Kinetic Basis of Metformin-MPP Interactions with the Organic Cation Transporter OCT2.

Kinetic Basis of Metformin-MPP Interactions with the Organic Cation Transporter OCT2. Am J Physiol Renal Physiol. 2019 Jul 17;: Authors: Sandoval PJ, Morales MN, Secomb TW, Wright SH Abstract The organic cation transporter OCT2 clears the blood of cationic drugs. Efforts to understand OCT2 selectivity as a means to predict the potential of new molecular entities (NMEs) to produce unwanted drug-drug interactions typically assess the influence of the NME on inhibition of transport. However, identity of the substrate used to assess transport activity can influence the quantitative profile of inhibition. Metformin and 1-methyl-4-phenylpyridinium (MPP), in particular, display markedly different inhibitory profiles, with IC50 values for inhibition of MPP transport often being >5-fold greater than IC50s for inhibition of metformin transport by the same compound, suggesting that interaction of metformin and MPP with OCT2 cannot be restricted to competition for a single binding site. Here we determined the kinetic basis for the mutual inhibitory interaction of metformin and MPP with OCT2 expressed in Chinese Hamster Ovary (CHO) cells. Although metformin did produce simple competitive inhibition of MPP transport, MPP was a mixed-type inhibitor of metformin transport, decreasing Jmax and increasing apparent Kt. Furthermore, whereas the IC50 for metformin's inhibition of MPP transport did not differ from the Ktapp for metformin transport, the...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research