ABSORPTION OF DIAZEPAM AFTER ITS RECTAL ADMINISTRATION IN DOGS

A cross-over study was performed in 6 healthy mixed-breed dogs and 4 h ealthy Beagles. Diazepam was administered per rectum to Beagles (0.5 m g/kg of body weight) and mixed-breed dogs (2 mg/kg), and Iv (0.5 mg/kg ) to both groups of dogs. Each dog received the drug by both routes, w ith a 1-week washout period between dosages. After diazepam administra tion, blood samples were collected to measure plasma concentration of diazepam and its active metabolites, desmethyldiazepam and oxazepam, b y use of reverse-phase high-performance liquid chromatography (HPLC). Systemic availability was assessed by comparing the area under the cur ve for diazepam metabolites for each route of administration. Mean (+/ - so) diazepam concentrations in plasma after rectal administration we re low in comparison with those obtained after Iv administration, with systemic availability of only 7.4 (+/- 5.9) and 2.7 (+/- 3.2)% for th e high and low dose, respectively. However, diazepam was converted to its metabolites within minutes after administration. Accounting for th e total concentration of benzodiazepines (diazepam plus desmethyldiaze pam and oxazepam) in plasma, systemic availability was 79.9 (+/- 20.7) and 66.0 (+/- 23.8)% for the high and low dosage, respectively. After IV administration, diazepam concentration decreased, with a half-life of only 14 to 16 minutes, but desmethyldiazepam and oxazepam concentr ations decreased more slowly, with a half-life of 2.2 to 2.8 hours and 3.5 to 5.1 hours, respectively. Each of the metabolites is reported t o have anticonvulsant activity. After rectal administration of the hig h dose, mean total benzodiazepine concentration was above 1.0 mu g/ml within 10 minutes and was maintained above this concentration for at l east 6 hours. We conclude that diazepam is absorbed after rectal admin istration in dogs, and that the pharmacologic effects are probably cau sed by the active metabolites, not the parent drug. Samples also were analyzed by use of a nonspecific commercial benzodiazepine fluorescenc e polarization immunoassay (FPIA). Correlation between the FPIA and HP LC assay was strongest for diazepam (R(2) = 0.84), weak for desmethyld iazepam (R(2) = 0.09), and nonexistent for oxazepam. We conclude from a comparison of assays that HPLC is preferred over the FPIA method for measuring benzodiazepines in dogs.