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Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake
Author(s) -
Choi MinKoo,
Song ImSook
Publication year - 2012
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.1783
Subject(s) - organic cation transport proteins , lamivudine , chemistry , pharmacology , metformin , transporter , biochemistry , biology , endocrinology , genetics , gene , hepatitis b virus , virus , diabetes mellitus
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 Cl int 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 Cl int 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.