Acute Hepatotoxicity after High‐Dose Methotrexate Administration to Rats

Abstract

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.

Microvascular Perturbations in Rats Receiving the Maximum Tolerated Dose of Methotrexate or Its Major Metabolite 7-Hydroxymethotrexate

“…This is a strong indication of the validity of our model. The ® ndings of ultrastructural changes in the kidney, also corroborates previous reports [ 22,29,30] .…”

“…Surprisingly, the mitochondria of the hepatocytes appeared unaltered after large doses of medication and at the end of our observation period, while the mitochondria of tubular epithelial cells showed irreversible changes. Apart from the observation of changes in smooth endoplasmatic reticulum presented here, MTX and 7-OH-MTX have previously been shown to cause a variety of ultrastructural changes in human liver samples [ 22,29,30] . This is a strong indication of the validity of our model.…”

“…The onset of toxicity in our model is very rapid and ultrastructural changes were demonstrated after less than 1 h. The present study therefore adds to data that, taken together, indicate that the mechanism of the acute lethal toxicity of MTX or 7-OH-MTX is probably not related to its antiproliferative or antifolate action. In our previous studies, using lower doses of MTX or 7-OH-MTX, we have demonstrated parenchymal changes in liver and kidney [ 22,29,30] . After 7-OH-MTX, changes in endothelial cell function were suggested in these organs [ 22] .…”

“…In our previous studies, using lower doses of MTX or 7-OH-MTX, we have demonstrated parenchymal changes in liver and kidney [ 22,29,30] . After 7-OH-MTX, changes in endothelial cell function were observed in these organs.…”

Clinical and Pharmacokinetic Risk Factors for High-dose Methotrexate-induced Toxicity in Children with Acute Lymphoblastic Leukemia: A Logistic Regression Analysis

“…Case reports suggest that decreased biotransformation of MTX to 7-OHMTX correlates with an increase in overall toxicity, especially mucositis and myelotoxicity (26 -28). In studies on rats, a high level of 7-OHMTX and a high percentage of precipitated material from 7-OHMTX in the bile have been associated with acute MTX hepatotoxicity (29,30). A low ratio of p-7-OHMTX 66 h /p-MTX 66 h was a significant risk factor for oral toxicity.…”