To evaluate methodology for in vivo interaction studies of benzodiazepines
(BZs) and ketoconazole (KCZ) in animal models, this study assessed the phar
macokinetics and electroencephalographic (EEG) effect of KCZ, and suitable
dosage regimens of KCZ to maintain sufficiently high KCZ concentrations to
inhibit metabolism of BZs in rats. Rats were injected intraperitoneally (i.
p.) with KCZ 10 mg kg(-1) No significant EEG change was detected regardless
of serum KCZ concentration, indicating that the EEG changes after both BZ
and KCZ administration can be attributed entirely to BZ. Serum KCZ concentr
ations showed an apparent nonlinear pattern of decline with a short half-li
fe (1.38 h). An additional dose of 5 mg kg(-1) i.p. given 180 min after the
initial dose sustained KCZ concentrations above 2 mu g mL(-1) until at lea
st 500 min after the initial dose. These results provide the basis for desi
gn of animal models for in vivo assessment of interactions of BZs and KCZ.
Copyright (C) 1999 John Wiley & Sons, Ltd.