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Hepatic Synthesis and Urinary Elimination of Acetaminophen Glucuronide Are Exacerbated in Bile Duct-Ligated Rats

Silvina S. M. Villanueva, María L. Ruiz, Carolina I. Ghanem, Marcelo G. Luquita, Viviana A. Catania and Aldo D. Mottino
Drug Metabolism and Disposition March 2008, 36 (3) 475-480; DOI: https://doi.org/10.1124/dmd.107.018127
Silvina S. M. Villanueva
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María L. Ruiz
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Carolina I. Ghanem
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Marcelo G. Luquita
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Viviana A. Catania
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Aldo D. Mottino
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Abstract

Renal and intestinal disposition of acetaminophen glucuronide (APAP-GLU), a common substrate for multidrug resistance-associated proteins 2 and 3 (Mrp2 and 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 acetaminophen (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, which also transports nontoxic 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 up-regulation of liver Mrp3 and renal Mrp2.

Footnotes

  • This work was supported by grants from Agencia Nacional de Promoción Científica y Tecnológica, Consejo Nacional de Investigaciones Científicas y Técnicas, and Universidad Nacional de Rosario, Argentina.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.018127.

  • ABBREVIATIONS: Bcrp, breast cancer-resistance protein; APAP, acetaminophen; APAP-GLU, acetaminophen-glucuronide; BDL, bile duct ligation; Mrp2, multidrug resistance-associated protein 2; Mrp3, multidrug resistance-associated protein 3; UGT, UDP glucuronosyltransferase; UDP-N-AG, UDP-N-acetylglucosamine; PLPC, palmitoyl-lysophosphatidylcholine; HPLC, high-performance liquid chromatography.

    • Received August 7, 2007.
    • Accepted December 19, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (3)
Drug Metabolism and Disposition
Vol. 36, Issue 3
1 Mar 2008
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OtherShort Communication

Hepatic Synthesis and Urinary Elimination of Acetaminophen Glucuronide Are Exacerbated in Bile Duct-Ligated Rats

Silvina S. M. Villanueva, María L. Ruiz, Carolina I. Ghanem, Marcelo G. Luquita, Viviana A. Catania and Aldo D. Mottino
Drug Metabolism and Disposition March 1, 2008, 36 (3) 475-480; DOI: https://doi.org/10.1124/dmd.107.018127

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OtherShort Communication

Hepatic Synthesis and Urinary Elimination of Acetaminophen Glucuronide Are Exacerbated in Bile Duct-Ligated Rats

Silvina S. M. Villanueva, María L. Ruiz, Carolina I. Ghanem, Marcelo G. Luquita, Viviana A. Catania and Aldo D. Mottino
Drug Metabolism and Disposition March 1, 2008, 36 (3) 475-480; DOI: https://doi.org/10.1124/dmd.107.018127
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