RENAL AND HEPATIC TOXICITY AFTER HIGH-DOSE 7-HYDROXYMETHOTREXATE IN THE RAT

To examine directly the hepatic and renal toxicity of 7-hydroxymethotr exate (7-OH-MTX) without interference of the parent compound methotrex ate (MTX), we purified and gave 100 mg/kg 7-OH-MTX to rats, a dose res ulting in serum levels of 7-OH-MTX comparable with those achieved in t he clinic after the administration of high-dose MTX (HD-MTX). After on ly 5 h, the 7-OH-MTX-treated rats demonstrated 2.6-fold increases in s erum creatinine values and 2-fold elevations in serum aspartate aminot ransferase (ASAT) levels as compared with the controls. Morphologic ev idence of toxicity, however, was apparent only in the kidneys. Intralu minal cellular debris containing membranous material and deteriorated organelles was seen, but no precipitate of the delivered drug. The pea k serum concentration of 7-OH was up to 939 mu M, and concentrations o f 7-OH-MTX declined triphasically, showing a t(1/2 alpha) value of 2.4 5 min, a t(1/2 beta) value of 30.5 min, and a terminal half-life (t(1/ 2 gamma)) of 240 min. The total clearance value was 14.5 mi min(-1) kg , and the postdistributional volume of distribution (V-beta) was 5070 ml/kg. Our results may indicate a direct toxic effect of 7-OH-MTX on k idney and liver cells.