Our overall goals are to identify determinants of drug clearance to improve medication therapy for older patients. Algorithms to estimate age, sex, and race effects on renal drug clearance exist. No such algorithms exist for non-renal drug clearance. Because the majority of non-renally cleared medications are metabolized by CYP3A, we began studies with drugs cleared by this enzyme. We have completed the first studies of steady-state CYP-mediated drug clearance in patient populations that include significant numbers of women, the very old (>80 years of age), and residents of assisted living and long-term care facilities. We used the population approach that allows sparse sampling from individuals. To our surprise, clearance rates were among the highest in patients from ages 65-90, and in the oldest nursing home residents. The age-related findings were consistent for three CYP3A substrate drugs that varied widely in pharmacological properties (bioavailabiltiy and transporter affinity). We also found faster clearance in women compared to men and identified covariates (smoking, alcohol intake) that affected clearance in men, but were not present in women, or the oldest patients. Clearance rates also varied by race with whites> blacks and > Hispanics. Dietary analyses suggest vitamin D intake influences CYP3A clearance rates. These results suggest studies of physiologic aging excluding the very old, women, and minority groups may not reflect clearance characteristics in older patients Ithat receive medications. We propose population studies of a CYP3A substrate, atorvastatin, in diverse clinical populations with an interventional study to investigate a potential mechanism for preserved clearance rates in older patients, and the first population studies of CYP2C19- mediated clearance of lansoprazole to investigate age, sex, and genotype (race) effect on steady-state clearance rates of this important polymorphic enzyme. The potential impact of these findings on the care of the growing number of very old patients, especially understudied women and minority groups, is great.