ABSTRACT
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. (every day for 3 days) followed by triazolam (4 mg/kg p.o.) 24 h after the last dose of rifampicin. Rifampicin and triazolam concentrations and Cyp3a11 RNA expression and activity in the liver were measured over the 4-day period. Elevations in Cyp3a11 RNA expression were observed 24 h after the first dose of rifampicin, reaching a maximum (â¼10 times baseline) after the third dose and were sustained until day 4 and began declining 48 h after the last rifampicin dose. Similar changes in enzymatic activity were also observed. The triazolam serum area under the curve (AUC) was 5-fold lower in mice pretreated with rifampicin, consistent with enzyme induction. The final PK-PD model incorporated rifampicin liver concentration as the driving force for the time-delayed Cyp3a11 induction governed by in vitro potency estimates, which in turn regulated the turnover of enzyme activity. The PK-PD model was able to recapitulate the delayed induction of Cyp3a11 mRNA and enzymatic activity by rifampicin. Furthermore, the model was able to accurately anticipate the reduction in the triazolam plasma AUC by integrating a ratio of the predicted induced enzyme activity and basal activity into the equations describing triazolam pharmacokinetics. In conjunction with the SXR humanized mouse model, this mathematical approach may serve as a tool for predicting clinically relevant drug-drug interactions via pregnane X receptor-mediated enzyme induction and possibly extended to other induction pathways (e.g., constitutive androstane receptor).
Subject(s)
Cytochrome P-450 CYP3A/biosynthesis , Membrane Proteins/biosynthesis , Receptors, Steroid/metabolism , Rifampin/pharmacology , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Enzyme Induction/drug effects , Enzyme Induction/physiology , Humans , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Pregnane X Receptor , Rifampin/pharmacokineticsABSTRACT
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.
Subject(s)
Cytochrome P-450 CYP3A/drug effects , Membrane Proteins/drug effects , Receptors, Steroid/agonists , Rifampin/pharmacology , Animals , Antibiotics, Antitubercular/administration & dosage , Antibiotics, Antitubercular/pharmacology , Cytochrome P-450 CYP3A/metabolism , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Induction/drug effects , Gene Expression Regulation, Enzymologic/drug effects , Humans , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Models, Animal , Pregnane X Receptor , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rifampin/administration & dosage , Species Specificity , Triazolam/pharmacokineticsABSTRACT
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.
