TAKE HOME MESSAGES FROM THE ITC PAPERS: part 2
In 2010 the ITC presented 7 transporters it considered clinically relevant, now often referred to as the ’ITC-7’: OAT1, OAT3, OCT2, OATP1B1, OATP1B3, P-gp and BCRP. Hillgren et al. summarize a number of transporters of emerging importance:
MATEs: MATEs are expressed in the liver (MATE1) and kidney (MATE1, MATE2-K) and are involved in the transport of cationic and zwitterionic molecules like Metformin and Cimetidine. Due to their important role in renal excretion of drugs the ITC suggests adding MATEs to the OAT1/3 and OCT2 decision trees, i.e. inhibition of MATEs should be studied for each new molecular entity (NME), whereas substrate studies should be performed for compounds showing more than 25% renal, active secretion.
MRPs: in particular MRP2, MRP3 and MRP4. Hillgren et al. recommend studying MRP2 inhibition for an NME if drug-induced conjugated hyperbilirubinemia is observed in patients or in preclinical species. Furthermore, in the cases where glucuronate or glutathione conjugates are formed, it is recommended to study whether these conjugates are either inhibitors or substrates of MRP2, MRP3 and MRP4.
BSEP: Due to its narrow substrate specificity, it is unlikely that BSEP will play a role in drug disposition and thus potential DDIs. Impaired BSEP function, however, leads to cholestasis, as is observed in PFIC-2 patients. Still, despite the lack of a back-up system for the secretion of bile salts, inhibition of BSEP does not necessarily lead to cholestasis. A variety of factors can complicate interpretation of BSEP inhibition data, e.g. the lack of correlation between plasma concentration of drugs that inhibit BSEP and DILI. Studying BSEP is therefore recommended either in the presence of a strategy to assess the clinical relevance of the observed inhibition or if cholestasis is observed in clinical trials or safety studies.
Apart from these transporters that should or can be considered for each NME, Hillgren et al.  also describe two classes of transporters that should be considered for NMEs with specific structures: nucleoside transporters (ENTs, CNTs) and peptide transporters (PEPTs). ENTs have been demonstrated to affect the clinical activity of nucleoside drugs like fludarabine, cladribine and zidovudine. PEPT1 has been demonstrated to enhance the bioavailability of amino acid-like drugs and some antibiotics, whereas PEPT2 is the primary mechanism for re-absorbtion of di- and tri-peptides from the urine. PEPT2 is also active in the brain, clearing di- and tri-peptides from the CSF, and in the lung, absorbing peptides.
Hillgren, K.M., et al., Emerging transporters of clinical importance: an update from the international transporter consortium. Clin Pharmacol Ther, 2013. 94(1): p. 52-63.