Dose-dependent kinetics of aminopyrine metabolism in the rat caused by product inhibition and determined by capillary GLC.

Aminopyrine (DMAP) and its metabolites were estimated in plasma and urine with a newly developed capillary GLC method, using nitrogen detection. Dose-dependent kinetics for DMAP was observed in the rat. An intravenous administration of 30 or 100 mg/kg of DMAP resulted in total body clearance values of 20 +/- 8 and 15 +/- 5 ml/min/kg (mean +/- SD), respectively. These values were associated with terminal half-lives of 45 +/- 10 and 79 +/- 23 min, respectively. Moreover, kinetic values for the primary metabolite monomethyl-4-aminoantipyrine (MMAP) were determined, as MMAP originated from DMAP (both doses). The terminal half-life of MMAP was significantly longer than that of DMAP (123 +/- 93 and 204 +/- 90 min after DMAP doses of 30 and 100 mg/kg, respectively). MMAP is known to inhibit DMAP-N-demethylation in vitro. Furthermore, terminal 14CO2 exhalation measured after in vivo 14C-DMAP administration originates largely from 14C-MMAP. Pretreatment of rats with MMAP decreased DMAP clearance. These observations indicate that in the rat DMAP metabolism exhibits product inhibition. Since dose-dependent kinetics of DMAP has previously also been observed in man, it is suggested that product inhibition is a determinant for DMAP metabolism both in man and in the rat.