Transport membranaire des médicaments utilisés en transplantation : étude du transporteur MRP4

Résumé fourni par la source

Membrane transporters are major determinants of the pharmacokinetics of drugs, in the same way as the enzymes of the metabolism. Among them, only a few have roles in the organism which are perfectly defined. However, numerous clinical observations suggest that membrane transporters are involved in the occurrence of drug-drug interactions, and more generally in the occurrence of treatment failures due to inefficiency or toxicity.The aim of our work was to study the role of membrane transporters in the pharmacokinetics of immunosuppressants prescribed in transplanted patients. These are drugs with a narrow therapeutic index and very complex kinetic profiles. They are subject to numerous drug-drug interactions and it is known that the P-gp, the OATP family of transporters, or the BCRP transporter play an important role in their pharmacology.We were particularly interested in the relationship between the MRP4 transporter and mycophenolic acid (MPA). For this, we developed vesicular transport models (in vitro approach) and molecular modelling (in silico approach). They showed that mycophenolic acid β-D glucuronide (MPAG), a major metabolite of MPA, is transported by MRP4. Obviously, this phenomenon contributes to the inter- and intra-individual variability in the exposure to MPA. This work also demonstrated that some frequently co-prescribed drugs (anti-infectious and anti-inflammatory drugs) can inhibit this transport.This example illustrates the value of exploring transport mechanisms through in vitro and in silico studies to better understand and anticipate drug-drug interactions

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