title: Metabolism of clentiazem in rats.
abstract: Following oral dosing of [14C]clentiazem to rats the metabolites in urine and bile were separated and their chemical structures were investigated by HPLC and GC-MS analyses. Fifteen basic, 6 acidic, 2 neutral and 4 conjugated metabolites were found in urine and/or bile. Eight basic metabolites (MB1-8) were identified as the synthetic compounds; deacetyl clentiazem (MB1), N-monodemethyl clentiazem (MB2), deacetyl-N-monodemethyl clentiazem (MB3), deacetyl-O-demethyl clentiazem (MB4), N-monodemethyl-O-demethyl clentiazem (MB5), deacetyl-N-monodemethyl-O-demethyl clentiazem (MB6), O-demethyl clentiazem (MB7) and N-didemethyl clentiazem (MB8). The chemical structures of seven basic metabolites (MB9-15) were assigned as follows, deacetyl-N-didemethyl clentiazem (MB9), O-demethyl-N-didemethyl clentiazem (MB10), deacetyl-O-demethyl-N-didemethyl clentiazem (MB11), N-monodemethyl-2-hydroxy-methoxyphenyl clentiazem (MB12), deacetyl-2-hydroxy-methoxyphenyl clentiazem (MB13), deacetyl-N-monodemethyl-2-hydroxy-methoxyphenyl clentiazem (MB14) and deacetyl-N-didemethyl-2-hydroxy-methoxyphenyl clentiazem (MB15). Four acidic metabolites were identified as the synthetic compounds: (+)-(2S,3S)-3-(acetyloxy)-8-chloro-3,4-dihydro-2-(4-methoxyphenyl) -4-oxo-1, 5-benzothiazepin-5(2H)-acetic acid (MA1), deacetyl-MA1 (MA2), O-demethyl-MA1 (MA3) and deacetyl-O-demethyl-MA1 (MA4); and the two remaining acidic metabolites, MA5 and MA6, were presumed to be hydroxylated MA3 and MA4, respectively. Two neutral metabolites were identified as the synthetic compounds; (+)-(2S,3S)-3-(acetyloxy)-8-chloro-3,4-dihydro-2-(4-methoxyphenyl) -4-oxo-1, 5-benzothiazepin-5(2H)-acetonitrile (MN1) and deacetyl MN1 (MN2). Other two metabolites conjugated with glucuronic acid were found in bile and the structures were presumed to be 8-chloro-2,3-dihydro-3-hydroxy-5-(2-hydroxyethyl)-2-(4-hydroxyphenyl)-1, 5-benzothiazepin-4(5H)-one (MN3) and 2-methoxyphenyl MN3 (MN4). The glucuronide or sulfate of MA4 was also detected. These metabolites were formed by a number of pathways including deacetylation, deamination, N-demethylation, O-demethylation, aromatic hydroxylation and conjugation.
authors.affiliation: Research Laboratory of Drug Metabolism, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Sugawara
authors.forename: T
authors.initials: T
authors.lastname: Fukushima
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.forename: M
authors.initials: M
authors.lastname: Ohashi
authors.forename: O
authors.initials: O
authors.lastname: Takaiti
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D001646:Bile / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; C056595:clentiazem; D004110:Diltiazem