Application of the stable isotope technique to the elucidation of the saturation phenomenon of nicardipine hydrochloride metabolizing enzyme activity in dogs.
The pharmacokinetics of 2-(N-benzyl-N-methylamino)ethyl methyl 2,6-dimethyl 4-(m-nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylate hydrochloride (nicardipine hydrochloride) was studied in dogs by using two deuterium labelled compounds (N-[2H3]methyl and N-[2H7]benzyl derivatives). The biological isotope effect of the [2H7]derivative, which was calculated from the half-lives in vivo and the metabolic rates in vitro, was 1.37 and 1.36, respectively, suggesting that debenzylation in the liver was one of the rate limiting steps of elimination of the drug, while the [2H3] derivative did not show this effect. The [2H3] derivative was administered orally or intravenously to dogs 2 h after oral administration of the non-labelled compound, and the plasma concentration of the [2H3] derivative was determined by the selected ion monitoring method. The biological half-lives, AUC and systemic availability increased with increasing doses of non-labelled nicardipine hydrochloride, while plasma clearance decreased, suggesting that the hepatic enzyme activity metabolizing the drug was partly saturated by the drug or its metabolites.
D000818:Animals; D003903:Deuterium; D004285:Dogs; D008401:Gas Chromatography-Mass Spectrometry; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D009529:Nicardipine; D009543:Nifedipine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism*; D014665:Vasodilator Agents / Q000097:blood / Q000378:metabolism*
D011725:Pyridines; D014665:Vasodilator Agents; D003903:Deuterium; D009529:Nicardipine; D009543:Nifedipine