Metabolism of barnidipine hydrochloride, a potent calcium antagonist, in rat and dog.
1. In vitro experiments in the rat indicated that barnidipine was metabolized extensively in the liver and was catalyzed by P450s. 2. After oral dosing, nine metabolites were identified in the urine and bile of rat and dog. No unchanged drug was detected in urine and bile. Ester hydrolysis and pyridine formation were the main metabolic pathways in urine in both species, whereas glucuronide conjugates of the debenzylated metabolite and the hydrolyzed pyrrolidine ester were noted in bile. 3. The metabolism of barnidipine in the rat and dog were qualitatively similar. Metabolites are generated by one or several of the following pathways: (a) N-debenzylation of the side chain, (b) hydrolysis of the pyrrolidine ester, (c) oxidation of the dihydropyridine ring to a pyridine ring, (d) hydrolysis of the methylester, (e) reduction of the nitro group to the amino group, and (f) conjugation of the generated metabolites with glucoronic acid.
Teramura
T
T
Drug Metabolism Department, Yamanouchi Pharmaceutical Co. Ltd, Tokyo, Japan.
Tokunaga
T
T
Matsumoto
H
H
Watanabe
T
T
Higuchi
S
S
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000493:pharmacokinetics; D003600:Cytosol / Q000378:metabolism; D004285:Dogs; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013347:Subcellular Fractions / Q000378:metabolism
D002121:Calcium Channel Blockers; C050699:mepirodipine; D009543:Nifedipine