2016 DECEMBER

SUBSTRATE-DEPENDENT INHIBITION AND TRANSPORTERS

In in vitro assays, substrate-dependent transporter inhibition is described. Thus, when the inhibition of a single transporter is investigated, prototypical substrates are often chosen because they characterise the transporter function. However, these substrates may be different from clinically relevant drugs, making difficult the in vivo prediction of drug-drug interactions. Several studies showed that transporter inhibition of a tested drug widely changes according to the chosen substrates (see following publications).

Predicting in vivo drug-drug interactions from in vitro assays should also take into consideration the various transporters potentially used by the chosen substrate and the tested inhibitor. Moreover, for each couple “chosen substrate and tested inhibitor”, both cellular uptake and efflux transporters must be investigated because some inhibitors are concomitantly substrates of uptake transporters and may then inhibit efflux transporters. This point has been recently studied by Yin and al. PubMed in doubled-transfected cells. They showed that cellular concentrations are unpredictable because they depend on the relative inhibition effect of the tested drug on both uptake and efflux transporters. Finally, interactions between the chosen substrate and the tested inhibitor are complicated by the fact that tested drugs can be concomitantly inhibitors and activators. For example, we showed that rifampicin inhibits Gd-BOPTA uptake into hepatocytes as well as efflux into bile canaliculi but activates the efflux from hepatocytes back to sinusoids PubMed.

  • J Pharmacol Exp Ther. 2016;359:401-410. Impact of substrate-dependent inhibition on renal organic cation transporters hOCT2 and hMATE1/2-K-mediated drug transport and intracellular accumulation. Yin J, Duan H, Wang J. PubMed
  • Drug Metab Dispos. 2016;44:1381-9. Impact of experimental conditions on the evaluation of interactions between multidrug and toxin extrusion proteins and candidate drugs. Lechner C, Ishiguro N, Fukuhara A, Shimizu H, Ohtsu N, Takatani M, Nishiyama K, Washio I, Yamamura N, Kusuhara H. PubMed
  • PLoS One. 2015;10:e0136451. Substrate-dependent inhibition of the human organic cation transporter OCT2: a comparison of metformin with experimental substrates. Hacker K, Maas R, Kornhuber J, Fromm MF, Zolk O. PubMed
  • Drug Metab Dispos. 2015;43:235-47. Investigation of the impact of substrate selection on in vitro organic anion transporting polypeptide 1B1 inhibition profiles for the prediction of drug-drug interactions. Izumi S, Nozaki Y, Maeda K, Komori T, Takenaka O, Kusuhara H, Sugiyama Y. PubMed
  • Drug Metab Dispos. 2014;42:1466-77. The need for human breast cancer resistance protein substrate and inhibition evaluation in drug discovery and development: why, when, and how? Poirier A, Portmann R, Cascais AC, Bader U, Walter I, Ullah M, Funk C. PubMed
  • Mol Pharmacol. 2014;86(1):86-95. A plasma concentration of α-ketoglutarate influences the kinetic interaction of ligands with organic anion transporter 1. Ingraham L, Li M, Renfro JL, Parker S, Vapurcuyan A, Hanna I, Pelis RM. PubMed
  • Pharm Res. 2014;31:2035-43. Substrate- and dose-dependent drug interactions with grapefruit juice caused by multiple binding sites on OATP2B1. Shirasaka Y, Mori T, Murata Y, Nakanishi T, Tamai I. PubMed
  • Drug Metab Dispos. 2013;41:1859-66. Substrate-dependent inhibition of organic anion transporting polypeptide 1B1: comparative analysis with prototypical probe substrates estradiol-17β-glucuronide, estrone-3-sulfate, and sulfobromophthalein. Izumi S, Nozaki Y, Komori T, Maeda K, Takenaka O, Kusano K, Yoshimura T, Kusuhara H, Sugiyama Y. PubMed
  • J Pharmacol Exp Ther. 2013;346:495-503. Substrate-dependent inhibition of human MATE1 by cationic ionic liquids. Martínez-Guerrero LJ, Wright SH. PubMed
  • Mol Pharm. 2013;10:3045-56. Substrate- and cell contact-dependent inhibitor affinity of human organic cation transporter 2: studies with two classical organic cation substrates and the novel substrate cd2+. Thévenod F, Ciarimboli G, Leistner M, Wolff NA, Lee WK, Schatz I, Keller T, Al-Monajjed R, Gorboulev V, Koepsell H. PubMed
  • J Pharmacol Exp Ther. 2013;346:300-10. Substrate-dependent ligand inhibition of the human organic cation transporter OCT2. Belzer M, Morales M, Jagadish B, Mash EA, Wright SH. PubMed
  • Drug Metab Dispos. 2007;35:1308-14. Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Noé J, Portmann R, Brun ME, Funk C. PubMed