Regulation of OATP1B1 Transporter Function by Tyrosine Kinase Phosphorylation

Elizabeth Hayden

drug-drug interaction and potential effects .

Drug-drug interaction and potential effects.

Graduate Student Project

Introduction

Over the past 15 years there has been an increasing prevalence in polypharmacy, the simultaneous use of multiple drugs by a single patient. Drug-drug interactions occur when one drug alters the body's sensitivity or response to the other drug; increasing the number of drugs a patient is on increases the risk for harmful drug-drug interactions. My name is Elizabeth Hayden, I am a PhD student studying pharmaceutical sciences at the University at Buffalo. With the support of my mentor, Dr. Jason Sprowl, I have been investigating the role of a specific protein involved in many clinically-relevant drug-drug interactions. My research is focused on a class of chemotherapeutics that cause increased exposure to substrates of this protein, leaving patients at a higher risk of adverse events. While impossible to prevent all interactions, characterizing the mechanism by which this drug transport and inhibition occurs may help predict potentially harmful drug-drug interactions.

Abstract

The organic anion transporting polypeptide, OATP1B1 (SLCO1B1) is responsible for the uptake of many endogenous and xenobiotic compounds. Therefore, drug-drug interactions (DDI's) are commonly mediated by OATP1B1 activity. For example, reduced drug elimination via this transporter can lead to increased rates of drug-associated adverse reactions, such as statin-induced rhabdomyolysis. Surprisingly, numerous tyrosine kinase inhibitors (TKIs) that are either weak OATP1B1 substrates or not substrates at all, increase systemic concentrations of various known OATP1B1 substrates by an unknown mechanism.  We hypothesize that OATP1B1 activity is mediated by a tyrosine phosphorylation event that is inhibited by many FDA approved TKIs, and inhibition of specific kinases can reduce transport activity. 

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