Severe acute hypoxia is known to inhibit markedly the elimination of oxidatively metabolized drugs by the isolated liver. However, little is known of the degree of hypoxia required to produce inhibition of drug elimination by oxidative pathways in the intact organ. This study, in the isolated perfused rat liver, examined the oxygen dependence of the hepatic elimination of omeprazole, a drug which undergoes extensive oxidative metabolism in the rat. The relationship between hepatic oxygen supply and the production of omeprazole's oxidative sulfone and reductive sulfide metabolites was also examined. Rat livers were perfused at 15 ml/min with a perfusate containing 5 micrograms/ml of omeprazole in a single-pass design. Omeprazole clearance and the formation clearance of the two metabolites were measured in each liver during normal oxygenation, at different levels of hypoxia and after reoxygenation. There was a linear relationship between omeprazole clearance and oxygen delivery over the whole range studied. Production of the sulfone was similarly oxygen-dependent whereas the sulfide was only detectable after a significant reduction in oxygenation. In a further group of experiments the oxygen dependence of omeprazole clearance was shown to not be altered when the concentration of drug was lowered to 1 microgram/ml. This study shows that oxygen delivery is a critical determinant of the rate of oxidative drug metabolism in the isolated liver and supports the contention that reductions in hepatic oxygen supply may significantly alter the hepatic disposition of oxidatively metabolized drugs in vivo.