Metabolic profiling of clobazam, a 1,5-benzodiazepine, in rats.
The metabolism of the 1,5-benzodiazepine clobazam (CLBZ) was investigated in the rat and in vitro by GC/MS using stable isotope techniques. Coadministration of CLBZ and pentadeuteriophenyl CLBZ to rats facilitated the identification of 4'-hydroxy CLBZ 7,4'-hydroxy N-desmethylclobazam (4'-hydroxy DMC) 5, 3',4'-dihydroxy CLBZ 13, 4'-hydroxy-3'-methoxy CLBZ 14, 3'-hydroxy-4'-methoxy CLBZ 15, and 4'-hydroxy-3'-methoxy DMC 16 in bile as both glucuronide and sulfate conjugates. Metabolites 7, 13, and 14 were present in urine as sulfate conjugates. 4'-Hydroxy CLBZ and 4'-hydroxy-3'-methoxy CLBZ were the major conjugated metabolites in bile and urine, respectively. An unusual in vivo disposition of CLBZ to the O-methyl catechols was discovered. In bile, the para O-methyl catechol 15 constituted 2% of the O-methyl catechols as a glucuronide conjugate, in contrast to constituting 30% (of the O-methyl catechols) as a sulfate. This marks an unprecedented observation of a different catechol O-methyl isomer ratio within the same biological fluid for different conjugate pools. The isotope effect associated with the microsomal N-demethylation of trideuteriomethyl CLBZ was determined. The values of kH/kD were calculated at 5.07 +/- 0.37 (N = 3) and 3.88 +/- 0.23 (N = 4) for control and induced microsomes, respectively.
Borel
A G
AG
Faculty of Pharmaceutical Sciences, University of British Columbia, Canada.
Abbott
F S
FS
D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D001570:Benzodiazepinones / Q000378:metabolism* / Q000493:pharmacokinetics; D001646:Bile / Q000737:chemistry; D002396:Catechols / Q000138:chemical synthesis / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D000078306:Clobazam; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010636:Phenols / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D002396:Catechols; D010636:Phenols; D001569:Benzodiazepines; D000078306:Clobazam