Factors influencing drug metabolism. Biotransformation of drugs - clinical pharmacology Metabolic drug interactions
Biotransformation
Kinds:
Metabolic transformation – transformation of substances through oxidation, reduction and hydrolysis.
Conjugation – This is a biosynthetic process accompanied by the addition of a number of chemicals to a drug or its metabolites.
Removing drugs from the body:
Elimination is the removal of drugs from the body as a result of biotransformation and excretion.
Presystemic - carried out when a 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 – removal of drugs (with urine, feces, gland secretions, exhaled air).
To quantitatively characterize 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 a 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 branch of pharmacology that studies the localization, mechanism of action of drugs and their biochemical effects (what the drug does to the body).
To exert its effect, a drug 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 have affinity and internal activity.
Affinity– the ability of a drug to form a complex with the receptor.
Internal activity– the ability to cause a cellular response upon communication with a 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
Agonists (blockers are substances with high affinity, but lacking internal activity (they close their receptors and interfere with the action of endogenous ligands or agonists).
Competitive
Non-competitive
Agonist – antagonist (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 effects
Local (on site application)
Resorptive (during absorption - onto the system)
General characteristics of the effect of drugs on the body (according to N.V. Vershinin).
Toning (functions to normal)
Excitement (functions above normal)
Calming effect (↓ increased function to normal).
Depression (↓ functions below normal)
Paralysis (cessation of function)
The main action of the drug
Side effects of the drug
Desirable
Unwanted
Adverse drug reactions:
1 type:
Overdose-related
Poisoning related
Type 2:
Associated with the pharmacological properties of medicinal substances
Type 2:
Direct toxic reactions
Neurotoxicity (CNS)
Hepatoxicity (liver function)
Nephrotoxicity (kidney function)
Ulcerogenic effect (intestinal and gastric mucosa)
Hematotoxicity (blood)
Effect on the embryo and fetus:
Embryotoxic effect
Teratogenic effect (deformity)
Fetotoxic effect (fetal death)
Mutagenicity(the ability of a drug to cause persistent 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 changes in the body's sensitivity:
Allergic reactions
Idiosyncrasy (an atypical reaction of the body to a drug associated with a genetic defect)
Factors influencing the action of drugs:
Physico-chemical properties of drugs and conditions of 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 allowance
Coursework
Minimum effective (threshold)
Medium 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 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 and form part of the same physiological system).
Pharmacodynamic interactions of drugs:
Synergism is the unidirectionality of the action of drugs:
Summed (additive)
Potentiated (the total effect exceeds the sum of the effects of both drugs).
Sensitization (one drug in a small dose enhances the effect of another in their combination)
Antagonism is a weakening of the effect of one drug by another (physical, chemical, physiological, indirect (different localization of action), direct (competitive and non-competitive)
Repeated use of drugs
Strengthening the effect (material and functional cumulation)
Reduced effect (decrease in receptor sensitivity - addiction or tolerance) (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 - eliminating the deficiency of a substance
Symptomatic – elimination of symptoms
Pathogenetic – on the pathogenesis of the disease
Algorithm for drug characteristics
Group affiliation
Pharmacodynamics
Pharmacokinetics
Purpose principle
Indications for use
Doses, release forms and routes of administration
Side effects and measures to prevent them
Contraindications for use
Most medicinal substances in the body undergo transformations (biotransformation). A distinction is made between 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. Typically, a 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 drugs 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 gender, age, liver disease, and the effect of certain medications.
Thus, in men the activity of microsomal enzymes is slightly 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 to be prescribed in the first weeks of life due to their pronounced toxic effect.
The activity of liver microsomal enzymes decreases in old age, so many medications are prescribed to people over 60 years of age in 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 effect intensifies and prolongs.
There are known medicinal substances that induce the synthesis of microsomal liver enzymes, for example, phenobarbital, griseofulvin, rifampicin. Induction of the synthesis of microsomal enzymes when using these medicinal substances develops gradually (over about 2 weeks). When other drugs (for example, glucocorticoids, oral contraceptives) are prescribed simultaneously, the effect of the latter may be weakened.
Some drugs (cimetidine, chloramphenicol, etc.) reduce the activity of microsomal liver enzymes and therefore can enhance the effect of other drugs.
Elimination (excretion)
Most drugs are excreted from the body through the kidneys unchanged 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 to transport systems. In this case, one substance can delay the secretion of another substance and thus delay its elimination 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.) may occur.
Lipophilic nonpolar substances in the tubules undergo reverse absorption (reabsorption) by passive diffusion. Hydrophilic polar compounds are poorly reabsorbed and excreted by the kidneys.
The removal (excretion) of weak electrolytes is directly proportional to the degree of their ionization (ionized compounds are little reabsorbed). Therefore, to accelerate the elimination of acidic compounds (for example, barbituric acid derivatives, salicylates), the urine reaction should be changed to the alkaline side, and to remove bases, to the acidic side.
In addition, medicinal substances can be excreted through the gastrointestinal tract (excretion with bile), with the secretions of sweat, salivary, bronchial and other glands. Volatile drugs are released 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 baby's body with milk. Therefore, nursing mothers should not be prescribed medications that may adversely affect the baby.
Biotransformation and excretion of drugs are combined with the term “elimination.” To characterize elimination, the elimination constant and the half-life period are used.
The elimination constant shows how much of a substance is eliminated per unit time.
Half-life is the time during which the concentration of a substance in the blood plasma is reduced by half.
Biotransformation of drugs– chemical transformations of drugs in the body.
Biological meaning of drug biotransformation: creation of a substrate convenient for subsequent utilization (as an energy or plastic material) or in accelerating the elimination of drugs from the body.
The main direction 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 extramicrosomal 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 through a) the formation of glucuronides b) glycerol esters c) sulfoesters d) acetylation e) methylation
The influence 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 original substance
2) in some cases, metabolites can remain active and even exceed the activity of the original substance (codeine is metabolized to the 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 receptor agonists have the properties of blockers of these receptors)
5) a number of substances are prodrugs that initially do not produce pharmacological effects, but during biotransformation are converted into biologically active substances (inactive L-dopa, penetrating the BBB, is converted in the brain into active dopamine, while there are no systemic effects of dopamine).
Clinical significance of drug biotransformation. The influence of gender, age, body weight, environmental factors, smoking, alcohol on the biotransformation of drugs.
Clinical significance of drug biotransformation: Since the dose and frequency of administration required to achieve effective concentrations in the blood and tissues may vary in patients due to individual differences in the distribution, metabolic rate and elimination of drugs, it is important to take them into account in clinical practice.
The influence of various factors on the biotransformation of drugs:
A) Functional state of the liver: with its diseases, drug clearance usually decreases, and the half-life increases.
B) Influence of environmental factors: smoking promotes the induction of cytochrome P450, resulting in accelerated drug metabolism 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 elderly people and in children under 6 months, the activity of microsomal oxidation is reduced)
D) in men, the metabolism of some drugs occurs faster than in women, because androgens stimulate the synthesis of microsomal liver enzymes (ethanol)
E) High protein content 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 quantity and activity due to the influence of certain drugs on them. Induction leads to an acceleration of drug metabolism and (usually, but not always) to a decrease in their pharmacological activity (rifampicin, barbiturates - inducers of cytochrome P450)
2) inhibition of drug metabolism enzymes - inhibition of the activity of metabolic enzymes under the influence of certain xenobiotics:
A) competitive metabolic interaction - drugs with high affinity for certain enzymes reduce the metabolism of drugs with lower affinity for these enzymes (verapamil)
B) binding to a gene that induces the synthesis of certain isoenzymes of cytochrome P450 (cymedine)
B) direct inactivation of cytochrome P450 isoenzymes (flavonoids)
Diseases affecting drug metabolism:
A) kidney diseases (impaired renal blood flow, acute and chronic kidney diseases, outcomes of long-term renal diseases)
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 - aspirin intolerance)
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 insignificant substrate specificity. The transformation of drugs can proceed either through the degradation of molecules (oxidation, reduction, hydrolysis), or through complication of the structure of the compound, binding with metabolites of the body (conjugation).
One of the leading transformation routes is the oxidation of drugs (addition of oxygen, removal of hydrogen, 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 nonspecific 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, occurring under the influence of nitroreductases and azoreductases and other enzymes. This metabolic pathway involves the addition of electrons to a molecule. It is characteristic of ketones, nitrates, insulin, and 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 is the binding of a drug molecule to some other compound that is an endogenous substrate (glucuronic, sulfuric, acetic acids, glycine, etc.).
During 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, turning into coenzymes; methanol is less toxic than its metabolite, formic aldehyde.
Most medications 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 pathways for the biotransformation of medicinal substances in the body:
- *microsomal oxidation
- *non-microsomal oxidation
- *conjugation reactions
The following pathways of non-microsomal oxidation of drugs are distinguished:
- 1. Hydrolysis reaction (acetylcholine, Novocaine, atropine).
- 2. The reaction of oxide deaminization (catecholamines, tyramine) - the MAO of the mitochondria of the corresponding aldehydes is oxidized.
- 3. Oxidation reactions of alcohols. The oxidation of many alcohols and aldehydes is catalyzed by enzymes in the soluble fraction (cytosol) of the cell - alcohol dehydrogenase, xanthine oxidase (oxidation of ethyl alcohol to acetaldehyde).
Excretion of the unchanged drug or its metabolites is carried out by all excretory organs (kidneys, intestines, lungs, mammary, salivary, sweat glands, etc.).
The main organ for removing drugs from the body is the kidneys. Drug excretion by the kidneys occurs by filtration and active or passive transport. Lipid-soluble substances are easily filtered in the glomeruli, but in the tubules they are again passively absorbed. Drugs that are poorly soluble in lipoids are excreted more quickly in the urine because they are poorly absorbed in the renal tubules. The acidic reaction of urine promotes the excretion of alkaline compounds and complicates the excretion of acidic ones. Therefore, for intoxication with acidic drugs (for example, barbiturates), sodium bicarbonate or other alkaline compounds are used, and for intoxication with alkaline alkaloids, ammonium chloride is used. It is also possible to speed up the removal of drugs from the body by prescribing potent diuretics, for example, osmotic diuretics or furosemide, while introducing a large amount of fluid into the body (forced diuresis). Removal of bases and acids from the body occurs through active transport. This process occurs with the expenditure of energy and with the help of certain enzyme transport systems. By creating competition for the carrier with any substance, it is possible to slow down the elimination of the drug (for example, etamide and penicillin are secreted using the same enzyme systems, so etamide slows down the elimination 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 into the intestine (enterohepatic circulation), or are excreted from the body with feces. Direct secretion of a number of drugs and their metabolites by the intestinal wall cannot be ruled out.
Volatile substances and gases (ether, nitrous oxide, camphor, etc.) are eliminated through the lungs. To speed up 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 drugs are partially excreted by the glands of the oral mucosa, having a local (for example, irritating) effect on the excretion pathways. Thus, heavy metals (mercury, lead, iron, bismuth), secreted by the salivary glands, cause irritation of the oral mucosa, causing stomatitis and gingivitis. 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. This “border” is a diagnostic sign of chronic heavy metal poisoning.
Most medicinal substances in the body undergo biotransformation - they are metabolized. Not one, but several metabolites, sometimes dozens, can be formed from the same substance, as shown, for example, for chlorpromazine. 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 - by hydrolysis). Metabolizing enzymes are mainly localized in the liver, although enzymes from the lungs, intestines, kidneys, placenta and other tissues can also play an important role in the metabolism of drugs. By regulating such pharmaceutical factors as the type of dosage form (suppositories instead of tablets, intravenous injection instead of oral dosage forms), it is possible to largely avoid the passage of the substance through the liver at first and, therefore, regulate biotransformation.
The formation of toxic metabolites can also be significantly reduced by regulating pharmaceutical factors. For example, when amidopyrine is metabolized in the liver, a carcinogenic substance is formed - dimethylnitrosamine. After rectal administration of the corresponding dosage forms of this substance, intense absorption is observed, 1.5 - 2.5 times more intense than 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 and inactivation of drugs. 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 splits off the glycosidic residue in the body, releasing the active antitumor antimetabolite - fluorouracil. The ester of chloramphenicol and stearic acid is tasteless, unlike bitter chloramphenicol. Enzymatic hydrolysis of the inactive ester occurs in the gastrointestinal tract, and the released chloramphenicol is absorbed into the blood. Levomycetin, which is poorly soluble in water, is converted into an ester with succinic acid (succinate) into a highly soluble salt - a new chemical modification, already used for intramuscular and intravenous administration. In the body, as a result of the hydrolysis of this ester, chloramphenicol itself is quickly separated.
To reduce toxicity and improve tolerability, a simple chemical modification of isoniazid - ftivazid (hydrazone of isoniazid and vanillin) was synthesized. The gradual release due to biotransformation of the anti-tuberculosis active part of the ftivazid molecule, isoniazid, reduces the frequency and severity of side effects characteristic of taking pure isoniazid. The same is true for saluzide (isoniazid hydrazone, obtained by condensing it with 2-carboxy-3, 4-dimethyl benzaldehyde), which, unlike isoniazid, can be administered parenterally.
Excretion (removal) of drugs and their metabolites
The main routes of excretion of medicinal substances and their metabolites are excretion in 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 adjusting pharmaceutical factors for a number of medicinal substances, excretion processes can also be regulated. Thus, by increasing the pH of urine (by simultaneous administration of alkaline-reacting 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, and probenicide by the kidneys. For medicinal substances - weak bases (novocaine, amphetamine, codeine, quinine, morphine, etc.) the opposite picture occurs - weak organic bases are better ionized at low pH values (acidic urine), while in the ionized state they are poorly reabsorbed by the tubular epithelium and are quickly excreted in the urine. Their introduction together with auxiliary substances that lower the pH of urine (aluminum chloride, for example) promotes their rapid elimination from the body.
Many drugs penetrate from the blood into the parenchymal cells of the liver. This group of substances includes chloramphenicol, erythromycin, oleandomycin, sulfonamides, a number of anti-tuberculosis substances, etc.
In 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. 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 ways of excretion of medicinal substances - with sweat, tears, milk - are less significant for the entire process of excretion.
Studies of absorption, distribution, biotransformation and excretion of many medicinal substances have shown that the ability of a medicinal substance to have a therapeutic effect is only its potential property, which can vary significantly depending on pharmaceutical factors.
By using different starting materials, various auxiliary substances, technological operations and equipment, it is possible to change not only the rate of release of the drug from the dosage form, but also the speed and completeness of its absorption, the characteristics of biotransformation and excretion, and ultimately its therapeutic effectiveness
Thus, all individual links in the transport of drugs in the body are influenced by various pharmaceutical factors. And since the therapeutic effectiveness 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, a thorough study of the influence of pharmaceutical factors on these processes, professional, scientific regulation of these factors at all stages of drug development and research will help optimize pharmacotherapy - increase 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 a drug is absorbed from the site of administration into the systemic bloodstream and the speed at which this process occurs.
Initially, the criterion for the degree of absorption of a drug substance was the relative level in the blood created when the substance was administered in the studied and standard form. As a rule, the maximum concentrations of the drug substance were compared. However, this approach to assessing the absorption of substances is inadequate for a number of reasons.
Firstly, because the severity of the biological effect 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 to realize the pharmacological effect. Secondly, the empirical estimate of the moment of maximum concentration of a substance in the blood may turn out to be incorrect. Third, this estimate may not be accurate due to definitional errors. All this prompted researchers to characterize the degree of absorption not with individual points, but with a pharmacokinetic curve
C = f(t) in general.
And since it is easier to obtain an integral idea of the curve by measuring the area bounded by this curve with the abscissa axis, it was proposed to characterize the degree of absorption of a drug by the area under the corresponding pharmacokinetic curve.
The ratio of the areas under the curves obtained upon administration of the drug in the studied and standard forms is called the degree of bioavailability:
S x - 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 carried out in the form of comparative experiments “in vivo”, in which the drug is compared with the standard (most accessible) dosage form of the same active substance.
A distinction is made between absolute and relative bioavailability. As a standard dosage form, when determining “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 useful to define relative bioavailability. In this case, the standard dosage form, as a rule, is a solution for internal use, and only in cases where the substance is insoluble or unstable in an aqueous solution, another dosage form for oral administration, which is well characterized and well absorbed, can be used, for example, a suspension of a micronized substance or a micronized drug enclosed in a gelatin capsule.
Biopharmaceutical experience has shown that the characterization of the absorption of a medicinal substance by the extent to which it is absorbed is insufficient. The fact is that even with complete absorption of a drug substance, its concentration in the blood may not reach the minimum effective level if the rate of absorption is low compared to the rate of release (elimination) of this substance from the body. In Fig. (Figure 5.1) presents some of the possible situations that arise when administering drugs A, B, C, containing the same dose of the same medicinal substance, differing in the pharmaceutical factors used in the process of their creation.
Figure 5.1
Changes in the concentration of a medicinal substance in biological fluid after administration of dosage forms that differ in pharmaceutical factors.
When administering drugs A and B, the concentration of the drug substance in the blood exceeds the minimum effective concentration (MEC) in the first case, greater than in the second, and when administering drug C, the concentration of the drug substance does not reach the minimum effective concentration, although the area under FC- the curves are the same in all 3 cases. Thus, visible differences in the pharmacokinetics of the drug after its administration in forms A, B, C are due to the unequal rate of absorption. That is why, when determining bioavailability since 1972 (Riegelman L.), mandatory determination of absorption rate has been introduced, i.e. the rate at which a substance enters the systemic circulation from the site of administration.
Thus, the definition of bioavailability reflects the integral (degree of absorption) and kinetic (rate of absorption) aspects of assessing the absorption process.
When determining bioavailability, sequential sampling of the necessary liquids (blood, urine, saliva, lymph, etc.) is carried out over a strictly determined period of time and the concentration of the substance in them is determined (see textbook by Muravyov I.A., I960, part. 1, p. 295, paragraphs I and 2 - determination of BD in healthy volunteers).
Samples to determine bioavailability are taken from various places depending on the therapeutic use of the drug substances. Typically, venous and arterial blood or urine are used for this. There are, however, drugs whose bioavailability is more appropriate to determine at the site of actual exposure to the drug substance. For example, medications 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 are constructed of the dependence of the concentration of the drug in biofluids on the time of its detection - (PK curves) C = f (t).
Thus, any difference in the bioavailability of the compared drugs is reflected in the concentration curve of the substance in the blood or in the pattern of its excretion in the urine. It should be taken into account that the concentration of the drug in the blood is also influenced by other variable factors: physiological, pathological (endogenous) and exogenous.
Therefore, in order to increase the accuracy of research, it is necessary to take into account all variables. The influence of factors such as age, gender, genetic differences in drug metabolism, and the presence of pathological conditions can be largely controlled using the crossover design.
The influence of factors that can be directly controlled by the researcher (food intake, simultaneous administration or use of other medications, amount of water drunk, urine pH, physical activity, etc.) is minimized by strictly standardizing the experimental conditions.
METHODS FOR ASSESSING BIOLOGICAL ACCESSIBILITY. ASSESSMENT OF THE DEGREE OF ABSORPTION. SINGLE DOSE STUDIES.
The degree of absorption is often determined by the results of a study of the content of the substance in the blood after a single dose.
The advantage of this method is that with single doses, healthy people are less exposed to the drug.
However, the concentration of the drug substance must be monitored at least during three half-periods of its presence in the body (or longer). With extravascular routes of administration of the drug, it is necessary to establish the time (t max.) to achieve the maximum concentration - C max.
To construct a 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 - area under the curve and dose of the test substance in the test dosage form;
S c and D C are the area under the curve and the dose of the same substance in a standard dosage form.
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Figure 5.2
Dependence of the concentration of substances in the blood on time.
Specific and highly sensitive analytical methods are essential for single dose bioavailability studies. Detailed knowledge of the pharmacokinetic characteristics of the drug substance is also necessary. This method may not be suitable in cases where the drug substance has complex pharmacokinetic properties. For example, when excretion in the bile is accompanied by reabsorption of the drug, which leads to its circulation in the liver.
REPEATED DOSE STUDIES.
In some cases, in particular to correctly assess the degree of bioavailability of drugs intended for long-term use, a repeat dose study is carried out.
This method is preferable in a clinical setting, where studies are conducted on patients receiving the medicine regularly according to the course of treatment. Essentially, the patient is treated with a drug, the effectiveness of which is monitored by its content in biological fluids.
Samples for analysis using this method can be obtained only after a stable concentration of the substance in the blood has been achieved. 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 a standard dosage form is determined, and then, after a set interval of time, the substance in the test dosage form is prescribed and its maximum concentration in the blood is also determined.
The degree of bioavailability is calculated using the formula:
, Where:
C x is the maximum concentration for the test drug;
C st - maximum concentration for the standard drug;
D x and D c – doses of the corresponding drugs;
T x and T c - time to reach maximum concentration after administration of the study and standard dosage forms.
The degree of bioavailability here can also be calculated using the area under the curve or maximum concentration values. The area under the curve, in this case, is measured during only one dosing interval, after a steady-state concentration has been reached.
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 EXCRETED IN THE URINE OR ITS METABOLITE.
Determining the degree of bioavailability based on the content of a substance excreted in urine requires the fulfillment of a number of conditions:
1) release of at least part of the substance unchanged;
2) complete and thorough emptying of the bladder at each sample collection;
3) The urine collection time, as a rule, is equal to 7-10 half-periods of the drug being in the body. It is during this period that 99.9% of the administered drug substance is released from the body. The most frequent sampling for analysis is desirable, as this allows you to more accurately determine the concentration of a substance; the degree of bioavailability is calculated using the formula:
, Where:
B is the amount of unchanged substance excreted in the urine after administration of the study (x) and standard (c) dosage forms;
D x and D c are the doses of the corresponding drugs.
DETERMINATION OF THE RATE OF DRUG SUBSTANCES ABSORPTION. ELEMENTS OF PHARMACOKINETICS MODELING.
Existing methods for assessing the rate of absorption of drugs are based on the assumption of linear kinetics of all processes of entry, 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 relationship 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 is the time to reach the maximum level of concentration of a substance in the body.
For this formula, a special table of the dependence of the product K el ·t max and function E has been compiled, which is then calculated using the formula:
Hence K sun = K el · E
Fragment of the table and example of calculation.
So, if K el = 0.456, and t max = 2 hours, then their product = 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 = K el · E = 0.456 2.5 = 1.1400 h -1 ;
The following formula has also been proposed for calculating the suction constant (based on a one-part model; Saunders, Natunen, 1973)
, Where:
C max - maximum concentration set after time t max;
C o is the concentration of a substance in the body at zero time, assuming that the entire substance (dose) enters the body and is instantly distributed in the blood, organs and tissues.
The calculation of these values, called pharmacokinetic parameters, is carried out using a simple graphical method. For this purpose, a pharmacokinetic curve is constructed in the so-called semi-logarithmic coordinate system. On the ordinate axis we plot the logС t values - the experimentally established values of the concentration of a substance in a biological fluid for time t, and on the abscissa axis - the time to achieve this concentration in natural values (seconds, minutes or hours). The segment of the ordinate axis cut off by the continuation (in the graph it is a dashed line) of the linearized curve gives the value C o , and the tangent of the angle of inclination 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 C o value, a number of other pharmacokinetic parameters for the one-part model can be calculated.
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. Dimensions - ml, l.
General clearance (plasma clearance) CI t is a parameter characterizing the rate of “cleansing” of the body (blood plasma) from a drug substance per unit time. Dimension - ml/min, l/hour.
Half-elimination (half-existence) period T1/2 or t1/2 is 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 bounded by the pharmacokinetic curve and the x-axis.
The true level of maximum concentration Cmax of a substance in the body and the time it takes to reach it tmax are calculated from the equation:
From this equation it follows 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 absorption and elimination constants.
The maximum concentration value is found using the equation:
Determination of pharmacokinetic parameters and, in particular, absorption rate constants for a two-part model is considered during the course of pharmacotherapy
Determination of parameters of PD, BD and pharmacokinetics are usually carried out in the process of developing or improving a medicinal product, with a comparative assessment of the same drug produced at different enterprises, in order to constantly monitor the quality and stability of medicinal products.
Establishing the bioavailability of drugs is of enormous pharmaceutical, clinical and economic importance.
Let us consider materials on the influence of various variable factors on the parameters of pharmaceutical and bioavailability.
DOSAGE FORMS AND THEIR IMPORTANCE 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 BD of certain types of liquid dosage forms, the quantity and nature of introduced stabilizers, taste, color and odor correctors are strictly regulated.
Orally administered liquid microcrystalline (particle size less than 5 microns) suspensions are also characterized by high bioavailability. It is not without reason that aqueous solutions and microcrystalline suspensions are used as standard dosage forms when determining the degree of absorption.
Capsules have an advantage over tablets, as they provide higher pharmaceutical and biological availability of the included medicinal substances. The rate and degree of absorption of substances from capsules is greatly influenced by the particle size of the ingredient placed in the capsule and the nature of the fillers (gliding, coloring, etc.) usually used to improve the packaging of bulk components into capsules.
According to Zak A.F. (1987) rifampicin capsules of 150 mg, manufactured by various companies, differ in the rate of transition of the antibiotic into solution by 2-10 times. When comparing the bioavailability of rifampicin capsules produced by companies 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 company A was 2.2 times higher than after taking capsules from company D. Maximum levels of rifampicin in the first case, they were determined after 117 minutes and equaled 0.87 μg/ml, in the second - after 151 minutes and equaled 0.46 μg/ml.
Tablets prepared by compression may vary significantly 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.), which determine the physical and mechanical properties of the tablets, can significantly change both the rate of release and absorption and the total amount of substance reaching the bloodstream.
Thus, given the identity of the composition, it was found that the bioavailability of salicylic acid and phenobarbital in tablets depended on the magnitude of the pressing pressure; amidopyrine, algin - depending 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-precision machine and, finally, the bioavailability parameters of phenylbutazone and quinidine in the form of tablets depended on the operating speed of the tablet machine, pressing or completely squeezing out air from 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. However, in many cases it is possible to accurately determine the influence of specific factors on bioavailability parameters. First of all, this concerns the two most important stages of the tabletting process - granulation and pressing.
The wet granulation stage is most responsible for changing the physical and mechanical properties of tablets and the chemical stability of the components. The use of adhesive, sliding, loosening auxiliary substances at this stage, mixing, contact of the moistened mass with a large number of metal surfaces, and finally, a change in temperature during the drying of granules - all this can cause polymorphic transformations of medicinal substances with a subsequent change in the parameters of their bioavailability.
Thus, the rate and extent of absorption of sodium salicylate in the gastrointestinal tract varies significantly depending on what type of granulation or tableting 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, the process of wet granulation allows for various transformations of medicinal substances - 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 destruction and their bioavailability in tablet form is reduced by almost 20% compared to tablets obtained by direct compression.
Compression pressure significantly affects the nature of the connection between particles in the tablet, the size of these particles, the possibility of polymorphic transformations, and therefore can significantly change not only pharmaceutical availability, but also pharmacokinetic parameters and bioavailability. The presence of large or durable 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.
Thus, at significant pressing pressures, large agglomerates of acetylsalicylic acid are formed, the hardness of the tablets increases and the solubility (release) time of the substance decreases. And a decrease in the solubility of poorly soluble drugs negatively affects their bioavailability.
According to data (Welling, I960) of biopharmaceutical studies in 6 American clinics (New York State), an increase in the incidence of strokes was observed after they began to use tablets with fentanyl (analgesic) from another manufacturer. It turned out that this phenomenon is associated with a change in the bioavailability of the 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 very significantly in bioavailability - from 20% to 70%. The problem of bioavailability of digoxin tablets turned out to be so acute that in the USA, after biopharmaceutical research, the sale of tablets from about 40 manufacturing companies was banned, since 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 (Kholodov L.E. et al., 1982).
Irrational selection of variable (technological) factors in the production of tablets can cause an increase in the side effects inherent in a given medicinal substance. Thus, 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 prescription 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 drugs is not as relevant as abroad, since tablets of the same name are produced by one or less often two or three enterprises according to the same technological regulations. The products therefore turn out to be homogeneous in all respects, including bioavailability.
When improving technology, replacing some excipients with others, etc., mandatory studies of the bioavailability of substances from tablets are carried out. For example, when producing nitroglycerin tablets using the trituration method, the 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 purchasing for import or reproduction of tablet technology under licenses, there is also a need to establish parameters of pharmaceutical and especially bioavailability. As an 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: parmidine (improving microcirculation in atherosclerosis of the brain and heart vessels) (Russia), angina (Japan) and prodectin (Hungary). It has been established that the concentration of the substance in the blood serum when taking parmidine and anginine is approximately the same, while taking prodectin leads to approximately half the concentration. The apparent initial concentration C0 and the area under the concentration-time curve for parmidine and anginine 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 less than for tablets of parmidine and anginine.
Rectal dosage forms - suppositories, ZhRK, microenemas 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.
Thus, for postoperative prevention of thromboembolism, suppositories with butadione are recommended, the administration 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 and phenylbutazone provides, in addition to high bioavailability, prolongation of the action of these anti-inflammatory drugs (Tentsova L.I., 1974; Reinicre 1984-85).
Rectal administration of morphine hydrochloride at a dose of 0.3 mg/kg to women before gynecological operations in terms of bioavailability and effectiveness is not inferior to intramuscular injections of this substance (Westerling I984).
Rectal dosage forms with cardiac glycoside preparations are of exceptional interest in cases of significant dysfunction of the cardiovascular system. Suppositories, microenemas, and rectoaerosols provide not only rapid delivery of active ingredients to the body, but also help reduce their undesirable side effects.
Thus, strophanthin and korglycon in rectal suppositories (Peshekhonova L.L., 1982-84) have very high bioavailability values, while there is a significant reduction in their undesirable side effects, characteristic of injectable drugs.
Particular attention should be paid to establishing the parameters of the bioavailability 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 ensures 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 microenemas 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 certain substances.
There is a significant influence of the nature of the suppository base on the pharmaceutical and biological availability of aminophylline, aminophylline, diprophylline, 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 visible after administering to patients suppositories containing large crystals of this substance coated with a protective shell.
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.
Thus, sulfonamide substances have the greatest therapeutic effect when 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 Butamedrol ointment developed at the Department of Drug Technology of ZSMU confirmed the significant dependence of the bioavailability of active ingredients from ointments on the nature of the ointment base. The polyethylene oxide ointment base not only provided intensive release of ingredients, but also contributed to a significantly higher level of bioavailability of quinazopyrine and butadione compared to other hydrophilic and hydrophobic bases. When comparing the imported ointment "Butadione" (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, thanks to the scientifically based choice of the carrier, the latter is 1.5 times superior to the imported drug - 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 ointment form, a number of authors established the influence of the ointment base on the bioavailability of dexamethasone (Moes-Henschel 1985), salicylic acid, etc.
For example, with the same dose of the anesthetic panakaine 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 processes of release and absorption is determined by its composition, the physical state of the components, 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 > film-coated tablets.
