Studies on the impact of the drug transporter OATP1B3 on the pancreatic effects of CCK-8 and sulfonylurea derivatives

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Transporters facilitating cellular uptake play a pivotal role in modulating the intracellular functions of their substrates. Organic Anion Transporting Polypeptides are one family of transporters mediating cellular uptake. Particularly, the members of the OATP1B-subfamily were focus of pharmacological studies as these proteins transport a variety of drugs in clinical use.In preparation of this proposal we were able to show expression of the uptake transporter OATP1B3 in the insulin-producing -islet cells of human pancreas. Considering that previous studies revealed choleystokinin-8 (CCK-8), an intestinal formed incretine as an OATP1B3-specific endogenous substrate and that our preliminary data and previous findings by others show interaction of several sulfonylurea derivatives with OATP1B3 the question of the physiological and pharmacological relevance of the pancreatic expression of OATP1B3 rises. In order to obtain insights in the function of OATP1B3 in -islet cells, a glucose-sensitive, insulin-producing, and OATP1B3-overexpressing cell-line will be generated and functionally characterized. The impact of the transporter on the cellular effects of CCK-8 and of sulfonylurea derivatives will be focus of the subsequent in vitro studies assessing the influence of the endogenous and exogenous substrates on the insulin secretion by transfected -islet cells. In addition, the potential interaction of sulfonylurea derivatives with the physiological function of CCK-8 will be determined. In addition to those cellular effects it will be aim to show direct transport of sulfonylurea derivatives by OATP1B3. Basis of a translational approach are our previous findings of function impairing, and frequently occurring genetic variants of OATP1B3. It is aim of the clinical study in healthy volunteers genotyped for OATP1B3 variants prior to study inclusion, to determine the influence of the respective polymorphisms on the physiological function of CCK-8. In order to do so, a two-armed study will be conducted. In the first treatment period the impact of the genetic variants on the systemic disposition of intestinal formed and secreted CCK-8 will be determined after intake of a standardized meal. It seems noteworthy, that OATP1B3 is highly expressed in hepatocytes and might therefore influence bioavailability of CCK-8. In the second treatment period the impact of genetic variants of OATP1B3 on the insulin release promoting effects of CCK-8 will be assessed after intake of 75 g Glucose. In addition to CCK-8, the levels of insulin and other known modulators of glucose homeostasis will be determined. The study has been approved by the local ethic committee and will be conducted in collaboration with the Department of Clinical Pharmacolgy of the Universitätsmedizin Greifswald.