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Metabolic Interaction between Methotrexate and 4'-(9-Acridinylamino)methanesulfon-M-anisidide in the Rabbit¹

School of Pharmacy and Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033

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 µMmin) with mAMSA (+mAMSA) remained essentially unchanged relative to that without mAMSA (-mAMSA) at the same dose (14832 ± 5151 µMmin), the mean AUC of the metabolite 7-hydroxymethotrexate (7-OH MTX) decreased from 9338 ± 3057 (n = 6, -mAMSA) to 5794 ± 1371 µMmin (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 <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 < 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. A Dixon plot gave an apparent K_i of mAMSA of approximately 2.5 x 10^-6 M. Thus, these results strongly suggest that the perturbation of MTX pharmacokinetics by mAMSA is mainly due to inhibition of 7-OH MTX formation, consistent with mAMSA being a potent aldehyde oxidase inhibitor previously reported.

¹ Supported by USPHS Grant CA14089 for the USC Comprehensive Cancer Center Core Grant of the Pharmacoanalytic Laboratory. Presented in part at the 77th Annual Meeting of the American Association of Cancer Research, 1986.

² To whom requests for reprints should be addressed, at USC School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033.

Received 2/13/87. Revised 2/ 8/88. Revised 5/31/88. Accepted 6/ 6/88.

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