Physiological and pharmacological functions of OATP1A/1B transporters

Abstract

Organic Anion Transporting Polypeptide (OATP; mouse Oatp) transporters of the 1A/1B subfamilies are uptake transporters that mediate the cellular uptake of a wide range of endogenous and xenobiotic compounds. Since OATP1A/1B transporters are expressed in pharmacological important organs, like liver, kidney and small intestine, it has been hypothesized that OATP1A/1B transporters play an important role in drug disposition and elimination. By generating and utilizing novel Oatp1a/1b cluster knockout mice and humanized transgenic mice specifically expressing one of the human OATP1A/1B transporters in the liver, we aimed to elucidate the physiological and pharmacological properties of OATP1A/1B transporters. These studies revealed important new physiological insights regarding the hepatic bilirubin detoxification process. We could demonstrate that under normal physiological conditions Oatp1a/1b transporters are involved in the hepatic re-uptake of conjugated bilirubin, which was first secreted over the sinusoidal membrane by the multidrug transporter Abcc3. We hypothesized that this sinusoidal secretion and subsequent re-uptake of conjugated compounds might be an important process in normal liver physiology, as it may prevent saturation of biliary excretion by spreading the process over the entire liver lobule. Many drugs, and in particular anticancer drugs, have a narrow therapeutic window, and are therefore often associated with adverse side effects in patients. It is therefore important to elucidate the different factors that determine the pharmacokinetics of these drugs. In this project we aimed to obtain a good understanding of the impact of (individual) OATP1A/1B transporters on plasma exposure, tissue distribution and elimination of drugs after treatment. We have established a marked impact of Oatp1a/1b transporters in vivo on a broad range of drug substrates, including charged organic anions (methotrexate), polar zwitterionic drugs (fexofenadine), and even highly hydrophobic drugs (paclitaxel). Moreover, by using the humanized transgenic mice it was suggested that in humans OATP1B1 and -1B3 are collectively involved in the hepatic uptake of methotrexate, whereas transporter-mediated liver uptake of paclitaxel is primarily mediated by OATP1B3. In conclusion, in this thesis we present important new insights into the physiological and pharmacological behavior of human and mouse OATP1A/1B transporters. We believe that the novel generated OATP1A/1B knockout and humanized transgenic mice presented in this thesis will be of great value during drug development and drug therapy optimization, allowing us to make a better prediction of drug-drug interactions, improve drug targeting and possibly minimize side effects in patients.