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Dose-dependent Pharmacokinetics of Methotrexate and 7-Hydroxymethotrexate in the Rat in Vivo¹

Department of Pharmacology, Institute of Medical Biology [R. M. B., L. S., J. A.], and Department of Oncology, Institute of Clinical Medicine [E. W.], University of Tromsø, N-9001 Tromsø, Norway

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 µM, 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 (Cl_T) and biliary clearance (Cl_B). 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) µM], 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.

¹ This study was supported financially by the Norwegian Cancer Society and the Erna and Olay Aakre Foundation for Cancer Research.

² Fellow of the Norwegian Cancer Society. To whom requests for reprints should be addressed.

³ Postdoctoral fellow of the Norwegian Cancer Society. Present address: Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

Received 5/24/89. Revised 8/16/89. Accepted 8/21/89.

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