Biotransformation of nifedipine in rat and dog.
Following oral and/or intraduodenal administration, the biotransformation of 14C-labelled nifedipine (dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3, 5-dicarboxylate, Bay a 1040, Adalat, CAS 21829-25-4) has been reinvestigated in rats and dogs (dose: 5 mg/kg body weight in both species) to complete the metabolic data. Thirteen metabolites were isolated from the perfusate and bile of the isolated perfused rat liver model. Their structures were elucidated by spectroscopic methods (FAB-MS, combined GC/MS, NMR). The analyzed samples were used for the chromatographic (HPLC) comparison with urine and bile from the in vivo studies. The metabolites identified in rat urine (oral dose) account for 47.4% of the dose administered. 82.8% (rat) and 62.8% (dog) of the dose, resp., could be attributed to known structures in urine and bile following intraduodenal administration. Based on the structures identified the following biotransformation steps occurred: dehydrogenation of the 1,4-dihydropyridine system, hydroxylation of the methyl groups at 2- or 6-position followed by glucuronidation or by subsequent oxidation to the carboxylic acid, and oxidative ester cleavage.
Scherling
D
D
Institute of Pharmacokinetics, Bayer AG, Wuppertal, Fed. Rep. of Germany.
Karl
W
W
Radtke
M
M
Ahr
H J
HJ
Siefert
H M
HM
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007441:Intubation, Gastrointestinal; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009543:Nifedipine / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar
D007202:Indicators and Reagents; D009543:Nifedipine