UC San Diego

Drug transporters are membrane proteins known for their role in handling pharmaceutical products. However, recent work suggests they contribute to physiology by transporting endogenous metabolites. This understudied function may explain some aspects of organ crosstalk, inter-organismal communication, and adverse drug side effects. This dissertation focuses on determining the endogenous compounds that renal organic anion transporter 1 (OAT1/SLC22A6) interacts with using in vivo, in vitro, and in silico methodologies. Chapter 1 presents the current state of drug transporter research. Chapter 2 of this dissertation is a reprint of published work that describes the role OAT1 plays in mediating the relationship between the host and the gut microbiome via regulation of circulating small molecule metabolites in a pre-clinical model. These in vivo results were supported with in vitro binding and transport assays. Chapter 3 of this dissertation is a reprint of published work that explores the role that a common OAT1-inhibiting drug, probenecid, has on the plasma and urine metabolomes of healthy humans. This revealed dozens of plasma and urine drug-metabolite interactions caused by short-term exposure, including multiple likely occurring at OAT1. Chapter 4 of this dissertation is a reprint of published work that combines genomic and metabolomic data to determine associations between single nucleotide polymorphisms and circulating small, polar, bioactive molecules. This work reveals that numerous drug transporter and drug metabolizing enzyme genes play important individual and combined roles in physiology. Chapter 5 describes in silico models used to better characterize the nature of protein-ligand interactions involving OAT1. By analyzing molecular descriptors of compounds known to interact with OAT1, we generated predictive ligand-based models. We then explored potential binding mechanisms for different classes of compounds using a predicted OAT1 structure. Chapter 6 is a summary of the contributions to the field and future directions in drug transporter research.