OBJECTIVE The hepatic 6-hydroxylation of chlorzoxazone in vitro is mediated primarily by CYP2E1, and measurement of this metabolic pathway may provide an in vivo probe of the enzyme. In animals, such as the rat, levels of CYP2E1 are induced by both fasting and obesity. This study investigated whether these two physiologic factors are determinants of the metabolism and disposition of chlorzoxazone in humans. METHODS The plasma concentration-time profiles of chlorzoxazone and its 6-hydroxy metabolite were determined after oral administration of parent drug (250 mg). The urinary excretion of the metabolite was also determined. In one study, the disposition profiles were obtained in six healthy white men, first after an overnight fast, and on a separate occasion after a 38-hour fast. The second study investigated the disposition of chlorzoxazone in nine obese women and in nine age-matched women. RESULTS Prolonged fasting produced a significant increase in circulating ketone bodies. This was associated with a reduction in the oral clearance of chlorzoxazone (mean +/- SD, 5.79 +/- 1.04 to 3.69 +/- 1.54 ml.min-1.kg-1; p < 0.03). The 0- to 24-hour urinary recovery of the 6-hydroxy metabolite was extensive (50% to 80%), and the reduced clearance reflected a lower 6-hydroxylating ability after fasting. The elimination half-life of the drug was increased by a similar extent to clearance (1.00 +/- 0.09 versus 1.50 +/- 0.42 hours; p < 0.004), whereas its apparent volume of distribution was unaffected by fasting. By contrast, obesity resulted in significant increases in the oral clearance and distribution of chlorzoxazone on both an absolute and weight-normalized basis; for example, 4.15 +/- 0.81 versus 6.23 +/- 1.72 ml.min-1.kg-1 and 0.50 +/- 0.28 versus 0.82 +/- 0.19 L.kg-1. Half-life of elimination was similar in both groups of subjects. Estimation of the fractional clearance of 6-hydroxychlorzoxazone showed that obesity increased this parameter to a similar extent as oral clearance. The difference in the oral clearance and 6-hydroxylating ability of nonobese men and women was also statistically different. CONCLUSIONS A discordancy was observed between the reported effect of fasting in rodents and that observed in humans. This may reflect an interspecies difference in CYP2E1 regulation or, more likely, destruction of the enzyme by lipid peroxidation resulting from the prolonged period of fasting. However, serious to morbid obesity in humans is associated with increased 6-hydroxylation of chlorzoxazone, consistent with induction of CYP2E1. Accordingly, such individuals may be at increased risk of CYP2E1-mediated toxicities and adverse effects caused by the formation of CYP2E1-mediated metabolites of environmental agents. In addition, the efficacy of an active drug that is a CYP2E1 substrate may be reduced in obese patients.