Disposition of clorazepate in dogs after single- and multiple-dose oral administration

Abstract

SUMMARY Clorazepate dipotassium was administered orally to 8 healthy dogs at a dosage of 2 mg/kg of body weight, q 12 h, for 21 days. Serum disposition of nordiazepam, the principle metabolite of clorazepate, was determined after the first and last dose of clorazepate. Disposition variables were analyzed by use of model-independent pharmacokinetics by the predictive equations method and the trapezoidal rule method. Complete blood counts, serum chemical analyses, and urinalyses were performed before administration of clorazepate and at 10 and 21 days after administration of clorazepate. Maximal nordiazepam concentrations ranged from 446 to 1,542 ng/ml (814 ± 334 ng/ml), at 59 to 180 minutes (97.9 ± 42.0 minutes) after a single oral dose of clorazepate. Maximal nordiazepam concentrations ranged from 927 to 1,460 ng/ml (1,308 ± 187.6 ng/ml), at 120 to 239 minutes (153 ± 57.9 minutes) after multiple oral doses of clorazepate. Serum disposition was significantly altered after multiple doses of clorazepate. Using data determined by the predictive equations method, the mean residence time after multiple doses (712 ± 214 minutes) was longer (P < 0.05) than after a single dose (527 ± 95.8 minutes). Oral volume of distribution after multiple doses of clorazepate (1.76 ± 0.647 L/kg) was smaller (P < 0.02) than after a single dose (3.18 ± 1.52 L/kg). Oral clearance after multiple doses of clorazepate (3.09 ± 0.726 ml/min/kg) was less (P < 0.001) than after a single dose (6.54 ± 2.15 ml/min/kg). Absorption half-life after multiple doses (72 minutes) was longer (P < 0.01) than after a single dose (33 minutes). The elimination half-life after a single dose (284 minutes) was not significantly different after multiple doses (355 minutes). Significant changes (P < 0.05) in serum chemical values after multiple doses of clorazepate included decreased concentrations of albumin, total protein, and calcium and increased concentrations of urea nitrogen and glucose. Serum activities of alkaline phosphatase and alanine transaminase increased after multiple doses of clorazepate. Significant changes (P < 0.05) in the hemogram included increased total wbc count, segmented neutrophils, lymphocytes, and eosinophils. Urine pH after multiple doses (5.88 ± 0.641) was lower (P < 0.01) than after a single dose (7.44 ± 1.29). All changes in laboratory values remained within our reference ranges. Mild sedation and ataxia developed in only 1 dog after the first dose of clorazepate. These effects were transient and did not redevelop with additional dosing. An oral clorazepate dosage of 2 mg/kg, q 12 h, maintains serum nordiazepam concentrations considered to be therapeutic in human beings (500 to 1,900 ng/ml).