Factors affecting drug metabolism. Biotransformation of drugs - clinical pharmacology Metabolic interaction of drugs
Biotransformation
Kinds:
Metabolic transformation - the transformation of substances through oxidation, reduction and hydrolysis.
Conjugation - this is a biosynthetic process, accompanied by the addition of a number of chemicals to medicinal substances or its metabolites.
Removal of drugs from the body:
Elimination - the removal of drugs from the body as a result of biotransformation and excretion.
Presystemic - is carried out when the drug passes through the intestinal wall, liver, lungs before it enters the circulatory system (before its action).
Systemic - removal of a substance from the circulatory system (after its action).
Excretion - excretion of drugs (with urine, feces, secretions of glands, exhaled air).
For the quantitative characterization of elimination, the following parameters are used:
Elimination rate constant (Kelim) - reflects the rate of removal of a substance from the body.
« Half-life"(T50) - reflects the time required to reduce the concentration of the substance in the blood plasma by 50%
Clearance- reflects the rate of purification of blood plasma from drugs (ml / min; ml / kg / min).
Pharmacodynamics
Pharmacodynamics- a section of pharmacology that studies the localization, mechanism of action of drugs and their biochemical effects (what the drug does to the body).
For the manifestation of the action of a drug, it must interact with biological substrates.
Targets:
Receptor
cell membranes
Enzymes
Transport systems
Receptor types:
Receptors that directly control the function of ion channels. (HXR…).
G protein-coupled receptors (R and G - protein - ion channels) (MXR).
Receptors that directly control the function of cell enzymes (R-insulin).
Receptors that control DNA transcription (intracellular receptors).
In relation to drug receptors possess affinity and internal activity.
Affinity (affinity)- the ability of a drug to form a complex with a receptor.
Internal Activity- the ability to cause the appearance of a cellular response when bound to the receptor.
Depending on the severity of affinity and the presence of internal activity, drugs are divided into:
Agonists (mimetics - substances with affinity and high internal activity).
Partial
Atogonists (blockers - substances with high affinity, but devoid of internal activity (they close their receptors and prevent the action of endogenous ligands or agonists).
Competitive
Non-competitive
Agonist - antagonist (it affects one receptor subtype as an agonist and another receptor subtype as an antagonist).
Types of drug action:
reflex
indirect
reversible
irreversible
electoral
Indiscriminate
side
Local (on site application)
Resorptive (with suction - per system)
General characteristics of the effect of drugs on the body (according to N.V. Vershininn).
Toning (functions to normal)
Excitation (functions above the norm)
Calming action (↓ increased function to normal).
Depression (↓ functions below normal)
Paralysis (cessation of function)
The main action of the LP
Side effects of drugs
Desirable
unwanted
Adverse drug reactions:
1 type:
Overdose related
associated with poisoning
2 type:
Associated with the pharmacological properties of drugs
2 type:
Direct toxic reactions
Neurotoxicity (CNS)
Hepatoxicity (liver function)
Nephrotoxicity (kidney function)
Ulcerogenic effect (intestinal and stomach mucosa)
Hematotoxicity (blood)
Impact on the embryo and fetus:
Embryotoxic action
Teratogenic effect (malformation)
Fetotoxic effect (fetal death)
Mutagenicity(the ability of a drug to cause permanent damage to the germ cell and its genetic apparatus, which manifests itself in a change in the genotype of the offspring).
Carcinogenicity(the ability of drugs to cause the development of malignant tumors).
Undesirable reactions may be associated with a change in the sensitivity of the body:
allergic reactions
Idiosyncrasy (atypical reaction of the body to a drug associated with a genetic defect)
Factors affecting the action of drugs:
Physical and chemical properties of drugs and conditions for their use (doses, repeated use, interaction with other drugs).
Individual abilities of the patient's body (age, gender, body condition).
Environmental factors.
Doses of drugs
Daily
coursework
Minimum effective (threshold)
Average therapeutic
Higher Therapeutic
toxic
deadly
Shock (double dose)
supportive
Breadth of therapeutic action - dose range, from average therapeutic to toxic.
The more STP, the less the danger of pharmacotherapy.
Types of drug interactions:
Pharmaceutical (occurs outside the patient's body, as a result of physical and chemical reactions, before being introduced into the body).
Pharmacological
Pharmacodynamic (one drug affects the implementation of the pharmacological effect of another drug)
Pharmacokinetic (under the influence of one drug, the concentration in the blood of another drug changes).
Physiological (drugs have an independent effect on different organs and tissues, form part of the same physiological system).
Pharmacodynamic drug interactions:
Synergism - unidirectional action of drugs:
Summarized (additive)
Potentiated (the total effect exceeds the sum of the effects of both funds).
Sensitization (one drug in a small dose enhances the effect of another in their combination)
Antagonism is the weakening of the action of one drug by another (physical, chemical, physiological, indirect (different localization of action), direct (competitive and non-competitive)
Reuse of drugs
Strengthening the effect (material and functional cumulation)
Reducing the effect (reducing the sensitivity of receptors - addiction or telerance) (simple, cross, congenital, acquired, taphylaxis - rapid addiction).
Drug dependence (mental, physical)
Sensitization (allergic reactions of 4 types)
Types of drug therapy
Preventive
Etiotropic - destruction of the cause
Substitution - elimination of a lack of a substance
Symptomatic - elimination of symptoms
Pathogenetic - on the pathogenesis of the disease
Algorithm for characterizing drugs
Group affiliation
Pharmacodynamics
Pharmacokinetics
Appointment principle
Indications for use
Doses, formulations and routes of administration
Side effects and measures to prevent them
Contraindications to the appointment
Most medicinal substances in the body undergo transformations (biotransformation). There are metabolic transformation (oxidation, reduction, hydrolysis) and conjugation (acetylation, methylation, formation of compounds with glucuronic acid, etc.). Accordingly, the transformation products are called metabolites and conjugates. Usually, the substance undergoes first metabolic transformation and then conjugation. Metabolites, as a rule, are less active than the parent compounds, but sometimes they are more active (more toxic) than the parent substances. Conjugates are usually inactive.
Most medicinal substances undergo biotransformation in the liver under the influence of enzymes localized in the endoplasmic reticulum of liver cells and called microsomal enzymes (mainly cytochrome P-450 isoenzymes).
These enzymes act on lipophilic non-polar substances, converting them into hydrophilic polar compounds that are more easily excreted from the body. The activity of microsomal enzymes depends on sex, age, liver diseases, and the action of certain drugs.
So, in men, the activity of microsomal enzymes is somewhat higher than in women (the synthesis of these enzymes is stimulated by male sex hormones). Therefore, men are more resistant to the action of many pharmacological substances.
In newborns, the system of microsomal enzymes is imperfect, therefore, a number of drugs (for example, chloramphenicol) are not recommended in the first weeks of life due to their pronounced toxic effect.
The activity of liver microsomal enzymes decreases in old age, therefore, many drugs are prescribed to people over 60 years of age at lower doses compared to middle-aged people.
In liver diseases, the activity of microsomal enzymes may decrease, the biotransformation of drugs slows down, and their action increases and lengthens.
Known drugs that induce the synthesis of microsomal liver enzymes, such as phenobarbital, griseofulvin, rifampicin. The induction of the synthesis of microsomal enzymes with the use of these medicinal substances develops gradually (approximately within 2 weeks). With the simultaneous appointment of other drugs with them (for example, glucocorticoids, contraceptives for oral administration), the effect of the latter may be weakened.
Some medicinal substances (cimetidine, chloramphenicol, etc.) reduce the activity of microsomal liver enzymes and therefore may enhance the effect of other drugs.
Withdrawal (excretion)
Most medicinal substances are excreted from the body through the kidneys in unchanged form or in the form of biotransformation products. Substances can enter the renal tubules when blood plasma is filtered in the renal glomeruli. Many substances are secreted into the lumen of the proximal tubules. The transport systems that provide this secretion are not very specific, so different substances can compete for binding with the transport systems. In this case, one substance can delay the secretion of another substance and thus delay its excretion from the body. For example, quinidine slows down the secretion of digoxin, the concentration of digoxin in the blood plasma increases, and the toxic effect of digoxin (arrhythmias, etc.) is possible.
Lipophilic non-polar substances in the tubules are reabsorbed (reabsorbed) by passive diffusion. Hydrophilic polar compounds are little reabsorbed and excreted by the kidneys.
The excretion (excretion) of weak electrolytes is directly proportional to the degree of their ionization (ionized compounds are little reabsorbed). Therefore, in order to accelerate the excretion of acidic compounds (for example, derivatives of barbituric acid, salicylates), the urine reaction should be changed to the alkaline side, and to excrete bases, to the acidic one.
In addition, medicinal substances can be excreted through the gastrointestinal tract (excretion with bile), with the secrets of sweat, salivary, bronchial and other glands. Volatile medicinal substances are excreted from the body through the lungs with exhaled air.
In women during breastfeeding, medicinal substances can be secreted by the mammary glands and enter the child's body with milk. Therefore, breastfeeding mothers should not be prescribed medications that may adversely affect the baby.
Biotransformation and excretion of medicinal substances are combined by the term "elimination". To characterize elimination, the elimination constant and the half-life are used.
The elimination constant shows how much of the substance is eliminated per unit time.
The elimination half-life is the time it takes for the concentration of a substance in the blood plasma to decrease by half.
Biotransformation of drugs- chemical transformations of drugs in the body.
The biological meaning of drug biotransformation: creation of a substrate convenient for subsequent utilization (as an energy or plastic material) or in accelerating the excretion of drugs from the body.
The main focus of metabolic transformations of drugs: non-polar drugs → polar (hydrophilic) metabolites excreted in the urine.
There are two phases of metabolic reactions of drugs:
1) metabolic transformation (non-synthetic reactions, phase 1)- transformation of substances due to microsomal and extra-microsomal oxidation, reduction and hydrolysis
2) conjugation (synthetic reactions, phase 2)- a biosynthetic process, accompanied by the addition of a number of chemical groups or molecules of endogenous compounds to a medicinal substance or its metabolites by a) the formation of glucuronides b) esters of glycerol c) sulfoesters d) acetylation e) methylation
The effect of biotransformation on the pharmacological activity of drugs:
1) most often, biotransformation metabolites do not have pharmacological activity or their activity is reduced compared to the parent substance
2) in some cases, metabolites can retain activity and even exceed the activity of the parent substance (codeine is metabolized to more pharmacologically active morphine)
3) sometimes toxic substances are formed during biotransformation (metabolites of isoniazid, lidocaine)
4) sometimes during biotransformation, metabolites with opposite pharmacological properties are formed (metabolites of non-selective b2-adrenergic agonists have the properties of blockers of these receptors)
5) a number of substances are prodrugs that initially do not give pharmacological effects, but during biotransformation they are converted into biologically active substances (inactive L-dopa, penetrating through the BBB, turns into active dopamine in the brain, while there are no systemic effects of dopamine).
Clinical significance of drug biotransformation. Influence of gender, age, body weight, environmental factors, smoking, alcohol on drug biotransformation.
Clinical significance of drug biotransformation: since the dose and frequency of administration necessary to achieve effective concentrations in the blood and tissues may vary in patients due to individual differences in the distribution, rate of metabolism and elimination of drugs, it is important to take them into account in clinical practice.
Influence on the biotransformation of drugs of various factors:
A) The functional state of the liver: with her diseases, the clearance of drugs usually decreases, and the half-life increases.
B) Influence of environmental factors: smoking contributes to the induction of cytochrome P450, resulting in an accelerated metabolism of drugs during microsomal oxidation
C) In vegetarians, the biotransformation of drugs is slowed down
D) elderly and young patients are characterized by increased sensitivity to the pharmacological or toxic effects of drugs (in the elderly and in children under 6 months, the activity of microsomal oxidation is reduced)
E) in men, the metabolism of some drugs is faster than in women, because androgens stimulate the synthesis of microsomal liver enzymes (ethanol)
E) High protein diet and intense physical activity: acceleration of drug metabolism.
AND) Alcohol and obesity slow down drug metabolism
Metabolic drug interactions. Diseases affecting their biotransformation.
Metabolic interaction of drugs:
1) induction of drug metabolism enzymes - an absolute increase in their number and activity due to exposure to certain drugs. Induction leads to an acceleration of drug metabolism and (usually, but not always) to a decrease in their pharmacological activity (rifampicin, barbiturates - cytochrome P450 inducers)
2) inhibition of drug metabolism enzymes - inhibition of the activity of metabolic enzymes under the action of certain xenobiotics:
A) competitive metabolic interaction - drugs with a high affinity for certain enzymes reduce the metabolism of drugs with a lower affinity for these enzymes (verapamil)
B) binding to a gene that induces the synthesis of certain cytochrome P450 isoenzymes (cymedin)
C) direct inactivation of cytochrome P450 isoenzymes (flavonoids)
Diseases affecting drug metabolism:
A) kidney disease (impaired renal blood flow, acute and chronic kidney disease, outcomes of long-term kidney disease)
B) liver diseases (primary and alcoholic cirrhosis, hepatitis, hepatomas)
C) diseases of the gastrointestinal tract and endocrine organs
C) individual intolerance to certain drugs (lack of acetylation enzymes - intolerance to aspirin)
The rate and nature of the transformation of medicinal substances in the body are determined by their chemical structure. As a rule, as a result of biotransformation, lipid-soluble compounds are converted into water-soluble ones, which improves their excretion by the kidneys, bile, and sweat. Biotransformation of drugs occurs mainly in the liver with the participation of microsomal enzymes that have little substrate specificity. The transformation of drugs can go either along the path of degradation of molecules (oxidation, reduction, hydrolysis), or through the complication of the structure of the compound, binding by metabolites of the body (conjugation).
One of the leading conversion pathways is the oxidation of drugs (oxygen addition, hydrogen removal, dealkylation, deamination, etc.). Oxidation of foreign compounds (xenobiotics) is carried out by oxidases with the participation of NADP, oxygen and cytochrome P450. This is the so-called non-specific oxidizing system. Histamine, acetylcholine, adrenaline and a number of other endogenous biologically active substances are oxidized by specific enzymes.
Reduction is a rarer pathway of drug metabolism that occurs under the influence of nitroreductases and azoreductases and other enzymes. This metabolic pathway is reduced to the attachment of electrons to a molecule. It is typical for ketones, nitrates, insulin, azo compounds.
Hydrolysis is the main way of inactivation of esters and amides (local anesthetics, muscle relaxants, acetylcholine, etc.). Hydrolysis occurs under the influence of esterases, phosphatases, etc.
Conjugation - the binding of a drug molecule to some other compound that is an endogenous substrate (glucuronic, sulfuric, acetic acids, glycine, etc.).
In the process of biotransformation, the medicinal substance loses its original structure - new substances appear. In some cases, they are more active and toxic. For example, vitamins are activated by turning into coenzymes, methanol is less toxic than its metabolite, formic aldehyde.
Most drugs are transformed in the liver, and with insufficient glycogen, vitamins, amino acids and poor oxygen supply to the body, this process slows down.
There are three main ways of biotransformation of medicinal substances in the body:
- *microsomal oxidation
- *non-microsomal oxidation
- *conjugation reactions
There are the following ways of non-microsomal oxidation of medicinal substances:
- 1. Hydrolysis reaction (acetylcholine, Novocain, atropine).
- 2. The reaction of oxide deamination (catecholamines, tyramine) - oxidized by MAO of mitochondria of the corresponding aldehydes.
- 3. Reactions of oxidation of alcohols. The oxidation of many alcohols and aldehydes is catalyzed by the enzymes of the soluble fraction (cytosol) of the cell - alcohol dehydrogenase, xanthine oxidase (oxidation of ethyl alcohol to acetaldehyde).
Excretion of unchanged drug or its metabolites is carried out by all excretory organs (kidneys, intestines, lungs, mammary, salivary, sweat glands, etc.).
The kidneys are the main organ for removing drugs from the body. Excretion of drugs by the kidneys occurs by filtration and by active or passive transport. Lipid-soluble substances are easily filtered in the glomeruli, but are passively reabsorbed in the tubules. Drugs that are poorly soluble in lipoids are more rapidly excreted in the urine, since they are poorly absorbed in the renal tubules. The acidic reaction of urine promotes the excretion of alkaline compounds and makes it difficult to excrete acidic ones. Therefore, in case of intoxication with acidic drugs (for example, barbiturates), sodium bicarbonate or other alkaline compounds are used, and in case of intoxication with alkaline alkaloids, ammonium chloride is used. It is also possible to accelerate the excretion of drugs from the body by the appointment of potent diuretics, for example, osmotic diuretics or furosemide, against the background of the introduction of a large amount of fluid into the body (forced diuresis). Bases and acids are excreted from the body by active transport. This process takes place with the expenditure of energy and with the help of certain enzymatic carrier systems. By creating competition for the carrier with some substance, it is possible to slow down the excretion of the drug (for example, etamide and penicillin are secreted using the same enzyme systems, so etamide slows down the excretion of penicillin).
Drugs that are poorly absorbed from the gastrointestinal tract are excreted by the intestines and are used for gastritis, enteritis and colitis (for example, astringents, some antibiotics used for intestinal infections). In addition, from the liver cells, drugs and their metabolites enter the bile and enter the intestine with it, from where they are either reabsorbed, delivered to the liver, and then with bile to the intestine (enterohepatic circulation), or excreted from the body with feces. Direct secretion of a number of drugs and their metabolites by the intestinal wall is not excluded.
Volatile substances and gases (ether, nitrous oxide, camphor, etc.) are excreted through the lungs. To accelerate their release, it is necessary to increase the volume of pulmonary ventilation.
Many drugs can be excreted in milk, especially weak bases and non-electrolytes, which should be taken into account when treating nursing mothers.
Some medicinal substances are partially excreted by the glands of the oral mucosa, exerting a local (for example, irritating) effect on the excretion pathways. So, heavy metals (mercury, lead, iron, bismuth), being released by the salivary glands, cause irritation of the oral mucosa, stomatitis and gingivitis occur. In addition, they cause the appearance of a dark border along the gingival margin, especially in the area of carious teeth, which is due to the interaction of heavy metals with hydrogen sulfide in the oral cavity and the formation of practically insoluble sulfides. Such a "border" is a diagnostic sign of chronic heavy metal poisoning.
Most medicinal substances in the body undergo biotransformation - they are metabolized. From the same substance, not one, but several metabolites, sometimes dozens, can be formed, as shown, for example, for chlorpromazine. The biotransformation of medicinal substances is carried out, as a rule, under the control of enzymes (although their non-enzymatic transformation is also possible, for example, chemical transformation by hydrolysis). Basically, metabolizing enzymes are localized in the liver, although enzymes of the lungs, intestines, kidneys, placenta and other tissues can also play an important role in the metabolism of drugs. By regulating pharmaceutical factors such as the type of dosage form (suppositories instead of tablets, intravenous injection instead of oral dosage forms), it is possible to largely avoid the initial passage of the substance through the liver and, therefore, regulate biotransformation.
The formation of toxic metabolites can also be greatly reduced by the regulation of pharmaceutical factors. For example, during the metabolism of amidopyrine in the liver, a carcinogenic substance, dimethylnitrosamine, is formed. After rectal administration of the appropriate dosage forms of this substance, intensive absorption is noted, exceeding by 1.5 - 2.5 in intensity that of oral administration, which makes it possible to reduce the dosage of the substance while maintaining the therapeutic effect and reducing the level of the toxic metabolite.
Biotransformation usually leads to a decrease or disappearance of biological activity, to drug inactivation. However, taking into account the pharmaceutical factor - a simple chemical modification, in some cases it is possible to achieve the formation of more active or less toxic metabolites. Thus, the antitumor drug ftorafur cleaves off the glycosidic residue in the body, releasing the active antitumor antimetabolite - fluorouracil. The ester of levomycetin and stearic acid is tasteless, unlike bitter chloramphenicol. In the gastrointestinal tract, enzymatic hydrolysis of the inactive ester occurs, and the released chloramphenicol is absorbed into the blood. Poorly soluble in water, levomycetin is converted into an ester with succinic acid (succinate) into a highly soluble salt - a new chemical modification used already for both intramuscular and intravenous administration. In the body, as a result of the hydrolysis of this ester, levomycetin itself is quickly separated.
To reduce toxicity and improve tolerability, a simple chemical modification of isoniazid, ftivazid (hydrazone of isoniazid and vanillin), has been synthesized. Gradual release due to biotransformation of the antituberculous active part of the ftivazid molecule - isoniazid, reduces the frequency and severity of side effects characteristic of pure isoniazid. The same is true for saluzide (isoniazid hydrazone obtained by its condensation with 2-carboxy-3, 4-dimethyl benzaldehyde), which, unlike isoniazid, can be administered parenterally.
Excretion (removal) of drugs and their metabolites
The main ways of excretion of medicinal substances and their metabolites is excretion with urine and feces, along with this, substances can be excreted from the body with exhaled air, with the secretion of mammary, sweat, salivary and other glands.
By appropriately regulating pharmaceutical factors for a number of medicinal substances, excretion processes can also be regulated. So, by increasing the pH of the urine (simultaneous administration of alkaline-reactive components, such as sodium bicarbonate and other relevant excipients, with medicinal substances - weak acids), it is possible to significantly increase the excretion (excretion) of acetylsalicylic acid, phenobarbital, probenecid by the kidneys. For medicinal substances - weak bases (novocaine, amphetamine, codeine, quinine, morphine, etc.), the opposite picture takes place - weak organic bases are better ionized at low pH values (acidic urine), while they are poorly reabsorbed in the ionized state by the tubular epithelium and rapidly excreted in the urine. Their introduction together with excipients that lower the pH of urine (aluminum chloride, for example) contributes to their rapid excretion from the body.
Many medicinal substances penetrate from the blood into the parenchymal cells of the liver. This group of substances includes levomycetin, erythromycin, oleandomycin, sulfonamides, a number of anti-tuberculosis substances, etc.
In the liver cells, medicinal substances partially undergo biotransformation and, unchanged or in the form of metabolites (including conjugates), are excreted in the bile or returned to the blood. The excretion of drugs by bile depends on a number of factors, such as molecular weight, the combined use of substances that enhance bile excretion - magnesium sulfate, pituitrin, or the secretory function of the liver - salicylates, riboflavin.
Other routes of excretion of medicinal substances - with sweat, tears, milk - are less significant for the entire excretion process.
Studies of the absorption, distribution, biotransformation and excretion of many drugs have shown that the ability of a drug to have a therapeutic effect is only its potential property, which can vary significantly depending on pharmaceutical factors.
Using different raw materials, various excipients, technological operations and equipment, it is possible to change not only the rate of release of the drug substance from the dosage form, but also the rate and completeness of its absorption, features of biotransformation and release, and ultimately its therapeutic efficacy.
Thus, various pharmaceutical factors influence all individual links in the transport of medicinal substances in the body. And since the therapeutic efficacy and side effects of drugs depend on the concentration of the absorbed drug substance in the blood, organs and tissues, on the duration of the substance’s stay there, on the characteristics of its biotransformation and excretion, then a thorough study of the influence of pharmaceutical factors on these processes, professional, scientific regulation of these factors at all stages of the creation and research of drugs will contribute to the optimization of pharmacotherapy - increasing its effectiveness and safety.
LECTURE 5
THE CONCEPT OF BIOLOGICAL AVAILABILITY OF DRUGS. METHODS OF ITS RESEARCH.
Biopharmacy, along with the pharmaceutical availability test, proposes to establish a specific criterion for assessing the influence of pharmaceutical factors on the absorption of a drug - bioavailability - the degree to which the drug substance is absorbed from the injection site into the systemic circulation and the rate at which this process occurs.
Initially, the criterion for the degree of absorption of the medicinal substance was the relative level in the blood, which is created when the substance is administered in the studied and standard form. Compared, as a rule, the maximum concentration of the drug. However, this approach to assessing the absorption of substances is inadequate for a number of reasons.
Firstly, because the severity of the biological action of many medicinal substances is determined not only by their maximum level, but also by the time during which the concentration of the substance exceeds the minimum level necessary for the implementation of the pharmacological effect. Secondly, the empirical estimate of the moment of maximum concentration of a substance in the blood may be incorrect. Thirdly, this estimate may not be accurate due to errors in the definition. All this prompted researchers to characterize the degree of absorption not by individual points, but by a pharmacokinetic curve.
C = f (t) in general.
And since it is easier to obtain an integral representation of the curve by measuring the area bounded by this curve with the abscissa axis, it was proposed to characterize the degree of drug absorption by the area under the corresponding pharmacokinetic curve.
The ratio of areas under the curves obtained with the introduction of a drug in the studied and standard forms is called the degree of bioavailability:
S x is the area under the PK curve for the test substance in the studied dosage form;
S c is the area under the PK curve for the same substance in a standard dosage form;
D c and D x are the doses of the substance in the test and standard dosage forms, respectively.
Bioavailability studies are conducted in the form of “in vivo” comparative experiments in which a drug is compared with the standard (most available) dosage form of the same active substance.
There are absolute and relative bioavailability. As a standard dosage form, when determining the "absolute" bioavailability, a solution for intravenous administration is used. Intravenous injection gives the most clear results, since the dose enters the large circulation and the bioavailability of the drug in this case is the most complete - almost one hundred percent.
However, it is more common and perhaps more appropriate to determine relative bioavailability. In this case, the standard dosage form, as a rule, is an oral solution, and only in cases where the substance is insoluble or unstable in an aqueous solution can another oral dosage form be used that is well characterized and well absorbed, for example, a suspension of a micronized substance or a micronized drug enclosed in a gelatin capsule.
The experience of biopharmacy has shown that characterizing the absorption of a medicinal substance by the degree to which it is absorbed is insufficient. The fact is that even with complete absorption of a medicinal substance, its concentration in the blood may not reach the minimum effective level if the absorption rate is low compared to the rate of excretion (elimination) of this substance from the body. On fig. (Figure 5.1.) presents some of the possible situations that arise when drugs A, B, C are administered, containing the same dose of the same drug substance, differing in the pharmaceutical factors used in the process of their creation.
Figure 5.1
Change in the concentration of the drug in the biological fluid after the introduction of dosage forms, differing in pharmaceutical factors.
With the introduction of drug A and B, the concentration of the drug in the blood exceeds the minimum effective concentration (MEC) in the first case more than in the second, and with the introduction of drug C, the concentration of the drug does not reach the minimum effective concentration, although the area under the FC- curves are the same in all 3 cases. Thus, the visible differences in the pharmacokinetics of the drug substance after its administration in the forms A, B, C are due to the unequal absorption rate. That is why, when determining bioavailability since 1972 (Riegelman L.), the obligatory establishment of absorption rates has also been introduced, i.e. the rate at which a substance enters the systemic circulation from the site of administration.
Thus, the integral (degree of absorption) and kinetic (rate of absorption) aspects of assessing the absorption process are reflected in the definition of bioavailability.
When determining the bioavailability, sequential sampling of the necessary fluids (blood, urine, saliva, lymph, etc.) is carried out for a strictly determined period of time and the concentration of the substance is determined in them (see the textbook Muravyov I.A., 1960, part 1). 1, str.295, I and 2 paragraphs - the definition of BD on healthy volunteers).
Bioavailability samples are taken from various locations depending on the therapeutic use of the drug substances. Usually, venous and arterial blood or urine is used for this. There are, however, drugs whose bioavailability is more appropriately determined at the site of actual drug exposure. For example, drugs that act in the gastrointestinal tract or dosage forms for application to the skin.
The obtained data on the content of substances (or their metabolites) in biofluids are entered into tables, on the basis of which graphs of the dependence of the concentration of a medicinal substance in biofluids on the time of its detection are built - (FK-curves) C = f (t).
Thus, any difference in the bioavailability of the compared drugs is reflected in the blood concentration curve of the substances or in the urinary excretion pattern. At the same time, it should be taken into account that other variable factors also influence the concentration of a medicinal substance in the blood: physiological, pathological (endogenous) and exogenous.
Therefore, in order to increase the accuracy of studies, it is necessary to take into account all variables. The influence of factors such as age, gender, genetic differences in the metabolism of drugs, as well as the presence of pathological conditions, can be largely controlled using the "cross experiment" method.
The influence of factors that can be directly controlled by the researcher (food intake, simultaneous administration or intake of other drugs, the amount of water drunk, urine pH, physical activity, etc.) is minimized by strict standardization of the experimental conditions.
METHODS FOR ASSESSING BIOLOGICAL AVAILABILITY. ASSESSMENT OF THE DEGREE OF SUCTION. SINGLE DOSE STUDIES.
The degree of absorption is often determined by the results of a study of the content of a substance in the blood after a single appointment.
The advantage of this method is that healthy people are less exposed to the drug when given in single doses.
However, the concentration of the drug substance must be monitored for a minimum of three half-periods of its presence in the body (or longer). With extravascular methods of drug administration, it is necessary to establish the time (t max .) to reach the maximum concentration - C max .
To plot the curve C = f (t) of the dependence of the concentration of substances in the blood on time, it is necessary to obtain at least three points on the ascending and the same number on the descending branches of the curve. Therefore, a large number of blood samples are required, which is a certain inconvenience for the persons participating in the experiment.
S x and Dx are the area under the curve and the dose of the test substance in the tested dosage form;
S c and D C - the area under the curve and the dose of the same substance in a standard dosage form.
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Figure 5.2
The dependence of the concentration of substances in the blood on time.
In studies of the degree of bioavailability using a single dose, specific and highly sensitive analytical methods are absolutely necessary. Detailed knowledge of the pharmacokinetic characteristics of the medicinal substance is also required. This method may not be suitable in cases where the drug substance has complex pharmacokinetic properties. For example, when excretion with bile is accompanied by reabsorption of the drug, which leads to its circulation in the liver.
REPEAT-DOSE STUDIES.
In some cases, in particular for a correct assessment of the degree of bioavailability of drugs intended for long-term use, a study with repeated doses is carried out.
This method is preferable in the clinic, where studies are carried out on patients receiving medication regularly in accordance with the course of treatment. Essentially, the patient is being treated with a drug whose effectiveness is controlled by its content in biofluids.
Samples for analysis with this method can only be obtained after a stable concentration of the substance in the blood is reached. It is usually achieved after 5-10 doses and depends on the half-life of the substance in the body. After reaching a stable concentration of a substance in the blood, the time to reach its maximum concentration becomes constant. In this case, the maximum concentration for the standard dosage form is determined, and then, after a set time interval, the substance in the studied dosage form is prescribed and its maximum concentration in the blood is also determined.
The calculation of the degree of bioavailability is carried out according to the formula:
, Where:
C x is the maximum concentration for the study drug;
C st - the maximum concentration for the standard drug;
D x and D c are the doses of the respective drugs;
T x and T s - the time to reach the maximum concentration after the appointment of the study and standard dosage form.
The degree of bioavailability here can also be calculated using the values of the area under the curve or the values of the maximum concentrations. The area under the curve, in this case, is measured over only one dose interval, after reaching a steady state.
The positive side of the method of prescribing repeated doses of substances is the relatively high content of the substance in the blood, which facilitates analytical determinations and increases their accuracy.
STUDIES TO DETERMINE THE CONTENT OF A SUBSTANCE EXHAUSTED WITH URINE OR ITS METABOLITE.
Determining the degree of bioavailability by the content of a substance excreted in the urine provides for the fulfillment of a number of conditions:
1) the release of at least part of the substance in an unchanged form;
2) complete and thorough emptying of the bladder at each sampling;
3) The time of urine collection, as a rule, is 7-10 half-life of the drug in the body. It is during this period that 99.9% of the administered medicinal substance manages to stand out from the body. The most frequent sampling for analysis is desirable, since this allows you to more accurately determine the concentration of a substance, the calculation of the degree of bioavailability is carried out according to the formula:
, Where:
B - the amount of unchanged substance excreted in the urine after the administration of the studied (x) and standard (c) dosage forms;
D x and D c are the doses of the respective drugs.
DETERMINATION OF THE RATE OF ABSORPTION OF MEDICINAL SUBSTANCES. ELEMENTS OF MODELING PHARMACOKINETICS.
Existing methods for assessing the rate of absorption of drugs are based on the assumption of linearity of the kinetics of all processes of intake, transfer and elimination of drugs in the body.
The simplest method for determining the absorption rate constant is the Dost method (1953), based on the use of the ratio between the elimination and absorption constants and the time of maximum concentration on the pharmacokinetic curve.
, Where:
e - base of natural logarithm = 2.71828...;
t max - the time to reach the maximum level of the concentration of the substance in the body.
To this formula, a special table of the dependence of the product K el t max and the function E is compiled, which is then calculated by the formula:
Hence K sun \u003d K el E
A fragment of a table and an example of a calculation.
So, if K el \u003d 0.456, and t max \u003d 2 hours, then their product \u003d 0.912. According to the table, this corresponds to the value of the function E 2.5. Substituting this value into the equation: K sun \u003d K el · E \u003d 0.456 2.5 \u003d 1.1400 h -1;
The following formula for calculating the suction constant has also been proposed (based on a one-part model; Saunders, Natunen, 1973)
, Where:
C max - maximum concentration, set after a time t max ;
C o is the concentration of a substance in the body at the zero moment of time, assuming that the entire substance (dose) enters the body and is instantly distributed in the blood, organs and tissues.
The calculation of these quantities, which are called pharmacokinetic parameters, is carried out by a simple graphical method. For this purpose, a pharmacokinetic curve is built in the so-called semi-logarithmic coordinate system. On the ordinate axis, lgС t values are plotted - experimentally established values of the concentration of a substance in a biological fluid over time t, and on the abscissa axis - the time to reach this concentration in natural terms (sec, min or hours). The segment of the ordinate axis cut off by the continuation (on the graph it is a dashed line) of the linearized curve gives the value of C o , and the value of the tangent of the slope of the linearized curve to the abscissa axis is numerically equal to the elimination constant. tgω=K el 0.4343
Based on the found values of the elimination constant and the value of C o, it is possible to calculate a number of other pharmacokinetic parameters for the one-part model.
The volume of distribution V is the conditional volume of liquid required to dissolve the entire dose of the administered substance until a concentration equal to C o is obtained. Dimension - ml, l.
Total clearance (plasma clearance) CI t , is a parameter that characterizes the rate of "purification" of the body (blood plasma) from the medicinal substance per unit time. Units - ml/min, l/hour.
The half-life (half-life) T1 / 2 or t 1/2 - the time of elimination from the body of half of the administered and absorbed dose of the substance.
Area under the pharmacokinetic curve AUC 0- ¥
or 
This is the area of the figure on the graph, limited by the pharmacokinetic curve and the x-axis.
The true level of the maximum concentration C max of a substance in the body and the time it takes to reach it t max is calculated from the equation:
It follows from this equation that the time to reach the maximum level of a substance in the body does not depend on the dose and is determined only by the ratio between the constants of absorption and elimination.
The value of the maximum concentration is found by the equation:
Determination of pharmacokinetic parameters and, in particular, absorption rate constants, for a two-part model is considered in the course of pharmacotherapy
Determination of the parameters of PD, DB and pharmacokinetics are usually carried out in the process of developing or improving a drug, with a comparative assessment of the same drug manufactured at different enterprises, in order to constantly monitor the quality and stability of drugs.
Establishing the bioavailability of drugs is of great pharmaceutical, clinical and economic importance.
Let's consider materials on the influence of various variable factors on the parameters of pharmaceutical and biological availability.
DOSAGE FORMS AND THEIR SIGNIFICANCE IN INCREASING PHARMACEUTICAL AND BIOLOGICAL AVAILABILITY
Aqueous solutions in the form of mixtures, syrups, elixirs, etc., as a rule, have the highest pharmaceutical and biological availability of active ingredients. To increase the database of certain types of liquid dosage forms, the amount and nature of the introduced stabilizers, correctors of taste, color and smell are strictly regulated.
Orally administered liquid microcrystalline (particle size less than 5 microns) suspensions are also distinguished by high bioavailability. No wonder aqueous solutions and microcrystalline suspensions are used as standard dosage forms in determining the degree of absorption.
Capsules have an advantage over tablets, as they provide a higher pharmaceutical and biological availability of the included medicinal substances. A great influence on the rate and degree of absorption of substances from capsules is exerted by the particle size of the ingredient placed in the capsule, the nature of the fillers (sliding, coloring, etc.), usually used to improve the packaging of bulk components in capsules.
According to Zak A.F. (1987) 150 mg rifampicin capsules manufactured by various companies differ in the rate of antibiotic transition into solution by 2-10 times. When comparing the bioavailability of rifampicin capsules produced by firms A and D, it was found that the amount of antibiotic in the blood of volunteers during 10 hours of observation, after taking capsules from firm A, was 2.2 times higher than after taking capsules from firm D. Maximum levels of rifampicin in the first case, they were determined after 117 minutes and were equal to 0.87 μg / ml, in the second - after 151 minutes and were equal to 0.46 μg / ml.
Tablets prepared by pressing can vary greatly in the pharmaceutical and biological availability of the included substances, since the composition and amount of excipients, the physical state of the ingredients, technology features (types of granulation, pressing pressure, etc.) that determine the physical and mechanical properties of tablets can significantly change both the rate of release and absorption, and the total amount of the substance that has reached the bloodstream.
So, with the identity of the composition, it was found that the bioavailability of salicylic acid and phenobarbital in tablets depended on the magnitude of the compression pressure; amidopyrine, algin - on the type of granulation; prednisolone, phenacetin - from the nature of the granulating liquid; griseofulvin and quinidine - on the material of the pressing device (press tool) of the tablet machine and, finally, the bioavailability parameters of phenylbutazone and quinidine in the form of tablets depended on the speed of the tablet machine, which compresses or completely squeezes air out of the pressed mass.
It is sometimes difficult to understand the complex complex of mutual influence of various factors on the bioavailability of substances in the form of tablets. Nevertheless, in many cases it is possible to accurately establish the influence of specific factors on bioavailability parameters. First of all, this concerns the two most important stages of the tableting process - granulation and pressing.
The stage of wet granulation is the most responsible for changing the physical and mechanical properties of tablets, the chemical stability of the components. The use of gluing, sliding, loosening excipients at this stage, mixing, contact of the moistened mass with a large number of metal surfaces, and finally, temperature changes during the drying of granules - all this can cause polymorphic transformations of medicinal substances with a subsequent change in their bioavailability parameters.
Thus, the rate and degree of absorption in the gastrointestinal tract of sodium salicylate varies significantly depending on what type of granulation or tabletting method is used in the production of tablets. With wet granulation, the absorption kinetics of sodium salicylate is characterized by a slow increase in the concentration of salicylates in the blood, which does not even reach the minimum effective concentration (MEC). At the same time, from tablets obtained by direct compression, rapid and complete absorption of sodium salicylate is noted.
As with any method of granulation in the process of wet granulation, various transformations of medicinal substances are possible - reactions of hydrolysis, oxidation, etc., which leads to a change in bioavailability. An example is information about tablets with rauwolfia alkaloids. Wet granulation leads to partial degradation and their bioavailability in the form of tablets is reduced by almost 20% in comparison with tablets obtained by direct compression.
The pressing pressure significantly affects the nature of the bond between the particles in the tablet, the size of these particles, the possibility of polymorphic transformations and therefore can significantly change not only the pharmaceutical availability, but also the pharmacokinetic parameters and bioavailability. The presence of large or strong aggregates of particles of medicinal substances that are inaccessible to the contents of the gastrointestinal tract ultimately affects the intensity of dissolution, absorption and the level of concentration of the substance in the blood.
So, at significant pressing pressures, large agglomerates of acetylsalicylic acid are formed, the hardness of the tablets increases and the time of solubility (release) of the substance decreases. A decrease in the solubility of poorly soluble drugs adversely affects their bioavailability.
According to data (Welling, 1960) of biopharmaceutical studies in 6 American clinics (New York state) an increase in the frequency of strokes was observed after they began to use fentanyl tablets (analgesic) from another manufacturer. It turned out that this phenomenon is associated with a change in the bioavailability of new tablets due to a change in the nature of the excipient and the compression pressure of the crushed fentanyl crystals.
Many researchers have shown that digoxin tablets commercially available abroad, manufactured using different technologies using various excipients and types of granulation, can vary greatly in bioavailability - from 20% to 70%. The problem of bioavailability of digoxin tablets has become so acute that in the United States, after biopharmaceutical studies, the sale of tablets by about 40 manufacturers was banned, because their bioavailability parameters turned out to be very low. By the way, digoxin tablets produced in the CIS turned out to be at the level of the best world samples in terms of bioavailability (L.E. Kholodov et al., 1982).
An irrationally carried out selection of variable (technological) factors in the production of tablets can cause an increase in the side effects inherent in this medicinal substance. So, in the case of acetylsalicylic acid, which, as is known, causes gastric and intestinal bleeding when taken orally, the most significant bleeding is 2; 3 ml daily for 7 days is noted after the appointment of tablets compressed without buffer additives, and for the so-called "buffered" - only 0.3 ml.
For our country, the problem of bioequivalence of tablet preparations is not as relevant as it is abroad, since tablets of the same name are produced by one or less often by two or three enterprises according to the same technological regulations. The products are therefore homogeneous in all respects, including bioavailability.
With the improvement of technology, the replacement of some excipients with others, etc., mandatory studies of the bioavailability of substances from tablets are carried out. For example, in the manufacture of nitroglycerin tablets by the trituration method, bioavailability became 2.1 times greater than that of tablets obtained using the previous technology, and the time to reach the maximum concentration in the blood was already 30 minutes (previously 3 hours), (Lepakhin V.K. ., et al., 1982).
Abroad, the most significant differences in the bioavailability of substances in the form of tablets were found, in addition to digoxin, for chloramphenicol, oxytetracycline, tetracycline, hydrochlorothiazide, theophylline, riboflavin and some others.
Therefore, when importing or reproducing tablet technology under licenses, there is also a need to establish the parameters of pharmaceutical and especially bioavailability. For example, we present the results of a study (Kholodov L.E. et al., 1982) of the bioavailability of the anti-sclerotic substance 2,6-pyridine dimethanol-bismethylcarbamate from its analogue tablets of 0.25 each: parmidine (improvement of microcirculation in atherosclerosis of the vessels of the brain and heart) (Russia), anginine (Japan) and prodectine (Hungary). It has been established that the concentration of the substance in the blood serum when parmidine and anginine are taken is approximately the same, while taking prodectin leads to about half the concentration. The apparent initial concentration of C 0 and the area under the "concentration - time" curve for parmidin and anginin do not differ significantly, and are approximately twice as high as for prodectin. Based on the data obtained, it was concluded that the bioavailability of 2,6-pyridine dimethanol-bismethylcarbamate when taking prodectin (tablets from VNR) is approximately 2 times lower than for parmidine and anginine tablets.
Rectal dosage forms - suppositories, ZhRK, microclysters and others. In-depth biopharmaceutical and pharmacokinetic studies have established significant advantages of rectal administration of various drugs with substances belonging to almost all known pharmacological groups.
So, for postoperative prevention of thromboembolism, butadion suppositories are recommended, the introduction of which provides a higher level of the substance in the blood and a decrease in the number of side effects of this substance than after oral administration of tablets (Thuele et al., 1981).
Rectal administration of indomethacin, phenylbutazone provides, in addition to high bioavailability, prolongation of the action of these anti-inflammatory drugs (LI Tentsova, 1974; Reinicre 1984-85).
Rectal administration of morphine hydrochloride at a dose of 0.3 mg/kg to women before gynecological operations is not inferior to intramuscular injections of this substance in terms of bioavailability and effectiveness (Westerling 1984).
Rectal dosage forms with preparations of cardiac glycosides are of exceptional interest for significant violations of the function of the cardiovascular system. Suppositories, microenemas, rectoaerosols provide not only the speed of delivery of active ingredients to the body, but also help to reduce their undesirable side effects.
Thus, strophanthin and corglicon in rectal suppositories (Peshekhonova LL, 1982-84) have very high bioavailability values, while there is a significant decrease in their side undesirable effect, characteristic of injectable drugs.
Particular attention deserves the establishment of bioavailability parameters of the substance in rectal dosage forms for induction of anesthesia in children. A number of authors note a higher bioavailability of flunitrazepam in rectal suppositories compared to intramuscular injection. It has been established that rectal premedication with flunitrazepam provides good adaptation of children to anesthesia, without side effects.
The results of successful premedication in children with compositions of tranquilizers and barbiturates in the form of suppositories and microclysters are described.
The type of suppository base, the nature of the surfactant used, the physical state of the administered medicinal substance (solution, suspension, emulsion), the intensity and type of technological processing (melting, pouring, pressing, etc.) have a significant impact not only on the speed and completeness of absorption of various substances from rectal dosage forms, but also on the level of side effects characteristic of some substances.
There is a significant influence of the nature of the suppository base on the pharmaceutical and biological availability of aminophylline, eufillin, diprophyllin, paracetamol and other substances in suppositories. Moreover, the bioavailability of paracetamol in the form of suppositories can vary from 68% to 87%, depending on the technology used and the suppository base (Feldman, 1985). For acetylsalicylic acid, a decrease in the level of elimination in the urine is clearly observed after the administration of suppositories containing large crystals of this substance coated with a protective shell to patients.
Ointments are the most common dosage form in dermatological practice. By introducing medicinal substances into various bases, using various excipients (solubilizers, dispersants, surfactants, DMSO, etc.), it is possible to sharply increase the intensity (speed and degree) of absorption of medicinal substances or, conversely, significantly reduce it.
So, sulfanilamide substances have the greatest therapeutic effect when they are introduced into emulsion ointment bases. By adding Tween-80, it is possible to increase the absorption of norsulfazole from the ointment base (Vaseline) from 0.3% to 16.6%. The addition of various non-ionic surfactants can dramatically increase the bactericidal effect of ointments with phenol, some antibiotics and sulfonamides.
Biopharmaceutical studies of ointments with fenchisol and ointment "Butamedrol" developed at the Department of Drug Technology of ZSMU confirmed a significant dependence of the bioavailability of active substances from ointments on the nature of the ointment base. The polyethylene oxide ointment base provided not only an intensive release of ingredients, but also contributed to a significantly higher level of bioavailability of quinazopyrine and butadione in comparison with other hydrophilic and hydrophobic bases. When comparing the imported ointment "Butadion" (VNR) and the ointment "Butamedrol" developed at the department (L.A. Puchkan), it was reliably established that in terms of the strength of the anti-inflammatory effect, due to the scientifically based choice of the carrier, the latter surpasses the imported drug by 1.5 - 2.1 times.
Stanoeva L. et al. confirmed the significant influence of the nature of the ointment base on the bioavailability of ethacridine lactate in the form of an ointment, a number of authors have established the effect of the ointment base on the bioavailability of dexamethasone (Moes-Henschel 1985), salicylic acid, etc.
For example, with the same dose of the anesthetic panakain in the ointment, the strength of the analgesic effect of the ointment with it, depending on the nature of the base, ranged from 10 to 30 times.
Thus, in a biopharmaceutical experiment, the influence on the parameters of pharmaceutical and biological availability and the type of dosage forms was established. The degree of influence of the dosage form on the release and absorption processes is determined by its composition, the physical state of the components, the technological features of preparation and other variable factors, which is especially evident for simulated dosage forms. According to Gibaldi (1980), in terms of pharmaceutical availability, all main dosage forms can be arranged in the following order: solutions > microcrystalline suspensions > RLF > capsules > tablets > coated tablets.
