INVESTIGADORES
RUIZ Maria Laura
artículos
Título:
Hepatic Synthesis and Urinary Elimination of Acetaminophen Glucuronide Are Exacerbated in Bile Duct-Ligated Rats
Autor/es:
VILLANUEVA SSM; RUIZ ML; GHANEM CI; LUQUITA MG; CATANIA VA; MOTTINO AD
Revista:
Drug Metabolism and Disposition
Referencias:
Año: 2008 vol. 36 p. 475 - 480
ISSN:
0090-9556
Resumen:
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 Mrp2.58%) 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.