Ontogeny of drug transport

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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 project will inform precision dosing of pediatric drugs secreted by kidneys during clinical trials and clinical use.