INTRACELLULAR BINDING IS AN IMPORTANT DETERMINANT OF THE AVID HEPATIC-UPTAKE OF THE HIGH CLEARANCE DRUG OMEPRAZOLE

The contribution of intracellular storage to hepatic uptake of the hig h clearance drug, omeprazole, was examined in the recirculating isolat ed perfused rat liver preparation. Following injection of [H-3]omepraz ole (7.5 mu Ci, 5 mg) into the portal vein over 1 min, livers were per fused for 5 min (N = 3) or 30 min (N = 3) and then homogenized at 4 de grees and fractionated by differential centrifugation. Radiolabelled o meprazole and metabolites were determined by scintillation counting of fractions of eluant from HPLC. Seventy per cent of drug had been take n up by the liver at 5 min and 85% at 30 min, with unchanged drug repr esenting 43 and 7.4%, respectively, of drug taken up. At both times, 7 0-75% of intracellular unchanged drug and the major metabolites were l ocated in the cytosol, and the cytosol:perfusate concentration ratio w as approximately 10:1. Mitochondrial, lysosomal and microsomal fractio ns contained relatively little drug. Extensive cytosolic binding of om eprazole therefore contributes substantially to the initial avid hepat ic first-pass uptake of this drug.