Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor

Abstract

Rifampicin, an important drug in the treatment of tuberculosis, is used extensively despite its broad effects on drug-drug interactions, creating serious problems. The clinical importance of such interactions includes autoinduction leading to suboptimal or failed treatment. The concomitantly administered effects of rifampicin on other drugs can result in their altered metabolism or transportation that are metabolised by cytochromes P450 or transported by p-glycoprotein in the gastrointestinal tract and liver. This review paper summarises recent findings with emphases on the molecular mechanisms used to explain these broad drug-drug interactions. In general, rifampicin can act on a pattern: rifampicin activates the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This pattern of action may explain many of the rifampicin inducing drug-drug interactions. However, effects through other mechanisms have also been reported and these make any explanation of such drug-drug interactions more complex.

Figure 1

Target genes activated by rifampicin via PXR and CAR. Rifampicin (Rif) induces nuclear receptors PXR and CAR that in turn activate a set of target genes including phase I enzymes such as CYP2B6, CYP2C8, CYP2C9 and CYP3A4, and phase II enzymes such as UGTs, GSTs and phase III enzymes such as p-glycoprotein. PXR and CAR are also regulated by HNF4α and these target genes are also regulated by Vitamin D3, and dexamethasone (Dex).

Figure 2

Transcriptional activation of rifampicin target genes. Pregnane X receptor (PXR) binds with rifampicin in the cytoplasm and enters into nucleus to form a heterodimer with retinoic acid receptor (RXR). The heterodimer binds to the promoter of a target gene to activate the transcription of its open reading frame (ORF).