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Pharmacokinetics of 7-hydroxy-methotrexate and methotrexate in the rat.

To investigate the pharmacokinetics of the active metabolite of methotrexate (MTX), 7-hydroxy-methotrexate (7-OH-MTX), 1 mg/kg of the compound was administered as single intravenous bolus injections to 6 unanaesthetized rats. For comparison, 1 mg/kg of the parent drug MTX was given to the same number of animals. Venous blood samples were drawn at intervals for a total of 120 min., and thereafter the rats were sacrificed and tissue samples were obtained from the brain, lungs, liver, kidneys, testes, fat, and muscle. Pharmacokinetics of 7-OH-MTX and MTX were biphasic, with a significantly (P less than 0.05) smaller central compartment of distribution (Vc) and a longer second phase half-life (t1/2(beta)) for 7-OH-MTX. MTX tissue concentrations exceeded those of 7-OH-MTX in all tissues examined. The highest 7-OH-MTX concentrations were found in renal tissue. It is implied that 7-OH-MTX is less extensively distributed than the parent compound.