Pharmacokinetic-pharmacodynamic modeling of rifampicin-mediated Cyp3a11 induction in steroid and xenobiotic X receptor humanized mice.

The purpose of this study was to develop a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to describe the effects of rifampicin on hepatic Cyp3a11 RNA, enzymatic activity, and triazolam pharmacokinetics. Rifampicin was administered to steroid and xenobiotic X receptor (SXR) humanized mice at 10 mg/kg p.o.

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.

The utility of stable cell lines to assess species differences in PXR transactivation.

A stable cell line was developed to assess activation of rat pregnane X receptor (rPXR) by xenobiotics. Characterization revealed that the greatest response occurred with dexamethasone (6-10 fold increase) while rifampicin failed to transactivate rPXR. Rodent PXR transactivation assays can be used to understand species differences in enzyme induction.