Disposition and Metabolic Fate of Clentiazem in Rats and Dogs

• Published in: Biological & pharmaceutical bulletin Vol. 16; no. 7; pp. 647 - 655
• Main Authors: NAKAMURA, Susumu, ITO, Yutaka, FUKUSHIMA, Takeshi, TAKAITI, Osasi, OHASHI, Motoaki, SUGAWARA, Yoichi
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1993; Maruzen; Japan Science and Technology Agency
• Subjects: Animals; Antihypertensive agents; Biological and medical sciences; Biotransformation; Cardiovascular system; clenitazem; Diltiazem - analogs & derivatives; Diltiazem - blood; Diltiazem - metabolism; Diltiazem - pharmacokinetics; Diltiazem - urine; dog; Dogs; Feces - chemistry; Female; Male; Medical sciences; metabolism; Microsomes, Liver - metabolism; Pharmacology. Drug treatments; rat; Rats; Rats, Sprague-Dawley; Sex Characteristics; sex difference; Fissipedia; Carnivora; Rat; Interspecific comparison; Rodentia; Calcium antagonist; Sex; Oral administration; Metabolism; Vertebrata; Mammalia; Animal; Antihypertensive agent; Pharmacokinetics; Dog
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.16.647

The plasma concentrations and time courses of radioactivity and unchanged drug, the excretion of radioactivity into urine and feces, and the proportion of metabolites in plasma and urine were studied after oral administration of [14C]clentiazem to male and female rats and dogs.Apparent sex-related differences were found in the disposition and metabolism of clentiazem in rats. The plasma levels of radioactivity and acidic metabolites were higher in males than in females. The plasma levels of unchanged drug, on the other hand, were about the same in both sexes.Higher conversion of clentiazem to its acidec metabolites in the liver of male rats and higher excretion of the acidic metabolites in the urine of female rats, presumably due to sex-related differences in cytochrome P-450 and renal clearance, respectively, seem to explain these differences in the disposition of clentiazem in male and female rats.No suggestion of a similar sex difference was found in dogs. The plasma concentrations and time courses of radioactivity and unchanged drug in male dogs were similar to those in female dogs, and the excretion of radioactivity in both sexes was also similar. The main plasma metabolite in male and female dogs was O-demethyl clentiazem (MB7).A species difference between rat and dog was suggested, since the major metabolic pathways were different and no sex difference was found in dogs.