Effect of hypoxia on oxidative and reductive pathways of omeprazole metabolism by the isolated perfused rat liver.
The effect of hypoxia on the elimination of omeprazole, a potent inhibitor of gastric acid secretion, was studied in the isolated perfused rat liver. During normal oxygenation, a 10 mg bolus dose was eliminated rapidly (T 1/2 beta = 8.0 +/- 1.1 min; mean +/- S.E.M., N = 4), while under hypoxic conditions T 1/2 beta was increased to 81.6 +/- 5.4 min (P less than 0.01). Upon reoxygenation, T 1/2 beta returned to 9.6 +/- 1.3 min. During hypoxia, perfusate concentrations of an oxidative metabolite (the sulphone) were reduced by 68%, while those of the reductively-generated sulphide increased 4-fold. With reoxygenation, both formation and elimination of the sulphone were increased, while the sulphide, which had accumulated during the hypoxic period, was eliminated rapidly. These findings were duplicated in steady-state experiments, in which omeprazole clearance during hypoxia fell by at least 70%, and sulphide concentrations in perfusate rose from undetectable levels to 200 ng/ml (at least a 10-fold increase). Sulphone concentrations did not change with hypoxia, consistent with a reduction in both its formation and elimination rates. We conclude that the hepatic elimination of omeprazole is severely retarded by hypoxia, but that this effect is promptly reversed by reoxygenation. The increased formation of reductive metabolite during hypoxia is not of sufficient magnitude to sustain the normal hepatic elimination of omeprazole.
D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008099:Liver / Q000378:metabolism*; D008297:Male; D009853:Omeprazole / Q000031:analogs & derivatives; D010084:Oxidation-Reduction; D010100:Oxygen / Q000502:physiology*; D010477:Perfusion; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains
D001562:Benzimidazoles; D007773:Lactates; D011773:Pyruvates; D019344:Lactic Acid; C040449:omeprazole sulfide; C040450:omeprazole sulfone; D019289:Pyruvic Acid; D009853:Omeprazole; D010100:Oxygen