Towards a better molecular understanding and safer drug therapies: The importance of stereoselectivity in genetically polymorphic drug membrane transporters of the solute carrier family

• Applicant: Dr. Muhammad Rafehi
• Subject Area: Pharmacology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437446827

Approximately 30 % of drugs currently on the market constitute racemic mixtures. Stereoisomers can differ significantly in their therapeutic and adverse effects. All stages in pharmacokinetics may also vary between stereoisomers, since absorption, distribution, metabolism, and elimination can be modulated by stereoselective processes. While stereospecificity has already been extensively studied in drug metabolism, relatively little is known about its importance in drug membrane transport.With this project, we intend to contribute to a more comprehensive knowledge of stereoselective recognition of substrates and inhibitors by drug membrane transporters. We will focus our studies on organic anion and organic cation transporters of the solute carrier family that mediate uptake of drugs into the liver and kidneys for metabolism and elimination. We are particularly interested in transport proteins that show pronounced differences in their activity due to inherited polymorphisms. A better understanding of stereoselectivity in solute carriers may be important for a more precise individualisation of drug therapy.We will investigate stereospecificity in clinically relevant substrate-transporter combinations (e.g. organic cation transporters with adrenergic and antiadrenergic drugs or organic anion transporters with non-steroidal anti-inflammatory drugs). Subsequently, we will determine whether stereospecificity differs between wild-type and common naturally occurring variants of these solute carriers. The in vitro experiments will be complemented by structural analyses based on molecular modelling. We will further study stereoselectivity in drug membrane transporter inhibition. Many racemic drugs are known to inhibit, for example, OCT1 or OAT1. Stereoselectivity of inhibition by racemic drugs can be clinically relevant and would, for instance, be a reason to prefer pure stereoisomers over the racemic drug. A better understanding of stereoselectivity of drug membrane transport inhibition will also provide new insights into structure-function relationships. Moreover, we will investigate in a smaller subproject whether stereospecific binding to plasma proteins (human serum albumin and alpha-1-acid glycoprotein) can influence the stereospecificity of solute carriers.Altogether, this project will greatly enhance our understanding of stereoselectivity in transmembrane drug transport and its inhibition. It will further provide new insights into the structure-function relationship of membrane transporters in general. This will be useful for the development of more effective and safe drugs as well as in individualised therapy.Future research perspectives include the combined analysis of stereoselective transport and biotransformation using primary and double-transfected recombinant cell lines as well as clinical studies to confirm the impact of our experimental results in humans.

• DFG Programme: Research Grants