RT Journal Article
SR Electronic
T1 Inhibition by ranitidine of acetaminophen conjugation and its possible role in ranitidine potentiation of acetaminophen-induced hepatotoxicity.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 887
OP 894
VO 245
IS 3
A1 S A Rogers
A1 K C Gale
A1 J F Newton
A1 J G Dent
A1 T B Leonard
YR 1988
UL http://jpet.aspetjournals.org/content/245/3/887.abstract
AB Pretreatment with ranitidine (RA) potentiates the hepatotoxicity of acetaminophen (APAP) in male Fischer 344 rats. The present studies were undertaken to investigate the role of APAP metabolism in this potentiation. Administration of RA (50 mg/kg p.o.) to male Fischer 344 rats 30 min before [3H]APAP (750 mg/kg p.o.) increased the plasma concentrations of acetaminophen at 2 hr (193%) and 4 hr (277%) after APAP. Covalent binding of [3H]APAP-related material to hepatic macromolecules in RA-pretreated animals was similar to APAP alone values up to 12 hr after treatment; however, 24 hr after APAP, binding in the RA-pretreated animals was twice that observed in animals given [3H]APAP alone. Urinary excretion (0-24 hr) of APAP and APAP glucuronide were reduced in ranitidine-pretreated animals to 64 and 66% of control, respectively, indicating that in vivo RA altered APAP conjugation with glucuronic acid. APAP uridine diphosphoglucuronyltransferase activity in rat hepatic microsomes was competitively inhibited by RA (0.1-2 mM). The Ki apparent for RA inhibition of APAP uridine diphosphoglucuronyltransferase was 0.04 mM. In contrast, neither APAP nor 4-nitrophenol sulfotransferase activity in rat hepatic cytosol was inhibited by RA at concentrations up to 5 mM. Together, these results support the suggestion that RA-mediated alterations of APAP conjugation may explain the potentiation of APAP-induced hepatotoxicity by RA in rats.