Figure 1.

Illustration of intestinal CYP3A4 regulation and the effect of its content and activity variation on orally administered drugs. Top left: CYP3A4 ligands belong to BDDCS Class 1 and Class 2 with varied solubilities and extensive metabolism, highlighted by the black rectangle; Bottom panel: intra-enterocytic CYP3A4 regulation by endogenous factors under disease conditions and xenobiotics from oral intake (e.g., drugs or food constituents). Normally, a PXR ligand enters the enterocyte and binds to PXR intracellularly. This then dimerizes with retinoid X receptor (RXR) and binds to the xenobiotic response enhancer module (XREM) to upregulate the CYP3A4 gene. Systemic inflammatory conditions such as cancer, infection and obesity increase circulating cytokines, such as IL-6, which activate the STAT3-MAPK pathway to downregulate CYP3A4 gene regulation. Intra- and inter-individual CYP3A4 variation can cause varied drug clearance, resulting in undesirable toxicity and ineffective therapy of drugs with a narrow therapeutic index. Abbreviation: RXR, retinoid X receptor; XREM, xenobiotic response enhancer module (XREM); STAT: signal transducer and activator of transcription-3; MAPK: a family of signaling cascade including Jun N-terminal kinase and mitogen-activated protein kinase 1 pathways.