DEVELOPMENT OF AN IN VIVO PRECLINICAL SCREEN MODEL TO ESTIMATE ABSORPTION AND FIRST-PASS HEPATIC EXTRACTION OF XENOBIOTICS. II. USE OF KETOCONAZOLE TO IDENTIFY P-GLYCOPROTEIN/CYP3A-LIMITED BIOAVAILABILITY IN THE MONKEY

• Published in: Drug metabolism and disposition Vol. 32; no. 2; pp. 172 - 177
• Main Authors: WARD, Keith W, STELMAN, Gary J, MORGAN, Jayme A, ZEIGLER, Kelli S, AZZARANO, Leonard M, KEHLER, Jonathan R, MCSURDY-FREED, Jeanelle E, PROKSCH, Joel W, SMITH, Brian R
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.02.2004
• Subjects: Absorption; Administration, Oral; Animals; Area Under Curve; Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors; Aryl Hydrocarbon Hydroxylases - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Biological Availability; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Erythromycin - pharmacokinetics; General pharmacology; Half-Life; Injections, Intravenous; Ketoconazole - blood; Ketoconazole - pharmacokinetics; Liver - metabolism; Macaca fascicularis; Male; Medical sciences; Oxidoreductases, N-Demethylating - antagonists & inhibitors; Oxidoreductases, N-Demethylating - metabolism; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Propranolol - pharmacokinetics; Time Factors; Xenobiotics - pharmacokinetics; Imidazole derivatives; Ketoconazole; Digestive system; Cytochrome P450; Liver; P Glycoprotein; Monkey; Preclinical trial; Bioavailability; In vivo; Vertebrata; Antifungal agent; Mammalia; Absorption; Animal; First pass effect; Primates; Models; Pharmacokinetics; Xenobiotic
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.32.2.172

The effect of P-glycoprotein (Pgp) and/or CYP3A on the disposition of xenobiotics has been extensively investigated and is often of interest during drug discovery lead optimization. We have previously described a monkey pharmacokinetic screen to rapidly estimate absorption and first-pass extraction. In the present work, this monkey screen has been expanded to include an assessment of Pgp/CYP3A effects on absorption and first-pass extraction, using ketoconazole as a prototypic dual Pgp/CYP3A inhibitor. To generate a ketoconazole dosing regimen, the pharmacokinetics of ketoconazole were first determined in the monkey and were found to be consistent with that previously described in the rat, dog, and human. Dose-ranging experiments demonstrated that a single 10-mg/kg intraduodenal ketoconazole dose would provide an appropriate exposure; this dose was used throughout subsequent interaction experiments. Next, erythromycin and propranolol were explored as positive and negative control substrates for Pgp/CYP3A interactions, respectively. As anticipated, ketoconazole produced no change in the absorption or first-pass extraction of propranolol but resulted in a substantial increase in absorption and decrease in first-pass extraction of erythromycin. Finally, this ketoconazole-based monkey screen was deployed in a drug discovery setting, and examples of such use are presented. These experiments have allowed a more complete characterization of ketoconazole as a prototypic dual Pgp/CYP3A inhibitor and its use as a tool in a preclinical setting and further demonstrate the use of the monkey to investigate the role of Pgp/CYP3A in limiting the oral bioavailability of new drug candidates.