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
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.