Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake
Article first published online: 17 MAR 2012
Copyright © 2012 John Wiley & Sons, Ltd.
Biopharmaceutics & Drug Disposition
Volume 33, Issue 3, pages 170–178, April 2012
How to Cite
Choi, M.-K. and Song, I.-S. (2012), Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake. Biopharm. Drug Dispos., 33: 170–178. doi: 10.1002/bdd.1783
- Issue published online: 4 APR 2012
- Article first published online: 17 MAR 2012
- Accepted manuscript online: 13 MAR 2012 11:30AM EST
- genetic polymorphism;
- OCT1, OCT2;
- transport activity;
The study sought to investigate the effect of genetic variants of OCT1 (OCT1-P283L and -P341L) and OCT2 (OCT2-T199I, -T201M and -A270S), which were identified in a Korean population, on the transport of lamivudine in vitro and to compare the substrate dependent effects of OCT1 and OCT2 variants with 1-methyl-4-phenylpyridinium (MPP+), tetraethyl ammonium (TEA), metformin and lamivudine as substrates for these transporters. When the transport kinetics of lamivudine uptake in oocytes overexpressing OCT1 and OCT2 wild-type (WT) and variant proteins were measured, lamivudine uptake mediated by OCT1-WT was saturable, and uptake was decreased in oocytes expressing OCT1-P283L and -P341L variants compared with that in OCT1-WT. The Clint of lamivudine in oocytes expressing OCT1-P283L was decreased by 85.1% compared with OCT1-WT, whereas it was decreased by 48.7% in oocytes expressing OCT1-P341L. The Clint of lamivudine in oocytes expressing OCT2-T199I, -T201M and -A270S was decreased by 86.2%, 88.9% and 73.6%, respectively, compared with OCT2-WT. When comparing various substrates such as MPP+, TEA, metformin and lamivudine, the effects of the OCT1 genetic polymorphisms on their uptake were not identical. However, contrary to the case of OCT1, the uptake of MPP+, TEA, metformin and lamivudine in oocytes expressing OCT2-T199I, -T201M and -A270S variants was decreased significantly compared with that in oocytes expressing OCT2-WT. In conclusion, the effect of genetic variations of OCT1 and OCT2 on the uptake of MPP+, TEA, metformin and lamivudine was substrate-dependent. Copyright © 2012 John Wiley & Sons, Ltd.