Cell membrane-bound carrier proteins called transporters are recognized as important factors in drug disposition. The Organic Anion Transporting Polypeptides (OATPs) are a superfamily of transporter proteins that facilitate the cellular uptake of a diverse range of endogenous compounds and drugs and are expressed in organs of importance to drug disposition, such as the liver, kidney and intestine. Cancer is the second most common cause of death in the US, exceeded only by heart disease, and accounting for nearly 1 of every 4 deaths. Chemotherapy comprises the backbone of therapy for most types of cancer. While chemotherapy is a crucial component in the treatment of cancer, its effectiveness is often mitigated by narrow therapeutic indices which increases the risks for untoward serious adverse effects associated with administration of such agents. Our preliminary data strongly supports a role for the hepatic OATPs, OATP1B1 and -1B3, to the disposition of the widely used chemotherapeutic agent docetaxel. Furthermore, commonly occurring OATP1B1 variants are associated with significant impairment of docetaxel transport, which may contribute to the oft-witnessed wide interpatient variability in docetaxel pharmacokinetics. Accordingly, we hypothesize that OATP1B1 and -1B3 play important roles in the hepatic disposition and interindividual variability in drug effect of commonly used chemotherapeutic agents known to be dependent on hepatic clearance, including docetaxel, vincristine and doxorubicin. Focused studies that aim to better delineate the kinetic and inhibition profiles, genetic basis for interindividual variability in drug response, and in vivo pharmacology of OATP1B1 and -1B3 to chemotherapy disposition are proposed.
Specific Aim 1 is focused on determining the pharmacologic roles of OATP1B1 and - 1B3 to the hepatic disposition and clearance of docetaxel, vincristine, and doxorubicin using an in vitro recombinant vaccinia-based method to express wild-type and variant transporters in a heterologous mammalian cell system.
In Specific Aim 2, the pharmacological relevance of OATP1B1 and -1B3 to the hepatic disposition of docetaxel, vincristine and doxorubicin in vivo will be evaluated using a humanized transgenic mouse model expressing OATP1B transporters in the background of the Oatp1b2 knockout mouse.
In Specific Aim 3, the functional consequences of OATP1B1 and -1B3 variants to the interpatient variability in disposition of the docetaxel will be explored by conducting a prospective pharmacogenetic:pharmacokinetic correlative study in oncology patients receiving docetaxel as part of their therapeutic regimen. The proposed studies will provide novel and important insights into the roles of the hepatic OATPs, OATP1B1 and -1B3, to the in vitro and in vivo pharmacology of commonly used chemotherapeutic agents. Long-term, a more comprehensive understanding of the molecular and clinical pharmacology of hepatic OATPs will have important implications not only for the evaluation of chemotherapy disposition, toxicity, and efficacy, but also for broad initiatives such as drug discovery, rational drug design and personalized medicine.
The goal of this project is to evaluate the roles of a family of drug uptake transporters known as organic anion transporting polypeptides (OATPs) to the hepatic disposition of the commonly used chemotherapeutic agents docetaxel, vincristine and doxorubicin. Chemotherapy is a crucial component of cancer therapy in general but , due in large part to their narrow therapeutic indices, their use is often complicated and limited by significant adverse effects and toxicities. The knowledge gained from these investigations will significantly aid efforts to individualize chemotherapy dosing in patients with cancer to improve efficacy while minimizing toxicity and will increase our understanding of the mechanisms by which drug transporters contribute to overall drug disposition and cancer pharmacology.
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