RT Journal Article
SR Electronic
T1 Evaluation of Cynomolgus Monkey Pregnane X Receptor, Primary Hepatocyte, and in Vivo Pharmacokinetic Changes in Predicting Human CYP3A4 Induction
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 16
OP 24
DO 10.1124/dmd.109.029637
VO 38
IS 1
A1 Kim, Sean
A1 Dinchuk, Joseph E.
A1 Anthony, Monique N.
A1 Orcutt, Tami
A1 Zoeckler, Mary E.
A1 Sauer, Mary B.
A1 Mosure, Kathleen W.
A1 Vuppugalla, Ragini
A1 Grace, James E.
A1 Simmermacher, Jean
A1 Dulac, Heidi A.
A1 Pizzano, Jennifer
A1 Sinz, Michael
YR 2010
UL http://dmd.aspetjournals.org/content/38/1/16.abstract
AB Monkeys have been proposed as an animal model to predict the magnitude of human clinical drug-drug interactions caused by CYP3A4 enzyme induction. To evaluate whether the cynomolgus monkey can be an effective in vivo model, human CYP3A4 inducers were evaluated both in vitro and in vivo. First, a full-length pregnane X receptor (PXR) was cloned from the cynomolgus monkey, and the sequence was compared with those of rhesus monkey and human PXR. Cynomolgus and rhesus monkey PXR differed by only one amino acid (A68V), and both were highly homologous to human PXR (∼96%). When the transactivation profiles of 30 compounds, including known inducers of CYP3A4, were compared between cynomolgus and human PXR, a high degree of correlation with EC50 values was observed. These results suggest that cynomolgus and human PXR respond in a similar fashion to these ligands. Second, two known human CYP3A4 inducers, rifampicin and hyperforin, were tested in monkey and human primary hepatocytes for induction of CYP3A enzymes. Both monkey and human hepatocytes responded similarly to the inducers and resulted in increased RNA and enzyme activity changes of CYP3A8 and CYP3A4, respectively. Lastly, in vivo induction of CYP3A8 by rifampicin and hyperforin was shown by significant reductions of midazolam exposure that were comparable with those in humans. These results show that the cynomolgus monkey can be a predictive in vivo animal model of PXR-mediated induction of human CYP3A4 and can provide a useful assessment of the resulting pharmacokinetic changes of affected drugs. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics