Insights into CYP2B6-mediated drug–drug interactions

Abstract

Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed. The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme. The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) in the liver. In addition to CYP2B6, these receptors also mediate the inductive expression of CYP3A4, and a number of important phase II enzymes and drug transporters. CYP2B6 has been demonstrated to play a role in the metabolism of 2%–10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide, anesthetics propofol and ketamine, synthetic opioids pethidine and methadone, and the antiretrovirals nevirapine and efavirenz, among others. Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs. These variances arise from a number of sources including genetic polymorphism, and xenobiotic intervention. In this review, we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug–drug interactions.

Methadone Disposition: Implementing Lessons Learned

“…CYP2B6 is now known to metabolize a broad range of substrates, constituting nearly 8% of marketed drugs. 30 Many drugs are metabolized by both isoforms. Induction of bupropion clearance by rifampin 31 was interpreted by some that the mechanism was CYP3A4 induction.…”

STUDY OF THE INTERACTION OF AN EXTRACT OBTAINED FROM THE MARINE PLANT Thalassia testudinum WITH PHASE I METABOLISM IN RATS

“…These, include impaired bioavailability of drugs with narrow therapeutic indices, altered plasma/ tissue levels, and enhanced bioactivation of drugs to reactive intermediates or toxic metabolites (Hedrich et al 2016).…”

Hepatocyte CYP2B6 Can Be Expressed in Cell Culture Systems by Exerting Physiological Levels of Shear: Implications for ADME Testing

“…It is increasingly apparent that many polymorphisms in CYP2B6 are both relatively common and have a substantive effect on rates of drug metabolism [3, 6, 36, 37]. Hence, in screening for CYP2B6-mediated drug metabolism, it is important not only to document expression but also to define the haplotype being studied.…”

“…The frequency of many CYP2B6 polymorphisms is unusually high [3, 6, 36, 37] but often race-dependent [4, 39]. For example, the C64T, G516T, C777A, A785G, and C1459T mutations were found in 5.3%, 28.6%, 0.5%, 32.6%, and 14.0%, respectively, of 215 Caucasian patients.…”

“…CYP2B6 metabolizes 2%–10% of clinically used drugs including antineoplastic agents such as cyclophosphamide and ifosfamide, anesthetics such as propofol and ketamine, synthetic opioids such as pethidine and methadone, and antiretrovirals such as nevirapine and efavirenz [1–3]. CYP2B is highly polymorphic [4], but, until recently, difficulties in maintaining its expression in cultured hepatocytes have limited studies on the impact of CYP2B polymorphisms, inhibitors, and inducers, on the dynamic range of its activity [1, 2, 5, 6].…”