METABOLIC PROFILING OF CLOBAZAM, A 1,5-BENZODIAZEPINE, IN RATS

The metabolism of the 1,5-benzodiazepine clobazam (CLBZ) was investiga ted in the rat and in vitro by GC/MS using stable isotope techniques. Coadministration of CLBZ and pentadeuteriophenyl CLBZ to rats facilita ted the identification of 4'-hydroxy CLBZ 7, 4'-hydroxy N-desmethylclo bazam (4'-hydroxy DMC) 5, 3',4'-dihydroxy CLBZ 13, 4'-hydroxy-3'-metho xy CLBZ 14, 3'-hydroxy-4'-methoxy CLBZ 15, and 4'-hydroxy-3'-methoxy D MC 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 metaboli tes in bile and urine, respectively. An unusual in vivo disposition of CLBZ to the O-methyl catechols was discovered. In bile, the para O-me thyl catechol 15 constituted 2% of the O-methyl catechols as a glucuro nide conjugate, in contrast to constituting 30% (of the O-methyl catec hols) as a sulfate. This marks an unprecedented observation of a diffe rent catechol O-methyl isomer ratio within the same biological fluid f or different conjugate pools. The isotope effect associated with the m icrosomal N-demethylation of trideuteriomethyl CLBZ was determined. Th e values of k(H)/k(D), were calculated at 5.07 +/- 0.37 (N = 3) and 3. 88 +/- 0.23 (N = 4) for control and induced microsomes, respectively.