Metabolic interaction between methotrexate and 4'-(9-acridinylamino)methanesulfon-M-anisidide in the rabbit

The interaction between methotrexate (MTX) and a new acridine antitumor agent and potent aldehyde oxidase inhibitor, 4'-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA), was investigated both in vivo and in vitro. New Zealand White male rabbits were used for the former experiments under three pharmacokinetic designs: (a) a zero order infusion of mAMSA at 9 mg/h to steady state followed by a single i.v. bolus dose of MTX at 50 mg/kg while maintaining the infusion; (b) a zero order infusion of MTX at 7 mg/h to steady state followed by a single i.v. bolus dose of mAMSA at 5 mg/kg while maintaining the infusion, and (c) a zero order infusion of MTX at 3 mg/h to steady state followed by a zero order infusion of mAMSA at 3 mg/h while maintaining the MTX infusion. In (a) while the mean AUC for MTX (15815 +/- 1317 microMmin) with mAMSA (+mAMSA) remained essentially unchanged relative to that without mAMSA (-mAMSA) at the same dose (14832 +/- 5151 microMmin), the mean AUC of the metabolite 7-hydroxymethotrexate (7-OH MTX) decreased from 9338 +/- 3057 (n = 6, -mAMSA) to 5794 +/- 1371 microMmin (n = 6, +mAMSA). Urinary excretion of 7-OH MTX also decreased from 40.3 +/- 9.5% (n = 6) (-mAMSA) to 23.8 +/- 6.1% dose (n = 6) (P less than 0.01) (+mAMSA) in 8 h with essentially no change in MTX excretion. The fractional rate conversion of MTX to this metabolite (fmi) also decreased from 0.60 +/- 0.19 (n = 6) to 0.40 +/- 0.10 (n = 6) (P less than 0.05). No change in terminal half-lives of MTX and 7-OH MTX was apparent. In (b) MTX steady state levels increased with the concomitant decrease in 7-OH MTX levels in the presence of mAMSA such that their concentration ratios (7-OH MTX/MTX) decreased to 43, 54, 75, and 76% of the pre-mAMSA values, respectively, in four rabbits. In the presence of mAMSA, clearance of MTX at steady state decreased significantly relative to those without mAMSA. Similar results were also observed in (c) except that the perturbation of MTX metabolism was more profound consistent with the experimental setting. No change in protein binding of MTX or the metabolite was apparent in the presence of mAMSA. Rabbit liver homogenate was used in the in vitro experiments which yielded a classical competitive inhibition on the double-reciprocal plot when conversion of MTX to 7-OH MTX was monitored.(ABSTRACT TRUNCATED AT 400 WORDS)