Dose-dependent pharmacokinetics of methotrexate and 7-hydroxymethotrexate in the rat in vivo.
The pharmacokinetics of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) in bile, urine, and serum was studied in rats in vivo after short-time infusions of 10, 50, 250, and 1000 mg/kg MTX. All animals were anesthetized and drained of bile during experiments. The biliary secretion rate of MTX approached saturation when serum MTX levels surpassed 700-800 microM, causing a significant reduction in biliary recovery as the parent compound (49 to 32%) at MTX doses exceeding 50 mg/kg. The hepatic metabolism of MTX to the 7-hydroxy metabolite was not saturated at the doses used. Serum MTX pharmacokinetics demonstrated dose dependency, inasmuch as doses exceeding 10 mg/kg were accompanied by a reduced total body clearance (Clr) and biliary clearance (ClB). A significant finding in relation to acute hepatotoxicity reported after high-dose MTX in humans was the occurrence of cholestasis 30-90 min after drug infusion and the observation of macroscopic precipitations in the bile duct in five of six animals treated with 1000 mg/kg MTX. In these five animals, cessation of bile secretion occurred at similar bile 7-OH-MTX levels [9800 +/- 1100 (SD) microM], while the single rat that secreted bile throughout the experiment had a 5-fold lower peak 7-OH-MTX concentration in bile. Analysis of biliary precipitates formed in vivo and in vitro found 7-OH-MTX to constitute 97% and MTX 3% of the drug content of the precipitated material.
Bremnes
R M
RM
Department of Pharmacology, University of Tromsø, Norway.
Slørdal
L
L
Wist
E
E
Aarbakke
J
J
D000818:Animals; D001646:Bile / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000031:analogs & derivatives; D051381:Rats; D011919:Rats, Inbred Strains
C011864:7-hydroxymethotrexate; D008727:Methotrexate