Diet and environmental factors contribute to individual variations in drug metabolism. Charcoal-broiled foods and cruciferous vegetables are known to induce CYP1A enzymes, whereas grapefruit juice is known to inhibit the CYP3A metabolism of co-administered drug substrates (Table 4–2; also see below). Cigarette smokers metabolize some drugs more rapidly than nonsmokers because of enzyme induction (see previous section). Industrial workers exposed to some pesticides metabolize certain drugs more rapidly than unexposed 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 very old patients compared with young adults (see Chapters 59 and 60). Although this may reflect differences in absorption, distribution, and excretion, differences in drug metabolism also play a role. 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. Clinical reports suggest that similar sex-dependent differences in drug metabolism also exist in humans for ethanol, propranolol, some benzodiazepines, estrogens, and salicylates.
Many substrates, by virtue of their relatively high lipophilicity, are not only retained at the active site of the enzyme but remain non-specifically bound to the lipid endoplasmic reticulum membrane. In this state, they may induce microsomal enzymes, particularly after repeated use. Acutely, depending on the residual drug levels at the active site, they also may competitively inhibit metabolism of a simultaneously administered drug.