Acute hepatotoxicity after high-dose methotrexate administration to rats.
Acute hepatotoxicity after administration of 10-1000 mg/kg methotrexate (MTX) to rats was studied by monitoring serum transaminases, liver morphology, and disposition kinetics of MTX and 7-hydroxy-methotrexate (7-OH-MTX). Half the control rats and rats administered 1000 mg/kg MTX, had their bile duct cannulated. One to 2 hr after administration of 1000 mg/kg MTX, 50% of MTX treated bile-drained rats (Ebc) developed cholestasis despite similar or larger initial bile flow rates than those which did not develop cholestasis (Ebn, controls). In Ebc animals, peak serum ASAT and ALAT levels were 6- and 4-fold higher than that of the control rats, and morphologically, prominent hepatocytic changes and grossly dilated bile canaliculi were found. Immediately prior to cholestasis, the Ebc animals reached biliary 7-OH-MTX levels (8.3 +/- 1.3 mM, mean +/- S.E.M.) which were equivalent to the threshold level for precipitation of 7-OH-MTX in rat bile in vitro, and 3-fold higher than the corresponding levels of 7-OH-MTX in the bile of Ebn rats. Ninety-five % of the drug in the precipitated material was 7-OH-MTX. Hence, 7-OH-MTX may play a role in acute MTX hepatotoxicity, a dose-limiting toxicity that may not be counteracted by leukovorin rescue.
Bremnes
R M
RM
Department of Pharmacology, University of Tromsø, Norway.
Smeland
E
E
Huseby
N E
NE
Eide
T J
TJ
Aarbakke
J
J
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D000637:Transaminases / Q000097:blood
D001647:Bile Acids and Salts; D000637:Transaminases; C011864:7-hydroxymethotrexate; D008727:Methotrexate