Metabolism of Cloxazolam. I. Distribution, Excretion and Biotransformation in Rats and Mice

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The distribution, excretion and biotransformation of ¹⁴C-cloxazolam were studied in rats and mice. The tissue concentration reached the maximum at about 1 and 3 hr after oral administration to rats and mice, respectively. The brain concentration was higher and lasted longer in mice than in rats. In the whole-body autoradiograms of mice, no significant radioactivity was detected in the tissues except the liver after 24 hr and the radioactivity disappeared almost completely after 72 hr. The recovery of radioactivity was considerably higher in the feces than in the urine and was about the same regardless of the route of administration in both rats and mice. In the in situ cannulated rats, the most of the oral dose was recovered in the bile in 24 hr period. Eighteen radioactive metabolites were detected in the liver, urine and feces after oral administration of ¹⁴C-cloxazolam. Among them, eight metabolites including 7-chloro-2, 3-dihydro-5-[o-chlorophenyl]-2H-1, 4-benzodiazepin-2-one, 7-chloro-5-[o-chlorophenyl]-1, 3-dihydro-3-hydroxy-2H-1, 4-benzodiazepin-2-one (COX) and 2-amino-3-hydroxy-2', 5-dichlorobenzophenone (ADCB-OH) were isolated and identified. The main metabolites in the mouse urine were the glucuronides of COX and ADCB-OH, while in the rat urine two unidentified metabolites in addition to the above two. In the mouse feces, COX and ADCB-OH and their conjugates were the main metabolites, while in the rat feces a much larger number of metabolites were detected.