RESUMEN
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).
Asunto(s)
Citocromo P-450 CYP3A/biosíntesis , Proteínas de la Membrana/biosíntesis , Receptores de Esteroides/metabolismo , Rifampin/farmacología , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inducción Enzimática/efectos de los fármacos , Inducción Enzimática/fisiología , Humanos , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Receptor X de Pregnano , Rifampin/farmacocinéticaAsunto(s)
Hidrocarburo de Aril Hidroxilasas/metabolismo , Pirazoles/farmacocinética , Sulfonamidas/farmacocinética , Alelos , Área Bajo la Curva , Hidrocarburo de Aril Hidroxilasas/genética , Celecoxib , Línea Celular Tumoral , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Inhibidores de la Ciclooxigenasa 2/farmacocinética , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Pirazoles/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sulfonamidas/administración & dosificaciónRESUMEN
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.
Asunto(s)
Citocromo P-450 CYP3A/efectos de los fármacos , Proteínas de la Membrana/efectos de los fármacos , Receptores de Esteroides/agonistas , Rifampin/farmacología , Animales , Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/farmacología , Citocromo P-450 CYP3A/metabolismo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inducción Enzimática/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Modelos Animales , Receptor X de Pregnano , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Rifampin/administración & dosificación , Especificidad de la Especie , Triazolam/farmacocinéticaRESUMEN
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.