Functions and interplay of drug transporters and CYP3A enzymes

Abstract

Interindividual variability in drug response and toxicity as well as drug-drug interactions complicate the treatment with many drugs, including the antineoplastic agents. Transmembrane drug transporters and the CYP3A metabolizing complex, given their broad substrate specificity and tissue distribution, may have substantial impact on these processes owing to their variable activities due to genetic polymorphisms, drug-drug interactions, and tumor-specific expression. The drug uptake transporters organic anion transporting polypeptides (OATP) and drug efflux ATP-binding cassette (ABC) transporters are expressed in pharmacologically important organs such as the liver, small intestine, kidney and the blood-brain barrier (BBB). Here they are of clinical importance in the absorption, disposition, elimination and toxicity of many drugs. In this thesis, we describe the generation and characterization of several new mouse models, which were used with the other currently available genetically modified mouse models and pharmacological inhibitors, to delve deeper into the physiological, pharmacological, toxicological roles and interplay of these transporters and CYP3A metabolizing enzyme in handling endogenous compounds and therapeutic drugs. Firstly, we present important new insights into the physiological and pharmacological behavior of the mouse and human OATP2B1 transporters using the newly generated knockout and humanized transgenic mouse models. Secondly, we demonstrate that ABCB1 and ABCG2 restrict the oral absorption and brain accumulation of several targeted anti-cancer drugs, and that this may be reversed by pharmacological inhibition of these transporters. Thirdly, we show that the multispecific drug-metabolizing enzyme complex CYP3A could markedly limit the systemic exposure of many tested antineoplastic drugs, without altering their relative tissue distribution. Lastly, we have demonstrated the interplay of these transporters and the CYP3A enzyme complex and showed that they work in collaboration to modulate the drug pharmacokinetics using pharmacological inhibitors and newly generated knockout mouse models. Notwithstanding all the findings described in this thesis, we believe that there is still much to be explored in the field of transporters and metabolizing enzymes in terms of pharmacological, toxicological as well as physiological functions. We also believe that the novel generated knockout and transgenic mouse models will be of great value during drug development and drug therapy optimization, allowing us to make a better prediction of drug-drug interactions, improving drug targeting and possibly minimizing side effects in patients.