Hypoxia impairs conjugation and elimination of harmol in the isolated perfused rat liver

Although studies in isolated hepatocytes have demonstrated that hypoxia adversely affects drug conjugation, the impact of hypoxia on drug elimination by conjugation in the intact liver has not been defined. This study in the isolated perfused rat liver examines the effect of acute hypoxia on the hepatic elimination of harmol, a phenolic compound eliminated by conjugation without first undergoing oxidative metabolism. In the preparation used in these experiments, harmol glucuronide is the major metabolite (greater than 80%), with the remainder being sulfate. The hypoxic insult consisted of an 80% reduction of hepatic oxygen delivery for 1 hr. During normal oxygenation, a 20-mumol dose was rapidly eliminated (T1/2 = 4.3 +/- 0.8 min; mean +/- S.D., n = 5). A second dose given after 30 min of hypoxia was eliminated much more slowly (T1/2 = 21 +/- 7.9 min, P less than .01). Upon reoxygenation, T1/2 recovered to 4.2 +/- 0.5 min. Similar effects were observed in steady-state experiments, in which perfusate levels rose from 15.7 +/- 1.3 microM to 31.0 +/- 1.6 microM (P less than .005) during hypoxia, indicating a fall in harmol clearance of at least 50%. In each group of experiments, there was a significant reduction in both the formation and elimination of harmol conjugates during hypoxia. Upon reoxygenation, harmol conjugation recovered, but conjugate elimination remained significantly impaired. The authors conclude that acute hypoxia slows the hepatic elimination of harmol by reducing drug conjugation, an effect that is promptly reversed by reoxygenation.(ABSTRACT TRUNCATED AT 250 WORDS)