Metabolism of Diltiazem. I. Structures of New Acidic and Basic Metabolites in Rat, Dog and Man

Abstract

The metabolites of diltiazem in the urine of rats, dogs and man and rat bile were investigated. New metabolites including six acidic metabolites (A1-A6) and four basic metabolites (M9, MB, MC, MD) were isolated by high performance liquid chromatography and their structures were characterized by gas chromatography-mass spectrometry. Acidic metabolites A1, A2, A3, A4 and basic metabolite MD identified by comparing their properties with the synthetic compounds ; (+)-(2S, 3S)-2-(4-methoxyphenyl)-3-acetoxy-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepin-5-acetic acid (A1), 3-deacetyl-A1 (A2), O-demethyl-A1 (A3), O-demethyl-3-deacetyl-A1 (A4) and N-didemethyl-diltiazem (MD). All acidic metabolites have a CH₂COOH group which may be formed by oxidative deamination of the CH₂CH₂N (CH₃)₂ group of diltiazem.