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Formation and Elimination of 7-Hydroxymethotrexate in the Rat in Vivo after Methotrexate Administration

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

Bile, urine, and serum concentrations of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) were monitored in rats in vivo following a short-time infusion of 10 mg/kg [³H]MTX. The experiments were performed in one group of anesthetized, bile-drained rats and in two control groups, one anesthetized and one unanesthetized, that were not bile-drained. Peak biliary levels of MTX (3.8 x 10^-3 M) and 7-OH-MTX (1.8 x 10^-4 M) appeared within 15 min after cessation of infusions. For two log ranges of serum MTX concentrations, biliary levels remained 180-fold higher. High bile 7-OH-MTX levels appeared few min after start of MTX administration, and were 720 times higher than the peak serum concentrations, indicating that the liver is a major site of 7-OH-MTX formation in the rat. 7-OH-MTX concentrations in bile declined monophasically with a half-life of 29.4 min, while MTX showed a biphasic elimination with initial and second phase half-lives of 23.1 and 86.4 min, respectively. Bile was the major excretory route for MTX and 7-OH-MTX, with 50% of the dose recovered as the parent compound and 3.6% as the metabolite. There was no difference in urinary recovery of MTX in bile-drained and control animals, indicative of insignificant enterohepatic circulation of MTX. This was further corroborated by the finding of just 2.1% urinary recovery of MTX in rats who received previously collected MTX-containing bile through a duodenal catheter. Serum concentration curves were analyzed according to a three-compartment open model with an initial elimination half-life of 1.7–3.3 min, a second phase half-life of 15.4–21.0 min, and a terminal phase half-life of 119–240 min. Our finding of 7-OH-MTX formation and high biliary levels of the metabolite in the rat, can be used as basis for studies of interactions with in vivo MTX conversion to the 7-hydroxy metabolite.

¹ Fellow of the Norwegian Cancer Society. To whom requests for reprints should be addressed, at the Department of Pharmacology, Institute of Medical Biology, University of Tromsø, P.O. Box 977, N-9001 Tromsø, Norway.

² Postdoctoral Fellow of the Norwegian Cancer Society. Present address: Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

Received 10/19/88. Revised 1/31/89. Accepted 2/ 7/89.

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