Vol. 288, Issue 2, 414-420, February 1999

Hepatic Disposition of the Acyl Glucuronide1-O-Gemfibrozil--D-Glucuronide: Effects of Dibromosulfophthalein on Membrane Transport and Aglycone Formation¹

Lucia Sabordo, Benedetta C. Sallustio, Allan M. Evans and Roger L. Nation

Department of Clinical Pharmacology, The Queen Elizabeth Hospital, Woodville, South Australia and Department of Clinical and Experimental Pharmacology, The University of Adelaide, Adelaide, South Australia (L.S., B.C.S.); and Centre for Pharmaceutical Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia (A.M.E., R.L.N.)

The liver plays an important role in the disposition of acyl glucuronides by determining their extent of formation, biliary excretion, and efflux into blood. Thus, both intrahepatic and extrahepatic exposure to these reactive polar conjugates depends on the efficiency of hepatic transport mechanisms, which may be shared with other nonbile acid organic anions. Using the isolated perfused rat liver preparation, the hepatic disposition of the acyl glucuronide, 1-O-gemfibrozil--D-glucuronide, was examined in the presence of the organic anion dibromosulfophthalein (DBSP). Using a recirculating system, livers were perfused for 90 min with an erythrocyte-free perfusion medium containing 1% (w/v) albumin and 1-O-gemfibrozil--D-glucuronide (3 µM) alone (n = 6) or with DBSP (200 µM, n = 7). The glucuronide was avidly taken up by the liver, excreted into bile, and hydrolyzed within the liver to its aglycone, gemfibrozil. DBSP significantly (P < .05) lowered the conjugate's mean hepatic clearance (8.98-5.17 ml/min), intrinsic clearance (44.0-17.7 ml/min), and fraction eliminated in bile (72.8-48.7% of the dose), while increasing perfusate gemfibrozil concentrations (0.52-0.92 µM at 90 min). Furthermore, DBSP significantly (P < .05) lowered the ratio of intrahepatic to unbound perfusate concentrations of 1-O-gemfibrozil--D-glucuronide (139.0-35.0) and showed a trend to lower the ratio of bile to intrahepatic concentrations (111.3-76.2, P = .05). Thus, the study demonstrated that DBSP inhibited both the sinusoidal uptake and canalicular transport of 1-O-gemfibrozil--D-glucuronide, suggesting that the hepatic membrane transport of acyl glucuronides is carrier mediated and shared with other organic anions.