TY - JOUR T1 - HEPATOBILIARY EXCRETION OF ACETAMINOPHEN GLUTATHIONE CONJUGATE AND ITS DERIVATIVES IN TRANSPORT-DEFICIENT (TR<sup>-</sup>) HYPERBILIRUBINEMIC RATS JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 798 LP - 804 DO - 10.1124/dmd.31.6.798 VL - 31 IS - 6 AU - Chuan Chen AU - Gayle E. Hennig AU - José E. Manautou Y1 - 2003/06/01 UR - http://dmd.aspetjournals.org/content/31/6/798.abstract N2 - The involvement of the canalicular multidrug resistance protein 2 (Mrp2) in the hepatobiliary excretion of acetaminophen (APAP)-glutathione (GSH) conjugate and its derivatives was investigated using transport-deficient (TR- rats. Although no differences in the biliary concentration of APAP itself were detected between normal Wistar and TR- rats, significant differences in the biliary disposition of several conjugated metabolites of APAP were detected. APAP-GSH was virtually absent in bile from TR- rats. Also, biliary concentrations of APAP-mercapturate (NAC; N-acetylated l-cysteine) and APAP-GLU were significantly reduced in TR- rats. No differences in the biliary concentration of APAP-cysteinylglycine/cysteine (CG/CYS) were detected between normal and mutant rats. The cumulative amounts of APAP-CG/CYS and APAP-NAC excreted in urine of mutant rats were decreased, whereas APAP-GLU was markedly increased. Analysis of liver samples revealed that APAP-GSH and APAP-NAC accumulate in mutant rat livers. Our results support the direct involvement of Mrp2 in the hepatobiliary excretion of several conjugated metabolites of APAP, including APAP-GSH and APAP-NAC, and provide relevant information on processes that may be involved with both their hepatic basolateral transport and renal elimination. The American Society for Pharmacology and Experimental Therapeutics ER -