Development of an in vivo rat screen model to predict pharmacokinetic interactions of CYP3A4 substrates.
With the advent of polytherapy, drug interactions have become a common clinical problem. Although in vitro data are routinely used for the prediction of drug interactions, in vitro systems are not dynamic and sometimes fail to predict drug interactions. We sought to use the rat as an in vivo screening model to predict pharmacokinetic interactions with ketoconazole. The pharmacokinetic studies were conducted following an oral dose of CYP3A substrates and an optimized oral regimen of ketoconazole. In vitro reaction phenotyping was conducted using individual human and rat cDNA-expressed CYP enzymes and human or rat liver microsomes in the presence of ketoconazole. The in vitro experiments indicated that the test compounds were largely metabolized by CYP3A in both human and rat. The compounds could be rank-ordered with respect to the increase in C(max) and area under the curve (AUC) values relative to midazolam in the presence of ketoconazole. The degree of pharmacokinetic interaction with ketoconazole was dependent, in part, upon their in vitro metabolism in the presence of rat CYP3A1/3A2 and in rat and human microsomes, co-incubated with ketoconazole, and on their fraction metabolized (f(m)) in the rat relative to other disposition pathways. Based on the rank-order of interaction, the compounds could be prioritized for further preclinical development.
Mandlekar
S V
SV
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA.
Rose
A V
AV
Cornelius
G
G
Sleczka
B
B
Caporuscio
C
C
Wang
J
J
Marathe
P H
PH
D000818:Animals; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D015262:Xenobiotics / Q000008:administration & dosage / Q000493:pharmacokinetics
D011994:Recombinant Proteins; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D007654:Ketoconazole