Pharmacokinetics and CSF Entry of Flurazepam in Dogs

Abstract

Anesthetized dogs received a single 1.0-mg/kg intravenous dose of flurazepam hydrochloride, following which multiple blood and cerebrospinal fluid (CSF) samples were taken over the next 8 h. Concentrations of flurazepam and its metabolite, desalkylflurazepam, were determined by gas chromatography with electron-capture detection. Mean kinetic variables for flurazepam were: volume of distribution 7.9 1/kg, elimination half-life 2.3 h, clearance 37 ml/min/kg, serum free fraction 25% unbound. The metabolic product desalkylflurazepam appeared in serum in low concentrations, and was eliminated with a half-life of 4.9 h. Flurazepam rapidly entered CSF, then was eliminated in parallel with flurazepam in serum. However, the extent of entry into CSF was limited, with the mean ratio of area under the curve for CSF versus serum (0.24) nearly identical to the serum free fraction. Thus, intravenous flurazepam in dogs is characterized by extensive distribution, high clearance, and short half-life. Entry into CSF is rapid, and appears governed by passive diffusion. The extent of CSF entry is limited by protein binding in serum.

Pharmacokinetics and preliminary observations of behavioral changes following administration of midazolam to dogs

“…Reported values for mean tIhp and Cl in man range from 1.9-2.5 h and 6.7-10.8 ml/min/kg, respectively (Greenblatt et al, 1981;Greenblatt et al, 1984;Langlois et al, 1987;Ochs, Greenblatt & Knuchel, 1985;Puglisi et al, 1978;Smith et al, 198 1). This is not surprising considering dogs are able to metabolize other benzodiazepines much more rapidly than man (Klotz, Antonin & Bieck, 1976;Ochs et al, 1988).…”