CHRONIC PHENOBARBITAL THERAPY REDUCES PLASMA BENZODIAZEPINE CONCENTRATIONS AFTER INTRAVENOUS AND RECTAL ADMINISTRATION OF DIAZEPAM IN THE DOG

Citation
So. Wagner et al., CHRONIC PHENOBARBITAL THERAPY REDUCES PLASMA BENZODIAZEPINE CONCENTRATIONS AFTER INTRAVENOUS AND RECTAL ADMINISTRATION OF DIAZEPAM IN THE DOG, Journal of veterinary pharmacology and therapeutics, 21(5), 1998, pp. 335-341
Citations number
36
Categorie Soggetti
Pharmacology & Pharmacy","Veterinary Sciences
ISSN journal
01407783
Volume
21
Issue
5
Year of publication
1998
Pages
335 - 341
Database
ISI
SICI code
0140-7783(1998)21:5<335:CPTRPB>2.0.ZU;2-S
Abstract
Disposition of diazepam (DZ) 2 mg/kg after single bolus intravenous (i .v.) and rectal (p.r.) administration before and after 30 day oral phe nobarbital therapy was investigated in normal dogs, Adverse cardiovasc ular and neurologic effects for each drug, dosage and route of adminis tration were evaluated. Plasma benzodiazepine concentrations were dete rmined by fluorescence polarization immunoassay, This assay measured D Z and its active metabolites, oxazepam and nordiazepam to provide a to tal benzodiazepine concentration. Mean peak plasma concentrations afte r i.v, administration were 5963 and 5565 ng/mL, before and after pheno barbital treatment, respectively. After p.r. administration, mean peak concentrations were 629 ng/mL and 274 ng/mL and were reached within 3 0 min before and after phenobarbital treatment, respectively. The targ et concentration for potential seizure control (i.e. 150 ng/mL) was at tained in five dogs in the post phenobarbital p.r. group with a median time to attainment of target concentration of 8 min, The administrati on of phenobarbital resulted in significantly lower areas under the pl asma concentration vs, time curves (AUC) for both i.v. and p.r. admini stration. Similarly, there was a reduction in maximal plasma concentra tion, bioavailability (F), mean residence time, and time to target and peak concentrations in the postphenobarbital p.r. group, as compared to the prephenobarbital p.r. group, Adverse cardiovascular and neurolo gic effects were short-lived and were considered of minor clinical sig nificance. Overall, chronic phenobarbital therapy in the dog reduces t otal benzodiazepine concentration after i.v. and p.r. administration p resumably due to increased hepatic clearance of DZ and its metabolites oxazepam and nordiazepam. Despite this finding, administration of DZ rectally at 2 mg/kg may be a clinically useful alternative to i.v. adm inistration to treat emergency seizures when i.v. therapy is not possi ble in dogs on chronic phenobarbital therapy.