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First published on December 20, 2007; DOI: 10.1124/dmd.107.018127

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Received for publication August 8, 2007.
Revised December 13, 2007.
Accepted for publication December 19, 2007.

HEPATIC SYNTHESIS AND URINARY ELIMINATION OF ACETAMINOPHEN GLUCURONIDE ARE EXACERBATED IN BILE DUCT-LIGATED RATS

Silvina SM Villanueva 1, Maria L Ruiz 1, Carolina I Ghanem 2, Marcelo G Luquita 1, Viviana A Catania 1, Aldo D Mottino 1*

1 Instituto de Fisiologia Experimental, Universidad Nacional de Rosario, Rosario 2 Instituto de Farmacologia Experimental, Universidad Nacional de Buenos Aires, Buenos Aires

* Address correspondence to: E-mail: amottino{at}unr.edu.ar

Abstract

Renal and intestinal disposition of acetaminophen glucuronide (APAP-GLU), a common substrate for multidrug resistance-associated proteins 2 and 3 (Mrp2, Mrp3), was assessed in bile duct ligated rats (BDL) 7 days after surgery, using an in vivo perfused jejunum model with simultaneous urine collection. Doses of 150 mg/Kg b.w. (i.v.) or 1 g/Kg b.w. (i.p.) of APAP were administered, and its glucuronide was determined in bile (only Shams), urine and intestinal perfusate throughout a 150 min period. Intestinal excretion of APAP-GLU was unchanged or decreased (-58%) by BDL for the 150 mg and 1 g/Kg b.w. doses of APAP, respectively. In contrast, renal excretion was increased by 200% and 320%, respectively. Western studies revealed decreased levels of apical Mrp2 in liver and jejunum but increased levels in renal cortex from BDL animals, whereas Mrp3 was substantially increased in liver and not affected in kidney or intestine. The global synthesis of APAP-GLU, determined as the sum of cumulative excretions, was higher in BDL rats (+51 and +110%) for these same doses of APAP, as a consequence of a significant increase in functional liver mass, with no changes in specific glucuronidating activity. Expression of apical breast cancer resistance protein (Bcrp), which also transports non-toxic metabolites of APAP, was decreased by BDL in liver and renal cortex, suggesting a minor participation of this route. We demonstrate a more efficient hepatic synthesis and basolateral excretion of APAP-GLU, followed by its urinary elimination in BDL group, the latter two processes consistent with upregulation of liver Mrp3 and renal Mrp2.


Key words: ABC transporters, biliary excretion, drug disposition, glucuronidation, hepatobiliary transport, hepatotoxicity, intestinal transport, membrane transport, MRP, UDP glucuronyltransferases


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