Head of Department University of Greifswald Greifswald, Germany
The organic cation transporter OCT1 (SLC22A1) is expressed strongly and almost exclusively in the sinusoidal membrane of human hepatocytes. It is by far the most strongly expressed transporter of organic cations in the human liver. Therefore, OCT1-mediated uptake may be the rate-limiting step in the hepatic clearance of weak basic drugs with low membrane permeability. OCT1 is genetically highly variable. One out of eleven Europeans and White Americans have substantially reduced or even lack OCT1 activity due to common polymorphisms in the OCT1 gene. This frequency is lower in African Americans and much lower in Asians. Taking advantage of the high genetic variability of OCT1, others and we demonstrated the important role of this transporter in the pharmacokinetics and/or efficacy of commonly used drugs like morphine, metformin, fenoterol, sumatriptan, and tramadol. Consequently, the International Transporter Consortium (ITC) recommended prospective evaluation of OCT1 during drug development. However, this recommendation is not reflected yet in the guidelines of the FDA. Beyond its role in drug pharmacokinetics, OCT1 has been suggested to contribute substantially to the hepatic uptake of thiamine (vitamin B1). OCT1 knockout mice have significantly reduced liver fat, pointing to OCT1 as a potential target for treating or preventing non-alcoholic fatty liver disease. This talk will summarize the available data about the role of OCT1 in drug pharmacokinetics and will discuss “the second face” of OCT1 – the potential to develop OCT1 as a drug target.
basic knowledge about OCT1: expression profiles, known substrates, and species differences
role of OCT1 in pharmacokinetics, efficacy and toxicity of approved drugs
possible strategies to evaluate OCT1 during drug development
potential physiological importance of OCT1 with a critical discussions of the discrepancies in the available data