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Evidence of nonlinear pharmacokinetics of methotrexate in the rat.

Three doses (0.31, 3.1 and 31 mg/kg) of methotrexate (MTX) were given intravenously to rats. The resulting concentration-time curves in plasma (normalized by dividing the plasma concentration by a multiple of the dose) were not superimposable, indicating nonlinear plasma pharmacokinetics. In liver, kidney, bone marrow and stomach a tissue-specific, very slowly (or not measurably) decreasing terminal plateau phase could be observed after administration of all three doses. This was explained by a strong binding of MTX to dihydrofolate reductase. The ratio, exchangeable MTX in tissue/plasma concentration, increased in liver and kidney with time after the higher doses, which is in accord with saturable transport to tissues.