Metabolism of diltiazem. II. Metabolic profile in rat, dog and man.
The metabolism of diltiazem was studied in male rats and dogs after intravenous administration of 14C-diltiazem.HCl or in men after oral administration of a tablet of diltiazem.HCl. The main metabolites in rat urine, in decreasing order of content, were A4, M6, M4 and M5. The unchanged drug in the urine accounted for only 0.7% of the administered drug based on radioactivity. About 81% of biliary radioactivity in rat was due to water-soluble metabolites and the remainder was mostly acidic metabolites such as A4 and A6. In dog urine, the unchanged drug was most abundant (30.6% of the radioactivity in the 6-h urine), followed by A2, A1 and M2. The main metabolites of diltiazem in rat plasma were A2 and A4, while in dog plasma, the unchanged drug and A2 were found as main components. In human urine, M4, the unchanged drug, A2, MB, MD and M2 were the major components. Acidic metabolites, A1-A4, were found also in human plasma and A2 was the main metabolite found. These results indicated that the main metabolic pathway of diltiazem was an oxidative deamination which is extensive in the rat. Other metabolic pathways recognized in this study were oxidative demethylation, deacetylation, hydroxylation of the aromatic ring and conjugation. Although direct comparison may not be appropriate because of the different routes of administration, the metabolism of diltiazem in man appears to be more similar to that in the dog than that in the rat.
Sugawara
Y
Y
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Nakamura
S
S
Usuki
S
S
Ito
Y
Y
Suzuki
T
T
Ohashi
M
M
Harigaya
S
S
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004110:Diltiazem / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000652:urine; D004285:Dogs; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D004110:Diltiazem