Species differences in oral bioavailability of methotrexate between rats and monkeys

The contributions of incomplete absorption and a first-pass effect to the l ow bioavailability (BA) of methotrexate (MTX) were evaluated pharmacokineti cally in rats and monkeys which respectively have a lower and higher aldehy de oxidase (AO) activity than humans. Plasma concentration profiles of MTX in rats showed linear and nonlinear pharmacokinetics respectively after int ravenous (i.v.) and oral dosing of 0.1, 0.5 or 2.5 mg/kg MTX. In rats, most of the dose was excreted as the parent compound into bile and urine after i.v. dosing of 0.5 mg/kg MTX, while the radioactivity was largely eliminate d in expired air after oral dosing of 0.5 mg/kg C-14-MTX. Elimination in ex pired air fell markedly following antibiotics treatment. 7-Hydroxymethotrcx ate (7-OH-MTX), formed from MTX by AO, was detected in monkey plasma after i.v. and ol al dosing of 0.5 mg/kg MTX, but not in rat plasma. The ratio of the cumulative urinary excretion of 7-OH-MTX to MTX in monkeys was higher after oral dosing than after i.v. dosing. The low BA in rats (10% at 0.5 mg /kg) was shown to be mainly due to incomplete absorption, including limited absorption and degradation to 2,4-diamino-N-10-methylpteroic acid (DAMPA) and glutamic acid (Glu) by the carboxypeptidase of intestinal bacteria. The low BA in monkeys (5% at 0.5 mg/kg) was shown to be mainly due to the exte nsive first-pass effect, including metabolism to 7-OH-MTX.