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.
D000818:Animals; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate