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

> **NIH NIH R35** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $396,250

## Abstract

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 circulatin...

## Key facts

- **NIH application ID:** 10830916
- **Project number:** 5R35GM145383-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Zeruesenay Desta
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830916

## Citation

> US National Institutes of Health, RePORTER application 10830916, Genomic and drug-drug interaction mechanisms of interindividual variability in drug disposition (5R35GM145383-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10830916. Licensed CC0.

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