title: Improvement of bioavailability of the HIV protease inhibitor SC-52151 in the beagle dog by coadministration of the CYP3A4 inhibitor, ketoconazole.
abstract: 1. SC-52151, an HIV protease inhibitor, is mainly metabolized by CYP3A4 and is poorly bioavailable after oral administration. After i.v. administration of SC-52151 to the female beagle dog (2.5 mg/kg), SC-52151 was rapidly eliminated in plasma with an elimination half-life of about 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 clearance of SC-52151 suggests an extensive hepatic first-pass metabolism since SC-52151 is highly protein bound and does not partition itself into red blood cells. 2. The extensive hepatic first-pass metabolism was reduced by coadministration of a CYP3A4 inhibitor, ketoconazole. 3. Dogs were dosed daily with ketoconazole at dose of 100 mg ketoconazole per dog (approximately 10 mg/kg) for 5 days prior to the initiation of coadministration 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 Cmax of SC-52151 from 0.41 to 0.83 microgram/ml. 4. Although the absolute bioavailability of SC-52151 was still low (approximately 10%), the Cmax and AUC achieved in this study were satisfactory for conducting chronic toxicology studies. No toxicity associated with the coadministration of ketoconazole was evident. Results from this study suggest that coadministration of ketoconazole might be a practical approach to increase the exposure of SC-52151 in both preclinical and clinical studies.
authors.affiliation: G.D. Searle R & D, Skokie, IL 60077, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Yuan
authors.forename: J C
authors.initials: JC
authors.lastname: Stolzenbach
authors.forename: C M
authors.initials: CM
authors.lastname: Salamon
authors.forename: S S
authors.initials: SS
authors.lastname: Snook
authors.forename: G L
authors.initials: GL
authors.lastname: Schoenhard
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity; D006207:Half-Life; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007654:Ketoconazole / Q000493:pharmacokinetics* / Q000633:toxicity; D008657:Metabolic Clearance Rate; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D007527:Isoenzymes; D014508:Urea; C079293:SC 52151; D007654:Ketoconazole