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 high clearance drug, omeprazole, was examined in the recirculating isolated perfused rat liver preparation. Following injection of [3H]omeprazole (7.5 microCi, 5 mg) into the portal vein over 1 min, livers were perfused for 5 min (N = 3) or 30 min (N = 3) and then homogenized at 4 degrees and fractionated by differential centrifugation. Radiolabelled omeprazole and metabolites were determined by scintillation counting of fractions of eluant from HPLC. Seventy per cent of drug had been taken up by the liver at 5 min and 85% at 30 min, with unchanged drug representing 43 and 7.4%, respectively, of drug taken up. At both times, 70-75% of intracellular unchanged drug and the major metabolites were located in the cytosol, and the cytosol:perfusate concentration ratio was approximately 10:1. Mitochondrial, lysosomal and microsomal fractions contained relatively little drug. Extensive cytosolic binding of omeprazole therefore contributes substantially to the initial avid hepatic first-pass uptake of this drug.