Interindividual variability in the beneficial and adverse effects of medications compromises safe and effective therapy. The long-term goal of this research is to understand the mechanisms that contribute to this variability. In the current funding period, we have focused on variability in drug disposition and response caused by CYP2B6. This hepatic enzyme metabolizes many clinically important drugs, but the clinical uses of these substrates are compromised by the extensive interindividual variability in CYP2B6 activity and its associated drug interactions. We discovered and validated clinically relevant novel substrate, inhibitors and genetic markers that now make CYP2B6 clinical research possible. Using these tools, we have demonstrated that CYP2B6 genetic variation not only affects substrate metabolism, but profoundly influences the degree of inhibition drug interactions in vitro and in vivo. This interplay between genotype and drug interactions is clinically important because an individual's genotype appears to affect dose adjustment needed for narrow therapeutic range CYP2B6 substrates (e.g., efavirenz and methadone) to avoid adverse effects. Despite these notable advances, the large portion of interindividual variability in CYP2B6 activity and associated drug interactions remains unexplained. In this competing renewal, we will capitalize on these novel and transformative clinical tools as well as exciting new data to comprehensively elucidate the mechanisms responsible for this variability in vivo.
In Aim 1, we will test the hypothesis that the effect of nonsynonomous SNPs in CYP2B6 are substrate dependent and this, in turn, affects drug interactions. We will determine the influence of the CYP2B6*6 allele on kinetics of metabolism and inhibition of a panel of substrates and inhibitors in vitro.
In Aim 2, we will determine how CYP2B6 genetic variants affect simultaneous auto- inhibition/autoinduction and collectively influence CYP2B6 activity. In vivo enzyme activity will be determined using bupropion as a probe at baseline (control), with a single 600 mg oral dose (inhibition) and after multiple doses (600 mg/day) (induction and inhibition) of efavirenz in healthy volunteers genotyped for CYP2B6*6 allele. A semi-PBPK model will be developed to predict the contribution each and interplay among these factors.
In Aim 3, we will the test the hypothesis that genetic variants in genes that regulate CYP2B6 expression and function predict basal and drug-induced CYP2B6 activity. This association will be tested clinically using DNA, plasma and urine samples from our proposed (Aim 2) and previously completed efavirenz clinical trials. Our pathway-guided approach is expected to identify novel genetic biomarkers of interindividual variability in CYP2B6-mediated drug clearance and interactions, and may serve as a paradigm for studying other genes involved in drug metabolism. Overall, we will develop a comprehensive understanding of mechanisms responsible for variable CYP2B6 activity and the metabolism of its substrates, and this information could be eventually used to personalize therapy.

Public Health Relevance

Some patients receive little or no clinical benefit from drugs and others may experience drug interactions and toxicity, with a huge toll in lives and public health costs. A person's genetic makeup can affect drug disposition and effects, as well as the susceptibility to drug interactions. The goal of this project is to improve understanding of the effect of these genetic changes on drug disposition and drug interactions, and use this information to avoid toxicity and maximizing benefit.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DKUS-D (03))
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Okita, Richard T
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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Burgess, Kimberly S; Ipe, Joseph; Swart, Marelize et al. (2018) Variants in the CYP2B6 3'UTR Alter In Vitro and In Vivo CYP2B6 Activity: Potential Role of MicroRNAs. Clin Pharmacol Ther 104:130-138
Robarge, Jason D; Metzger, Ingrid F; Lu, Jessica et al. (2017) Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition. Antimicrob Agents Chemother 61:
Gufford, Brandon T; Lu, Jessica Bo Li; Metzger, Ingrid F et al. (2016) Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo. Drug Metab Dispos 44:544-53
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Masters, Andrea R; Gufford, Brandon T; Lu, Jessica Bo Li et al. (2016) Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers. J Pharmacol Exp Ther 358:230-8
Abdelhady, Ahmed M; Shugg, Tyler; Thong, Nancy et al. (2016) Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers. J Cardiovasc Electrophysiol 27:1206-1213
Masters, Andrea R; McCoy, Michael; Jones, David R et al. (2016) Stereoselective method to quantify bupropion and its three major metabolites, hydroxybupropion, erythro-dihydrobupropion, and threo-dihydrobupropion using HPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 1015-1016:201-208
Cardoso, Josiane de Oliveira; Oliveira, Regina Vincenzi; Lu, Jessica Bo Li et al. (2015) In Vitro Metabolism of Montelukast by Cytochrome P450s and UDP-Glucuronosyltransferases. Drug Metab Dispos 43:1905-16
Michaud, V; Kreutz, Y; Skaar, T et al. (2014) Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype dependent. Pharmacogenomics J 14:151-9

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