Insights into CYP2B6-mediated drug–drug interactions
Authors: William D. Hedrich, Hazem E. Hassan, Hongbing Wang
Abstract:
Emerging evidence indicates that the role of CYP2B6 in human drug metabolism is more significant than previously understood. The identification of numerous crucial substrates of CYP2B6, along with the presence of polymorphic differences, has generated growing interest in understanding the genetic and xenobiotic factors that influence the expression and activity of this enzyme. In the liver, the expression of CYP2B6 is primarily regulated by the xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR). These receptors not only control the expression of CYP2B6 but also mediate the induction of CYP3A4, several important phase II enzymes, and drug transporters. The involvement of CYP2B6 in the metabolism of 2%–10% of clinically utilized drugs has been well-documented. This includes widely prescribed antineoplastic agents such as cyclophosphamide and ifosfamide, anesthetics like propofol and ketamine, synthetic opioids including pethidine and methadone, and antiretrovirals like nevirapine and efavirenz, among others. Substantial inter-individual variation in the expression and function of the human CYP2B6 gene exists, which can lead to altered clinical outcomes in patients undergoing treatment with drugs that are metabolized by CYP2B6. These variations can arise from various sources, including genetic polymorphisms and exposure to xenobiotics. This review aims to provide an overview of the key factors involved in the expression and function of CYP2B6 and discuss recent advancements in assessing the clinical implications of significant drug–drug interactions mediated by CYP2B6.
Abbreviations
CAR, constitutive androstane receptor; C/EBP, CCAAT/enhancer-binding protein; CHOP, cyclophosphamide–doxorubicin–vincristine–prednisone; CITCO, (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime); COUP-TF, chicken ovalbumin upstream promoter-transcription factor; CPA, cyclophosphamide; 4-OH-CPA, 4-hydroxycyclophosphamide; CYP, cytochrome P450; DDI, drug–drug interaction; DEX, dexamethasone; EFV, efavirenz; E2, estradiol; ERE, estrogen responsive element; GR, glucocorticoid receptor; GRE, glucocorticoid responsive element; HAART, highly active antiretroviral therapy; HNF, hepatocyte nuclear factor; IFA, Ifosfamide; MAOI, monoamine oxidase inhibitor; NNRTI, non-nucleotide reverse-transcriptase inhibitor; NR1/2, nuclear receptor binding site 1/2; NVP, nevirapine; PB, phenobarbital; PBREM, phenobarbital-responsive enhancer module; PCN, pregnenolone 16 alpha-carbonitrile; PXR, pregnane X receptor; RIF, rifampin; SNP, single nucleotide polymorphism; TCPOBOP, 1,4-bis[3,5-dichloropyridyloxy]benzene; UGT, UDP-glucuronosyl transferase
Key Words
CYP2B6; CAR; PXR; Polymorphism; Drug–drug interaction; Cyclophosphamide; Efavirenz
Citation: William D. Hedrich, Hazem E. Hassan, Hongbing Wang Insights Into Cyp2b6-mediated Drug–drug Interactions http://dx.doi.org/10.1016/j.apsb.2016.07.016
Received: 29 March 2016, Revised: 18 May 2016, Accepted: 27 May 2016, Available online: 9 August 2016
Copyright: © 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical
Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Acknowledgments
The authors are grateful to Dr. Maria R. Baer (University of Maryland School of Medicine and Stewart and Marlene Greenebaum Cancer Center) for discussions regarding the content of this manuscript. We apologize to the scientists who made contributions to this field, but have not been cited due to space limitations. This work was supported by research grants from the U. S. National Institute of Health (DK061652 and GM107058).
