PHENOTYPIC BIOMARKERS FOR ASSESSING INTERINDIVIDUAL VARIABILITY IN RENAL DRUG SECRETION BY ORGANIC ANION TRANSPORTERS (OAT1 AND OAT3)

Aarzoo Thakur

doi:10.7273/000007480

Renal organic anion transporter 1 (OAT1) and OAT3 are involved in the basolateral uptake of various drugs (e.g., furosemide, penicillin, and methotrexate) and endogenous metabolites (e.g., pyridoxic acid, taurine, steroids, and bile acids). Interindividual variability in the abundance and/or activity of OAT1/3 due to various intrinsic factors (e.g., age, sex, genetic polymorphisms, pregnancy, and disease) and extrinsic factors (e.g., diet, drugs, environmental compounds, and natural products) can influence the renal secretion of substrate drugs and cause safety and efficacy concerns. Therefore, accurate prediction of OAT1/3 transport function is critical for precision dosing of drugs eliminated via kidneys. Due to the lack of data for reliable physiologically based pharmacokinetic (PBPK) modeling and the limitation of clinical studies involving drugs, endogenous substrates of transporters have gained traction for accurate prediction of protein function. These endogenous substrates can be discovered using liquid chromatography-tandem mass spectrometry (LC-MS)-based metabolomics approaches. Here, we utilized a comprehensive metabolomics approach to identify OAT1/3 biomarkers in rats and humans. Chapter 1 focuses on the transporters of interest, i.e., OAT1 and OAT3, highlighting their physiological relevance and effect of interindividual variability in transport function on drug pharmacokinetics and tools to predict this variability, with emphasis on the biomarker approach and metabolomics approach for biomarker discovery. The chapter concludes with highlighting the knowledge gap, hypothesis, and dissertation specific aims. Chapter 2 includes the identification of 21 putative Oat1/3 biomarkers in a rat model using probenecid/furosemide (inhibitor/substrate) pharmacokinetic drug-drug interaction (DDI) study coupled with metabolomics analysis. Chapter 3 evaluates the cross-species differences in the abundance of renal membrane drug metabolizing enzymes and transporter (DMET) protein among humans, rats, and mice. Because the abundance of Oat1/3 were significantly different between humans versus rats or mice, and >50% of the membrane DMET proteins were unique to one or more species, Oat1/3 biomarkers identified in Chapter 2 could potentially be insensitive for predicting OAT1/3 function in humans. Therefore, in Chapter 4, 23 OAT1/3 biomarkers were identified and qualified in humans, with a utility to predict probenecid-mediated renal DDIs. Indole-3-carboxylic acid glucuronide was discovered as a sensitive and robust OAT1/3 biomarker. In summary, this research utilized pharmacokinetic DDI studies and metabolomics approaches for the discovery of Oat1/3 biomarkers in rats and humans with the scope to predict DDIs and interindividual variability in transport function. While the rat Oat1/3 biomarkers have potential utility during early drug development stages, the qualified human OAT1/3 biomarkers can predict the DDI potential of investigational drugs during Phase I clinical trials and can inform OAT1/3 substrate drug dosing in specific populations.

PHENOTYPIC BIOMARKERS FOR ASSESSING INTERINDIVIDUAL VARIABILITY IN RENAL DRUG SECRETION BY ORGANIC ANION TRANSPORTERS (OAT1 AND OAT3)

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