Renal and hepatic toxicity after high-dose 7-hydroxymethotrexate in the rat.
Cancer Chemother Pharmacol
; 34(2): 119-24, 1994.
Article
em En
| MEDLINE
| ID: mdl-8194163
ABSTRACT
To examine directly the hepatic and renal toxicity of 7-hydroxymethotrexate (7-OH-MTX) without interference of the parent compound methotrexate (MTX), we purified and gave 100 mg/kg 7-OH-MTX to rats, a dose resulting in serum levels of 7-OH-MTX comparable with those achieved in the clinic after the administration of high-dose MTX (HD-MTX). After only 5 h, the 7-OH-MTX-treated rats demonstrated 2.6-fold increases in serum creatinine values and 2-fold elevations in serum aspartate aminotransferase (ASAT) levels as compared with the controls. Morphologic evidence of toxicity, however, was apparent only in the kidneys. Intraluminal cellular debris containing membranous material and deteriorated organelles was seen, but no precipitate of the delivered drug. The peak serum concentration of 7-OH was up to 939 microM, and concentrations of 7-OH-MTX declined triphasically, showing a t1/2 alpha value of 2.45 min, a t1/2 beta value of 30.5 min, and a terminal half-life (t1/2 gamma) of 240 min. The total clearance value was 14.5 ml 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 kidney and liver cells.
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Base de dados:
MEDLINE
Assunto principal:
Metotrexato
/
Antagonistas do Ácido Fólico
/
Rim
/
Fígado
Idioma:
En
Revista:
Cancer Chemother Pharmacol
Ano de publicação:
1994
Tipo de documento:
Article
País de afiliação:
Noruega