IMPROVEMENT OF BIOAVAILABILITY OF THE HIV PROTEASE INHIBITOR SC-52151IN THE BEAGLE DOG BY COADMINISTRATION OF THE CYP3A4 INHIBITOR, KETOCONAZOLE

1. SC-52151. an HIV protease inhibitor, is mainly metabolized by CYP3A 4 and is poorly bioavailable after oral administration. After i.v. adm inistration of SC-52151 to the female beagle dog (25 mg/kg), SC-52151 was rapidly eliminated in plasma with an elimination half-life of abou t 1 h, a plasma clearance of 44 ml/min/kg and an apparent steady-state volume distribution of 2.2 litre/kg. The high value of plasma clearan ce of SC-52151 suggests an extensive hepatic first-pass metabolism sin ce SC-52151 is highly protein bound and does not partition itself into red blood cells. 2. The extensive hepatic first-pass metabolism was r educed by coadministration of a CYP3A4 inhibitor, ketoconazole. 3. Dog s were dosed daily with ketoconazole at dose of 100 mg ketoconazole pe r dog (similar to 10 mg/kg) for 5 days prior to the initiation of coad ministration of SC-52151 for 15 days. The doses used for SC-52151 was 0, 60 and 120 mg SC-52151/kg/day (divided t.i.d., 8-h dosing interval) . Coadministration of ketoconazole improved the bioavailability of SC- 52151 from 4.1 to 9.6 % and also improved the C-max of SC-52151 from 0 .41 to 0.83 mu g/ml. 4. Although the absolute bioavailability of SC-52 151 was still low (similar to 10 %), the C-max and AUC achieved in thi s study were satisfactory for conducting chronic toxicology studies. N o toxicity associated with the coadministration of ketoconazole was ev ident. Results from this study suggest that coadministration of ketoco nazole might be a practical approach to increase the exposure of SC-52 151 in both preclinical and clinical studies.