Shift from Biliary to Urinary Elimination of Acetaminophen-Glucuronide in Acetaminophen-Pretreated Rats

GHANEM CI; RUIZ ML; VILLANUEVA SSM; LUQUITA MG; CATANIA VA; JONES B; BENGOCHEA LA; VORE M; MOTTINO AD

The Journal of Pharmacology and Experimental Therapeutics

Aspet

Año: 2005 vol. 315 p. 987 - 995

Despite its toxicity, acetaminophen (APAP) is used increasingly as an analgesic, antipyretic, and anti-inflammatory agent. We examined the effect of prior exposure to APAP on its biliary and urinary elimination. The biliary and urinary elimination of a test dose of APAP (150 mg/kg i.v.) was determined in male Wistar rats 24 h after pretreatment with vehicle, a single dose (1.0 g/kg i.p.), or increasing daily doses (0.2, 0.3, 0.6, and 1.0 g/kg/day i.p.) of APAP. Although elimination of the parent APAP was minimally affected, biliary excretion of APAP glucuronide was significantly decreased 70 and 80%, whereas urinary excretion was significantly increased 90 and 100% in the groups pre-treated with single and repeated doses of APAP, respectively,relative to vehicle controls. Western analysis and confocal im-munofluorescent microscopy indicated a marked increase in hepatic expression of multidrug resistance-associated protein 3 (Mrp3) in both groups pretreated with APAP, relative to ex-pression of Mrp2. ATP-dependent transport of [3H]tauro-cholate, an Mrp3 substrate, was significantly increased in ba-solateral liver plasma membrane vesicles from rats pretreated with repeated doses of APAP relative to controls. Enterohepatic recirculation of APAP glucuronide after administration of the same test dose of the drug was significantly decreased in rats pretreated with repeated doses of APAP. These data indicate that APAP pretreatment induced a shift from biliary to urinary elimination of APAP glucuronide, consistent with the increased expression of Mrp3 in the basolateral domain of the hepato-cyte. We postulate that decreased enterohepatic recirculation contributes to decreased APAP hepatotoxicity by reducing liver exposure.