Hepatobiliary excretion of acetaminophen glutathione conjugate and its derivatives in transport-deficient (TR-) hyperbilirubinemic rats.
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.
Chen
Chuan
C
Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 372 Fairfield Road, Box U-2092, Storrs, CT 06269-2092, USA.
Hennig
Gayle E
GE
Manautou
Jose E
JE
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006932:Hyperbilirubinemia / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000378:metabolism*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D000082:Acetaminophen; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C037386:acetaminophen glucuronide