RT Journal Article
SR Electronic
T1 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
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 172
OP 177
DO 10.1124/dmd.32.2.172
VO 32
IS 2
A1 Keith W. Ward
A1 Gary J. Stelman
A1 Jayme A. Morgan
A1 Kelli S. Zeigler
A1 Leonard M. Azzarano
A1 Jonathan R. Kehler
A1 Jeanelle E. McSurdy-Freed
A1 Joel W. Proksch
A1 Brian R. Smith
YR 2004
UL http://dmd.aspetjournals.org/content/32/2/172.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics