Evaluation of cynomolgus monkey pregnane X receptor, primary hepatocyte, and in vivo pharmacokinetic changes in predicting human CYP3A4 induction.
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 (approximately 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 EC(50) 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.
Kim
Sean
S
Metabolism and Pharmacokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA. sean.kim@bms.com
Dinchuk
Joseph E
JE
Anthony
Monique N
MN
Orcutt
Tami
T
Zoeckler
Mary E
ME
Sauer
Mary B
MB
Mosure
Kathleen W
KW
Vuppugalla
Ragini
R
Grace
James E
JE
Simmermacher
Jean
J
Dulac
Heidi A
HA
Pizzano
Jennifer
J
Sinz
Michael
M
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003001:Cloning, Molecular; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D020902:Hypericum / Q000737:chemistry; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D008874:Midazolam / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D008875:Middle Aged; D023421:Models, Animal; D008969:Molecular Sequence Data; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D010936:Plant Extracts / Q000097:blood / Q000493:pharmacokinetics; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D012293:Rifampin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D013729:Terpenes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D015262:Xenobiotics / Q000493:pharmacokinetics*
D001643:Bridged Bicyclo Compounds; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013729:Terpenes; D015262:Xenobiotics; D010696:Phloroglucinol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; C001654:hyperforin; D012293:Rifampin