Pharmacokinetics of a nootropic agent, BMY-21502, and its metabolites in beagle dogs

Abstract

A preliminary investigation into the pharmacokinetics of BMY-21502, a nootropic agent, and two of its metabolites, BMY-42191 and BMY-40440, was performed in 4 beagle dogs. Following oral dosing of a solution of BMY-21502 (0.61 mmoles), plasma samples were obtained for 24 h and analyzed for the three analytes by a validated HPLC assay. BMY-21502 was rapidly absorbed (Tmax = 0.5 +/- 0.3 h), followed by a rapid decline of the plasma levels (T1/2 = 0.95 +/- 0.1 h). The hydroxy metabolite, BMY-42191, was rapidly formed and the peak concentrations in plasma were obtained by 2.88 +/- 0.2 h. On the contrary, there was a considerable delay in the peaking of the ketone metabolite, BMY-40440 (Tmax = 6 h). The T1/2 values for BMY-40440 (5.58 +/- 0.5 h) were longer than those for BMY-42191 (4.28 +/- 1.2 h). Comparison of AUC values for BMY-42191 (326.43 +/- 63.3 h x microM) with those of BMY-40440 (67.52 +/- 8.4 h x microM) or BMY-21502 (69.35 +/- 7.3 h x microM) indicated that BMY-42191 was the major circulating species in dog plasma. In conclusion, the preliminary data indicate that the metabolism of BMY-21502 is complex and may encompass hydroxy-ketone metabolic interconversions, as reported for other xenobiotics.