General factors and influence of sex
The activity of biotransformation enzymes and the resulting metabolic rate depend on numerous endogenous and exogenous causes. Basic factors include the patient's sex and age, their physiological and pathological condition, diet specifics (food components), environmental influence, and drug interactions when taking multiple medications simultaneously.
Among physiological features, gender differences stand out most markedly. They are due to the fact that male sex hormones—androgens—act as natural stimulators of the synthesis of microsomal liver enzymes. As a result, the activity of these enzymes is physiologically higher in men than in women.
The practical significance of this fact lies in the accelerated metabolism of a number of substances in the male body. In particular, this applies to:
- ethyl alcohol (Spiritus aethylicus);
- benzodiazepine derivatives;
- salicylates;
- exogenous estrogens.
Role of comorbidities
Various diseases can drastically alter the rate of biotransformation. This factor is most pronounced in pathologies of organs responsible for metabolism and hemodynamics.
- Liver diseases (e.g., hepatitis and cirrhosis). When liver tissue is damaged, the activity of microsomal enzymes naturally decreases. As a result, biotransformation processes slow down, leading to an increased and significantly prolonged pharmacological effect of the administered drugs.
- Cardiovascular failure. Due to myocardial weakness, the blood flow velocity in the liver decreases. This is critically important for drugs with high hepatic clearance (e.g., morphine or lidocaine — Lidocainum). In heart failure, their metabolism slows down, creating a risk of toxic effects even at standard therapeutic dosages.
- Thyroid dysfunction. In hyperthyroidism, the metabolism of medicinal substances increases significantly, while in hypothyroidism, it decreases accordingly.
Influence of genetics on biotransformation
A crucial factor determining individual response to pharmacotherapy is genetic polymorphism. This term refers to the presence of hereditary mutations in genes encoding the synthesis of biotransformation enzymes. Genetics is precisely what accounts for vast interindividual differences in the rate and efficiency of metabolism.
Depending on genetically determined enzyme activity, the entire human population is divided into three major groups: rapid, normal, and slow metabolizers. The clinical effect directly depends on this activity:
- Increased enzyme activity: leads to accelerated biotransformation. The drug concentration in plasma drops, resulting in a weakened therapeutic effect.
- Decreased activity (deficiency): biotransformation slows down. The substance begins to accumulate in the body, leading to an enhanced effect up to the development of toxic effects.
A classic example of pharmacogenetic influence is the acetylation process. There are "fast" and "slow acetylators". If a patient with reduced enzyme activity (a slow acetylator) is prescribed a standard dose of isoniazid, its concentration in blood plasma will be 4–6 times higher than in rapid metabolizers. This creates a direct risk of severe toxic effects due to excessive drug accumulation.
Briefly: answers to topical questions
Which drugs have a high hepatic clearance?
A high hepatic clearance is indicated for drugs metabolized predominantly in the liver. Sources classify morphine and lidocaine as such when hepatic blood flow is reduced, as well as lipophilic $\beta$-blockers: propranolol, metoprolol, and carvedilol.
Which cytochrome P450 isoenzymes are most susceptible to genetic polymorphism?
Sources confirm genetic polymorphism for the following cytochrome P450 isoenzymes:
- CYP2D6 — its activity is genetically determined and affects the metabolism of metoprolol, nebivolol, and carvedilol.
- CYP2C19 — its polymorphism affects the bioactivation of clopidogrel.
What dietary components can inhibit microsomal liver enzymes?
Grapefruit juice is capable of inhibiting biotransformation enzymes among dietary components. The furanocoumarins it contains, primarily in the intestinal wall, inhibit CYP3A4, increasing the bioavailability and concentration of many drugs and the risk of toxicity. Consumption of grapefruit juice is contraindicated when taking astemizole and terfenadine.
What age-related features affect drug biotransformation in newborns?
In newborns, drug biotransformation is slowed down due to the immaturity of enzyme systems. In the first 2–4 weeks of life, the activity of most enzymes, especially conjugation reactions, is low; normalization of activity occurs by 1–6 months. This increases the risk of toxicity and drug accumulation. An example is chloramphenicol, the use of which in the first weeks of life is contraindicated due to the accumulation of a toxic metabolite caused by insufficient conjugation processes.
Class and exam questions
Why is there a high risk of lidocaine overdose in heart failure?
Due to a drop in the pumping function of the heart, the rate of blood flow in the liver decreases. Lidocaine has a high hepatic clearance, so it does not have time to be degraded and accumulates in the body, causing toxic effects.
How do thyroid disorders affect drug metabolism?
Thyroid hormones regulate overall metabolism. In hyperthyroidism, the rate of drug degradation increases, while in hypothyroidism, it decreases.
What happens in the case of genetically determined high enzyme activity?
The drug undergoes accelerated biotransformation. Because of this, its plasma concentration drops rapidly, and its therapeutic effect is significantly weakened.
What else to study on this topic
- The influence of patient age on biotransformation (pharmacokinetic features in children and the elderly).
- Clinical examples of genetic polymorphism (additional drugs).
- Genetic enzyme deficiencies (enzymopathies) and classification of adverse reactions.
- The influence of environmental factors and dietary components (diet) on liver function.
- Drug interactions: enzyme induction and inhibition during concurrent drug administration.
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