General Factors and the Influence of Sex
The activity of biotransformation enzymes and the resulting rate of metabolism depend on numerous endogenous and exogenous causes. Basic factors include the patient's sex and age, physiological and pathological status, diet (food components), environmental influences, and drug interactions during simultaneous administration of multiple medications.
Among physiological characteristics, gender differences are particularly prominent. They are driven by male sex hormones—androgens—acting as natural stimulators of the synthesis of hepatic microsomal enzymes. Consequently, 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:
- ethanol (Spiritus aethylicus);
- benzodiazepines;
- salicylates;
- exogenous estrogens.
The Role of Comorbid Pathologies
Various diseases can drastically alter the rate of biotransformation. This factor is most pronounced in disorders of organs responsible for metabolism and hemodynamics.
- Liver diseases (e.g., hepatitis and cirrhosis). When liver tissue is damaged, the activity of microsomal enzymes predictably decreases. As a result, biotransformation processes slow down, leading to an enhanced and significantly prolonged pharmacological effect of administered drugs.
- Heart failure. Due to impaired myocardial pumping function, hepatic blood flow velocity decreases. This is critical for drugs with a 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 doses.
- Thyroid dysfunction. In hyperthyroidism, drug metabolism is markedly increased, whereas in hypothyroidism, it is correspondingly decreased.
The Influence of Genetics on Biotransformation
A crucial factor determining individual response to pharmacotherapy is genetic polymorphism. This term refers to hereditary mutations in genes encoding biotransformation enzymes. Genetics are responsible for vast interindividual differences in metabolic rate and efficiency.
Depending on genetically determined enzyme activity, the human population is divided into three major groups: ultra-rapid, extensive (normal), and poor metabolizers. The clinical effect directly depends on this activity:
- Increased enzyme activity: leads to accelerated biotransformation. Plasma drug concentrations drop, resulting in a diminished therapeutic effect.
- Decreased activity (deficiency): biotransformation slows down. The substance begins to accumulate in the body, leading to amplified effects and potential toxic outcomes.
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 given a standard dose of isoniazid, their plasma drug concentration will be 4–6 times higher than that of rapid metabolizers. This creates a direct risk of severe toxicity due to drug accumulation.