# Ontogeny of drug transport

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2024 · $598,784

## Abstract

PROJECT SUMMARY
 Our long-term goal is to establish non-invasive approaches to predict drug disposition in children, which
includes developing phenotypic biomarkers of drug transporters and drug metabolizing enzymes and pediatric
physiologically-based pharmacokinetic (PBPK) models. During the previous funding period, we gained a
considerable understanding of age-dependent hepatic metabolism and transport from neonates to adults, which
was used to develop PBPK models to predict the disposition of hepatically cleared pediatric drugs. However,
ontogeny data remain limited for another key drug elimination organ: the kidney. The main objective of this
proposal is to define the ontogeny of drug transport in the kidney. Filling this knowledge gap is critical, as
approximately 30% of prescription drugs are cleared predominantly by the kidneys, including several drugs
prescribed to children. Further, tubular secretion plays a crucial role in drug detoxification in children, which is
often regulated by the rate-limiting organic anion or cation transporters (OATs and OCTs, respectively). Although
we and others recently quantified clinically relevant drug transporters in archived kidney tissue samples, these
data are highly variable and are from a limited number of subjects, precluding a meaningful interpretation of
transporter ontogeny. To address these knowledge gaps, we hypothesize that endogenous substrates of
OATs and OCTs in blood and urine can be used as surrogate, non-invasive markers of kidney transporter
function in children and adults. We will test this hypothesis via three Specific Aims. Aim 1: Establish robust
biomarkers of renal OAT and OCT transport activity in adult humans in a controlled clinical drug-drug interaction
study using furosemide and metformin as probe drugs, respectively. The effects of OAT and OCT inhibition by
probenecid and cimetidine, respectively, on both exogenous and endogenous probes will be determined. Aim
2a: Confirm the utility of Oat and Oct transporter biomarkers in predicting ontogeny of renal transporter
abundance and activity in Sprague-Dawley rats. Aim 2b: Characterize the ontogeny of renal transporters in
humans using exogenous (furosemide and metformin) and endogenous (biomarkers) probes of renal
transporters. Aim 3a: Characterize the selectivity of renal uptake of the biomarkers in vitro. Aim 3b: Develop and
validate biomarker-informed PBPK models for renally secreted anionic and cationic drugs in children and adults.
Collectively, this innovative project will establish non-invasive biomarkers that can be used to predict transporter-
mediated renal secretion and drug-drug interaction potential in children and adults. Specifically, the effect of
inhibition of renal transporters by an investigational drug on xenobiotic or endobiotic toxins (e.g., drugs or uremic
toxins) can be predicted in children and adults using these biomarkers. The validated transporter activity
biomarkers garnered from this translational p...

## Key facts

- **NIH application ID:** 10885151
- **Project number:** 5R01HD081299-10
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Bhagwat Prasad
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $598,784
- **Award type:** 5
- **Project period:** 2015-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885151

## Citation

> US National Institutes of Health, RePORTER application 10885151, Ontogeny of drug transport (5R01HD081299-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10885151. Licensed CC0.

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