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 N detection. Dose-dependent kinetics for DMAP was observed in the rat. I.v. administration of 30 or 100 mg/kg of DMAP resulted in total body clearance values of 20 .+-. 8 and 15 .+-. 5 ml/min per kg (mean .+-. SD), respectively. These values were associated with terminal half-lifes of 45 .+-. 10 and 79 .+-. 23 min, respectively. 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 inhibits DMAP-N-demethylation in vitro. Terminal 14CO2 exhalation measured after the in vivo 14C-DMAP administration originates largely from 14C-MMAP. Pretreatment of rats with MMAP decreased DMAP clearance. Evidently, in the rat DMAP metabolism exhibits product inhibition. Since dose-dependent kinetics of DMAP has also been observed in man, product inhibition may be a determinant for DMAP metabolism both in man and in the rat.