EFFECTS OF A 44-DAY ADMINISTRATION OF PHENOBARBITAL ON DISPOSITION OFCLORAZEPATE IN DOGS

The disposition of clorazepate, a benzodiazepine anticonvulsant, was d etermined in dogs after administration of a single oral dose of cloraz epate (2 mg/kg of body weight) and after oral administration of cloraz epate (2 mg/kg, q 12 h) concurrently with phenobarbital (5 mg/kg, q 12 h) for 44 consecutive days. Serum concentrations of nordiazepam, the active metabolite of clorazepate, were measured. After a single oral d ose of clorazepate, maximal nordiazepam concentrations ranged from 569 .6 to 1,387.9 ng/ml (mean, 880.2 +/- 248.9 ng/ml) and were detected 16 .8 to 131.4 minutes (mean, 85.2 +/- 36 minutes) after dosing. After ad ministration of phenobarbital for 44 consecutive days, maximal nordiaz epam concentrations were significantly (P < 0.01) lower, ranging from 209.6 to 698.5 ng/ml (mean, 399.3 +/- 155.6 ng/ml) at 68.4 to 145.8 mi nutes (mean, 93 +/- 25.8 minutes) after dosing. Mean area under the cu rve (AUC) on day 1 (mean, 3.37 +/- 0.598 ng.min/ml) was significantly (P < 0.001) greater than AUC on day 44 (1.66 +/- 0.308 ng.min/ml). Ora l clearance was significantly (P < 0.01) greater on day 44 (12.44 +/- 2.55 ml/min/kg), compared with that on day 1 (6.16 +/- 1.35 ml/min/kg) . Values for area under the first moment curve, oral volume of distrib ution, mean residence time, and elimination half-life were not signifi cantly altered by concurrent administration of phenobarbital. Administ ration of phenobarbital altered the disposition of clorazepate such th at the amount of nordiazepam in circulation during each dose interval was significantly reduced. Adequate control of seizures in epileptic d ogs, therefore, may require higher dosages of clorazepate when it is c oadministered with phenobarbital.