Genetic and environmental factors are determinants of the interindividual and interethnic variability in drug metabolism. The metabolism of several important drugs (e.g. haloperidol) cosegregates with that of debrisoquine. Thus, interethnic differences in debrisoquine hydroxylation polymorphism (CYP2D6) might be partly responsible for the variation in haloperidol disposition between races. The influence of tobacco, ethanol, caffeine, gender, and oral contraceptive use on the debrisoquine metabolic ratio (MR) has been analyzed in 633 Spanish healthy volunteers. MR was also determined in panels of healthy volunteers. 18 smokers were studied during a tobacco abstinence period, and 31 women three times during the same menstrual cycle. Among EMs, debrisoquine MR was significantly (P < 0.05) lower during smoking cessation (mean antilog +/- SD, 0.48 +/- 0.29) compared to a smoking period (0.61 +/- 0.23). During the lutheal phase of the menstrual cycle, debrisoquine MR was also significantly (P < 0.01) lower (0.33 +/- 0.41) compared to the ovulatory-phase (0.41 +/- 0.34) and the phase before ovulation (0.44 +/- 0.36). Among EMs, it is suggested that debrisoquine MR may be modified by tobacco smoking and sexual hormones. The clinical relevance of these findings remains unclear.