Many pharmacokinetic investigations in the elderly population reveal decreased clearance of lipophilic drugs metabolized by the cytochrome P450 enzymes; however, few studies have evaluated aging-dependent or gender-related changes in specific cytochrome P450 enzymes. The clearance of quinidine, midazolam, triazolam, erythromycin, and lidocaine declines with age; these drugs are metabolized by the isoform, CYP3A. To determine whether these metabolic effects are due to changes in CYP3A, the effects of age and gender on CYP3A activity were examined. The activity of the human hepatic cytochrome P450, CYP3A, was quantified in vitro as erythromycin N-demethylation in microsomes prepared from forty-three resected human liver specimens obtained from patients, age 27 to 83, with normal liver function. Erythromycin N-demethylation varied 5-fold in human liver microsomes. CYP3A activity was 24% higher in females than males (P = 0.027). CYP3A activity did not correlate with age, smoking status, ethanol consumption or percent ideal body weight. Large interindividual differences and a small female-specific increase in CYP3A activity were obtained. However, CYP3A activity was unaffected by age over the range of 27-83 years, suggesting that the aging-related alteration in the clearance of CYP3A substrates is secondary to changes in liver blood flow, size, or drug binding and distribution with aging.