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.
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.
Ward
Keith W
KW
Preclinical Drug Discovery, Cardiovascular & Urogenital CEDD, GlaxoSmithKline, King of Prussia, PA 19406, USA. Keith_W_Ward@GSK.com
Stelman
Gary J
GJ
Morgan
Jayme A
JA
Zeigler
Kelli S
KS
Azzarano
Leonard M
LM
Kehler
Jonathan R
JR
McSurdy-Freed
Jeanelle E
JE
Proksch
Joel W
JW
Smith
Brian R
BR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004917:Erythromycin / Q000493:pharmacokinetics; D006207:Half-Life; D007275:Injections, Intravenous; D007654:Ketoconazole / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011433:Propranolol / Q000493:pharmacokinetics; D013997:Time Factors; D015262:Xenobiotics / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015262:Xenobiotics; D004917:Erythromycin; D011433:Propranolol; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D007654:Ketoconazole