The dose and the frequency of administration required to achieve effective therapeutic blood and tissue levels vary in different patients because of individual differences in drug distribution and rates of drug metabolism and elimination. These differences are determined by genetic factors and nongenetic variables such as age, sex, liver size, liver function, circadian rhythm, body temperature, and nutritional and environmental factors such as concomitant exposure to inducers or inhibitors of drug metabolism. The discussion that follows will summarize the most important variables relating to drug metabolism that are of clinical relevance.

Individual differences in metabolic rate depend on the nature of the drug itself. Thus, within the same population, steady-state plasma levels may reflect a 30-fold variation in the metabolism of one drug and only a 2-fold variation in the metabolism of another. Genetic factors that influence enzyme levels account for some of these differences. Succinylcholine, for example, is metabolized only half as rapidly in persons with genetically determined defects in pseudocholinesterase as in normals. Analogous pharmacogenetic differences are seen in the acetylation of isoniazid and the hydroxylation of warfarin.

Environmental factors also contribute to individual variations in drug metabolism. Cigarette smokers metabolize some drugs more rapidly than nonsmokers because of enzyme induction. Industrial workers exposed to some pesticides metabolize certain drugs more rapidly than nonexposed individuals. Such differences make it difficult to determine effective and safe doses of drugs that have narrow therapeutic indices.

Increased susceptibility to the pharmacologic or toxic activity of drugs has been reported in very young and old patients as compared to young adults. Although this may reflect differences in absorption, distribution, and elimination, differences in drug metabolism cannot be ruled out. Studies in several mammalian species indicate that drugs are metabolized at reduced rates during the prepubertal period and senescence. Slower metabolism could be due to reduced activity of metabolic enzymes or reduced availability of essential endogenous cofactors.

Sex-dependent variations in drug metabolism have been well documented in rats but not in other rodents. Young adult male rats metabolize drugs much faster than mature female rats or prepubertal male rats. These differences in drug metabolism have been clearly associated with androgenic hormones. A few clinical reports suggest that similar sex-dependent differences in drug metabolism also exist in other animals for benzodiazepines, estrogens, and salicylates.