Biotransformation of nitrendipine in rat, dog, and mouse.
14C-Labelled Nitrendipine (Bay e 5009; Baypress, Bayotensin; CAS 39562-70-4) was administered by the oral and intraduodenal route to rats, dogs, and mice (oral dosing only) to elucidate the biotransformation pathways in these three species. The drug was extensively metabolized: 20 biotransformation products were identified by comparison with synthetic reference compounds using two-dimensional TLC, HPLC, GC/radio-GC, combined GC/MS (EI-, CI-mode), FAB-MS, and 1H-NMR-spectroscopy. The metabolites identified accounted for approx. 72 to 73% of the dose administered in rats and dogs (bile and urine) and 48 to 56% in male and female mice (urine only). Based on the structures identified the following biotransformation reactions occurred: Dehydrogenation of the 1,4-dihydropyridine (primary metabolic step), oxidative ester cleavage as further basic biotransformation reaction (also at the dihydropyridine state), hydroxylation of the methyl groups in 2- or 6-position as separated and important metabolic reaction (at the dihydropyridine as well as pyridine state), reduction of the aromatic nitro group (important only in mice) and subsequent acetylation (dog only), and glucuronidation as phase II reaction forming ether and ester type glucuronides.
Scherling
D
D
Institute of Pharmacokinetics, Bayer AG, Wuppertal, Fed. Rep. of Germany.
Karl
W
W
Ahr
H J
HJ
Kern
A
A
Siefert
H M
HM
D000818:Animals; D001711:Biotransformation / Q000502:physiology; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D004950:Esterases / Q000378:metabolism; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006372:Helix, Snails / Q000378:metabolism; D006900:Hydroxylation; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009568:Nitrendipine / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D005965:Glucuronates; D007202:Indicators and Reagents; D009568:Nitrendipine; D004950:Esterases