# Predicting intracellular drug concentrations in the presence of transporters

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $308,020

## Abstract

The overarching goal of the proposed research is to predict the intracellular and extracellular concentration-
time profiles using models that include membrane partitioning, membrane permeability, organ blood flow,
active transport, and metabolism. In the funding period from 2013-2016, we have made significant progress in
incorporating explicit membrane compartments into predictive models, and we have evaluated in depth the
impact of various membrane geometries and related factors on intracellular concentration prediction. We are
now using the basic principles underlying permeability and partitioning to build a new framework for PBPK
models. This will allow us to incorporate permeability-limited distribution, partitioning, organ blood flow, and
active transport into PBPK models with explicit membrane kinetics (memPBPK). This new paradigm will
provide markedly better predictions of intracellular concentrations, and will address an unmet critical need for
cost effective drug development by providing novel predictive tools for drug disposition in humans.
Three specific aims are proposed. 1) Novel biophysical methods will be used to study the cellular kinetics of
drug permeability and partitioning. Specifically, novel cell microscopy techniques will be used to evaluate the
time-course of cellular distribution and conduct cellular permeability studies in monolayers, and a range of
explicit membrane models developed during the current funding period will be evaluated for their ability to
quantify the observed membrane, organelle, and cellular distribution kinetics. 2) Develop a new framework for
PBPK and hybrid compartmental-PBPK models that incorporate membrane partitioning, permeability-limited
diffusion, and organ blood flow (memPBPK). Components include organ-specific models for use in hybrid and
full PBPK approaches, and models for absorption using our published convection-diffusion-reaction approach.
These models will be used in Aim 3 to incorporate active uptake/efflux transport and metabolism to predict
intra- and extracellular concentration-time profiles. 3) In vivo experimental data from rats and humans will be
used to expand and validate models to predict the time course of intra- and extracellular drug concentrations.
We will focus on modeling the disposition of drugs in the liver and the absorption of drugs from the
gastrointestinal tract in the presence of transporters and drug metabolizing enzymes.

## Key facts

- **NIH application ID:** 9978828
- **Project number:** 5R01GM104178-07
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Kenneth Ray Korzekwa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $308,020
- **Award type:** 5
- **Project period:** 2013-01-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978828

## Citation

> US National Institutes of Health, RePORTER application 9978828, Predicting intracellular drug concentrations in the presence of transporters (5R01GM104178-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978828. Licensed CC0.

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