changed look. Drugs, rather well soluble in lipids, are exposed in kidneys to the return absorption by an epithelium of tubules and come to the blood circulatory system again. Such substances are emitted with kidneys only after they by metabolic transformations form well water soluble (polar) connections. Metabolic transformations of drugs in an organism conditionally divide into two types of processes — biotransformation and conjugation. Mean reactions (oxidation, recovery, hydrolysis) by biotransformation, at to-rykh one functional group of a molecule of medicine turns into another or the polar group is entered into unpolar connection. Biosynthetic processes of compound of medicines with endogenous substances, napr, with glucuronic, sulfuric and acetic to-tami, and also with and - amino acids or the methyl radical belong to conjugation tests.
Biotransformation is carried out in an endoplasmic reticulum (see) hepatocytes and catalyzed by system of oxidases (see). Conjugation happens also preferential in a liver, but out of endoplasmic a reticulum — in mitochondrions (see) or in a soluble phase. As a result of biotransformation and conjugation hydrophily (see) pharmaceuticals therefore degree of their reabsorption an epithelium of gyrose tubules of kidneys goes down increases. Glucuronides (see), besides, can cosecrete bile and an intestinal epithelium. Thus, biol. value of biotransformation and conjugation consists in preparation of lipidorastvorimy medicinal substances for removal from an organism. At the same time usually there is an easing or there comes full loss pharmakol. activities of medicinal substances. However in the course of biotransformation metabolites of nek-ry drugs can become is more active than initial drugs. So, Phthazinum (see) and Ftalazolum (see) in the course of metabolism in an organism is formed by more active molecules of Norsulfazolum (see) and Sulfapyridazinum (see). In some cases as a result of metabolism of drugs also toxic products can be formed. Toxic metabolites are formed, e.g., at biotransformation of an isoniazid (see), paracetamol (see), furosemide (see) etc.
Removal of drugs from an organism happens not only through kidneys, but also to saliva and through lungs.
Removal of drugs with bile or through a wall went. - kish. a path it is possible to consider as excretion or an inkretion depending on whether drug with excrements is removed or it is soaked up in intestines again. In the latter case there is a possibility that at secondary passing through a liver with blood of a portal vein of nek-paradise a part of drug will be allocated with bile again. As a result the so-called gepatoportalny circle of the address of drug is formed. Such feature F. differ digitoxin (see), rifampicin (see Rifamycinums) and some other drugs.
Modeling of pharmacokinetic processes. Principles of modeling of basic processes F. it is possible to consider on the following example borrowed from physical chemistry.
The vessel divided by a semipermeable membrane into two parts is filled with liquid in equal volumes. If substance X is dissolved in the camera A and can get through a membrane into the camera B (but not back), then transport rate of molecules of substance of X of the camera A in the camera B depends at each this moment on its quantity (concentration) in the camera A. It follows from this that transport rate of substance X is changeable. If transport rate of substance X of the camera A in the camera B did not depend on its concentration, then it would be expressed by the equation of elementary algebra:
where MA — amount of substance in the camera A at the initial moment, t — time, V — the speed, k — coefficient of proportionality.
However considering that transport rate in each time slice (t — tt) different, the equation is written down as follows:
tj — l i
Is natural that speed at any moment of a time slice (t — f) is defined by that more precisely, than the interval is less. It gives infinitesimal sizes in this connection it is possible to remove the differential equation of the following look in a limit:
The solution of the equation (2) leads to the so-called exponential equation:
MDSO = M°e ~ M,
in Krom, as well as in the equation (2), k — a constant of transfer, M ° — amount of drug in the camera in initial
timepoint, t — time, e — the basis Nata
of rolled logarithms.
The curve corresponding to exponential function (3) corresponds to change of transport rate depending on amount of substance X or its instant concentration.
During the logarithming exponential function (3) turns into the equation of a straight line of a classical look: at = a-\-Kh, (4)
1pma = 1pma — ht. (5)
Brought physical. - the chemical model of transfer of substance of X of the camera A in the camera B is at the same time the elementary odnochaste-howl model of pharmacokinetics, in a cut the camera A is accepted to the whole organism, and the camera B — to external environment where drug X is removed. This model is applicable only provided that the drug is administered in an organism in one step, i.e. intravenously.
At peroral administration of drug the model considerably becomes complicated. The coefficient of proportionality of k in pharmacokinetic model gains sense of important parameter — a constant of elimination, to-ruyu designate in the form of the el index.
There are some more parameters, to-rymi it is accepted to characterize pharmacokinetic properties of different drugs. One of them is the so-called seeming volume of distribution of V. This parameter is defined as coefficient of proportionality between amount of substance M and its concentration of Page. Thus, to true volume biol. Wednesdays where drug is dissolved, it has no relation. Nevertheless, this parameter is very important as with its help it is possible to receive mathematical expression of dependence of transport rate on concentration of drug: substituting dependence of M from At in the differential equation (2), receive actually pharmacokinetic equation:
-§ = kelc. (6)
The solution of this differential equation is the exponential function (7) similar to function (3):
With (0 = k*lU
Function (7) by means of logarithming can be given by S°e to a type
of a straight line: In C = 1ps ° — heit similar
to function (5).
On the basis of odnochastevy model (and also more difficult models) it is possible to judge pharmacokinetics of drug not only according to concentration him in blood, but also according to cumulative excretion of drug with urine, with saliva, etc. For odnochastevy model the speed of cumulative excretion is expressed by the equation close to the equation (2), but with the return sign:
dM dt ~
This equation describes accumulation of substance in the camera B. The method of cumulative excretion is less exact, than a method of studying of concentration of drug in blood since it does not give the chance to establish concentration of drug in each timepoint, and allows to reveal only average concentration for a certain interval of time. However practical conveniences of this method are obvious. Special value has the parallel definition of concentration of drug in urine and blood which is one of methods of check of adequacy of odnochastevy model of pharmacokinetics.
The Odnochastevy model reflects only a final phase of stay of drug in an organism, but does not concern its distribution between fabrics and bodies. In this regard it is used for the analysis of rather simple pharmacokinetic processes. So-called mnogochastevy (multichamber) models of different type are more perfect.
If the right parts of the differential equations describing transfer of drug from the camera in the camera, and also its removal represent expression of a straight line, i.e. curve of the first order as in the equations (2) and (6), then such equations are linear, and model, to-ruyu they describe, belongs to the class of linear. In classical multichamber linear models division of an organism into cameras is made formally on the basis of the analysis of a curve of removal of drug, but not on a basis anatomo-fiziol. divisions of an organism. So, if at logarithmic transformation of empirical data of concentration of drug to blood only a part of a curve well is approximately expressed by a straight line, then it demonstrates that the odnochastevy linear model is inadequate to real process of removal of drug. In such cases it is necessary to check degree of approximation of the experimental data by means of dvukhchastevy or trekhchastevy linear models.
For odnochastevy most often the insufficient number of the samples taken at the very beginning of the pharmacokinetic research is the reason of wrong acceptance of dvukhchastevy model.
Early tests are especially important for identification of trekhchastevy model. Difficulty of implementation of this requirement, perhaps, the trekhchaste-vy linear model in F explains the reason, on a cut. it is used rather seldom.
Though allocation of the second and cameras is based further on the formal analysis of a curve of removal of drug, there is a nek-swarm a preferable reference of certain parts of an organism to the first, second and third cameras. Usually mean that a liquid part of blood, intersticial liquid and richly vaskulyarizirovan-ny bodies (heart, a brain, lungs, a liver, kidneys and closed glands) conditionally belongs to the first camera; to the second camera — all other fabrics and bodies. During the use of three-chambered model to the second camera conditionally carry muscular tissue, and to the third — bone and fatty fabrics.
Due to the development of computer facilities the dvukhchastevy linear model became especially widespread. The large number of the pharmaceuticals which are earlier studied within odnochastevy model was studied repeatedly using dvukhchastevy model. As a result the specified values of pharmacokinetic parameters were ruled and the specified recommendations concerning the mode of treatment are made.
The right part of the equations (2) and (6) sometimes corresponds to any curve of the second or even high order. Such models are called nonlinear. The most widespread equation of pharmacokinetics of the second order is expression:
~ dt ~ Km 4-C ’
where Km and Vtnax — constants of the equation: Mikhaelis — Menthene (see Kinetics of biological processes).
The right part of this equation corresponds to a hyperbole. It cannot be brought to a type of a straight line neither in natural numbers, nor by logarithmic transformation. Approach to a straight line takes place only under conditions when values of concentration of drug are very big or very small in comparison with value of a constant of Kt. According to kinetics of the second order all processes of removal of pharmaceuticals by metabolism proceed.
A special class of pharmacokinetic models are so-called perfused (physiological) models. They are based on the assumption of proportional communication between the speed of reversible transfer of drug between blood and fabrics and intensity of blood supply of the last. Such approach allows to give to cameras of model real fiziol. contents. The habit view of the equations of perfused models differs from a type of the equations of classical models in the fact that instead of the constants Ki } parameters of speed of a blood-groove through bodies, constants of the equation of Mikhaelis — Menthene (in case of the description of metabolism of drugs), and also others fiziol are entered. and biochemical constants.
Pharmacokinetic parameters depend on a condition of an organism. They are influenced by character of food, climate, smoking and other factors. Some values of parameters are genetically determined, napr, the speed of acetylation of an izoniaza yes. Removal of drugs at newborns occurs much more slowly, than at adults. But within the first years of life the speed of elimination sharply increases, exceeding the speed of elimination at adults. At advanced age the speed of elimination is slowed down. Among various factors influencing processes F., it is possible to call also biorhythms (see. Biological rhythms). However - they to a crust, time were studied preferential from the point of view of a pharmacodynamics (see).
Among patol. the states influencing on F. pharmaceuticals, first of all it should be noted disturbance of secretory function of kidneys (see). For many pharmaceuticals empirical coefficients of dependence between an indicator of secretory function of kidneys, on the one hand, and the size of a dose and intervals of its introduction — with another are found.
Value F. for a wedge, medicine is defined by its practical applications, the most important of to-rykh are: establishment is dependent
st between degree of efficiency of drug and its level in blood and
the optimization of the mode of treatment based on it; definition biol. availability of pharmaceuticals
from ready forms; studying of interaction of pharmaceuticals on the ways of their absorption, distribution and elimination (see Incompatibility of pharmaceuticals). Knowledge F. each of the pharmaceuticals applied in clinic it nvlya-tsya by one of fundamentals of rational tactics of medicinal treatment (see Pharmacotherapy).
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ta-r i R. E. Biopharmaceutics and pharmacokinetics, N. Y., 1975; Pfeifer S.
Biotransformation von Arznein; i t teln, Bd 1 — 3, B., 1975 — 1979;
Pharmacokine tics, ed. by T. Teorell and. lake, N. Y. — L., 1974; W a g n e r J. G. Fundamentals of clinical pharmacokinetics, Hamilton, 1975. Century of H. Nightingales.