eng Oriental Scientific Publishing Company Biomedical and Pharmacology Journal 0974-6242 2025-06-30 18 2 1188 1204 10.13005/bpj/3162 66526 article Muhammad Najmi Munawwar Mohd Hatta 1 Normala Abd Latip 2 Department of Pharmacology and Pharmaceutical Life sciences, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM) Cawangan Selangor, Puncak Alam, Malaysia. Department Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM) Cawangan Selangor, Puncak Alam, Malaysia. Cytochrome P450 2B6 (CYP2B6) plays a significant role in the metabolism of various drugs, yet its regulation and clinical relevance are often underappreciated. Numerous substrates of CYP2B6 have been identified to date, and these findings may contribute to potential drug-drug interactions in patients. Extensive research has been conducted to assess how drugs affect the activity of CYP2B6 and, consequently, impact therapy effectiveness in patients. These investigations are crucial for establishing safe drug dosages for patients. The objective of this review is to offer insights into the drug-drug interactions associated with CYP2B6 and to provide an overview of its impact on drug administration in patients. This review systematically explores CYP2B6 transcriptional control, polymorphism-dependent activity, and drug-drug interaction (DDI) potential. We emphasize the influence of nuclear receptors, including CAR, PXR, HNF3β, and oestrogen receptor on CYP2B6 gene expression, as well as the consequences of allelic variants such as *6, *16, and *18 on drug metabolism. Using a PRISMA-guided literature search, we synthesized 96 original studies addressing modulators of CYP2B6 and their clinical implications. Our findings demonstrate that regulatory mechanisms and genetic diversity significantly shape interindividual differences in CYP2B6-mediated drug metabolism. Clinically important substrates like efavirenz, cyclophosphamide, artemisinin, and tamoxifen exhibit interaction profiles shaped by both enzyme induction and inhibition. This review evaluates CYP2B6-mediated interactions through the lens of nuclear receptor-driven transcriptional control and polymorphism-associated enzyme variability. https://biomedpharmajournal.org/vol18no2/comprehensive-review-of-cyp2b6-transcriptional-modulators-variants-and-their-role-in-drug-interactions/ Constitutive androstane receptor (CAR) CYP2B6 Inducer Inhibitor Pregnane X receptor (PXR)