Genomic and drug-drug interaction mechanisms of interindividual variability in drug disposition

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Project Summary/Abstract Large degree of interindividual variability in drug response frequently compromises drug safety and efficacy. The long-term goal of my research is a mechanistic and clinical understanding of this variability and then personalized drug therapy. My research, funded mainly by NIGMS, has focused on the changes in drug pharmacokinetics due to both 1) inherited differences in drug disposition and 2) unpredictable drug-drug interactions (DDIs). This work produced new and novel mechanisms of drug disposition and identified genetic and DDI factors responsible for interindividual variability in drug and/or active metabolite exposure and effects. Novel in vitro and clinical phenotyping tools, genomic biomarkers and LC/MS/MS methods were developed that significantly advanced the science of drug disposition and stimulated collaborative and worldwide research endeavors. Examples include revision of the FDA package insert for efavirenz, development of dosing guidelines and position papers on efavirenz and CYP2B6, and the use of efavirenz as in vitro and in vivo probe of CYP2B6 activity. Yet, incomplete understanding of the mechanisms for interindividual variability in drug disposition persists for many other clinically important drugs and continues to compromise the implementation of maximum drug efficacy with minimal toxicity. This knowledge gap is the focus of this MIRA application. 1) The combined effect of genetic variability in drug disposition and DDIs on drug exposure and effect has rarely been studied. Efavirenz (a CYP2B6 substrate and a critical drug for the treatment of HIV) induces hepatic CYP2B6 and inhibits hepatic CYP1A2 in CYP2B6 genotype-dependent fashion. We hypothesize that interplay of genetic variations and DDIs is a key driver of intersubject differences in drug disposition and effect. In healthy volunteers genotyped for CYP2B6 variants, the stereoselective disposition and effect (e.g., pupil diameter) of methadone (a CYP2B6 substrate) and the disposition and effect (systolic and diastolic blood pressures) of tizanidine (a sensitive CYP1A2 substrate) will be determined at baseline and after pretreatment with efavirenz (600 mg/day PO for 17 days). 2) UGTs are differentially expressed in extrahepatic tissues, but their role in in drug metabolism is incompletely understood. Building on our recent publication with dolutegravir (a UGT1A1 and UGT1A9 substrate), we will test the hypothesis that modulation of extrahepatic metabolism of UGT substrates contributes to the variability in exposure of UGT substrates. In-depth in vitro kinetic and inhibition studies will be performed in microsomes derived from UGT genotyped human hepatic, intestinal and kidney tissues. 3) Some clinically observed complex DDIs are unpredictable based on current knowledge. Capitalizing on our work with bupropion-CYP2D6 interaction, in vitro DDI studies are proposed to identify the mechanistic basis of clinically observed DDIs, focusing on circulating metabolites/stereoisomers and less well- understood metabolic pathways. Appropriate in silico approaches will complement our studies. The results will enhance our ability to personalize drug therapy.