Quantitative relationship between rifampicin exposure and induction of Cyp3a11 in SXR humanized mice: extrapolation to human CYP3A4 induction potential.
The SXR humanized mouse model was used to quantitatively assess an in vivo induction response of the human PXR agonist, rifampicin. Three days of rifampicin treatment increased RNA expression and microsomal enzyme activity of CYP3A11, as well as significantly reduced triazolam plasma exposure. These results indicate that the humanized SXR mouse can be used as a model to predict human CYP3A4 induction and the resulting pharmacokinetic changes of CYP3A4 substrates in humans.
Kim
Sean
S
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Wallingford, CT 06492, USA. sean.kim@bms.com
Pray
Devin
D
Zheng
Ming
M
Morgan
Daniel G
DG
Pizzano
Jennifer G
JG
Zoeckler
Mary E
ME
Chimalakonda
Anjaneya
A
Sinz
Michael W
MW
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D023421:Models, Animal; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists*; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D013045:Species Specificity; D014229:Triazolam / Q000493:pharmacokinetics
D000904:Antibiotics, Antitubercular; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D014229:Triazolam; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D012293:Rifampin