Pharmacokinetics and electroencephalographic effects of ketoconazole in the rat

To evaluate methodology for in vivo interaction studies of benzodiazepines (BZs) and ketoconazole (KCZ) in animal models, this study assessed the pharmacokinetics 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(-2). 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 concentrations showed an apparent nonlinear pattern of decline with a short half-life (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 pg mL(-1) until at least 500 min after the initial dose. These results provide the basis for design of animal models for in vivo assessment of interactions of BZs and KCZ.