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The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro , on the disposition of lamivudine
Author(s) -
Kim HoSook,
Sunwoo Yu Eun,
Ryu Ji Young,
Kang HoJin,
Jung HyeEun,
Song ImSook,
Kim EunYoung,
Shim JooCheol,
Shon JiHong,
Shin JaeGook
Publication year - 2007
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2007.02944.x
Subject(s) - disposition , lamivudine , pharmacology , in vitro , medicine , biology , genetics , psychology , virus , hepatitis b virus , social psychology
Aims To evaluate the effects of three ABCG2 variants (Q141K, V12M and Q126X), which are known to have altered transport properties in vitro , on the disposition of lamivudine in healthy subjects. Methods To evaluate whether lamivudine is a substrate of ABCG2, intracellular accumulation and vectorial transport of 3 H‐lamivudine were determined in MDCK‐ABCG2 cells. The pharmacokinetic parameters of lamivudine were compared among subjects with four different ABCG2 genotypes, including wild type (seven subjects), K141/K141 (six subjects), Q126/Stop126 (four subjects) and M12/M12 (five subjects) after a single oral dose of 100 mg lamivudine. Results The intracellular accumulation of lamivudine in MDCK‐ABCG2 cells was significantly lower than that in MDCK‐mock cells, but fumitremorgin C reversed the intracellular lamivudine concentration to that of MDCK‐mock cells. The ABCG2‐mediated transport of lamivudine was saturable and the values of K m and V max were 216.5 ± 58 µ m and 20.42 ± 2.9 nmol h −1 per 10 6 cells, respectively. After lamivudine administration to healthy subjects, the AUC of lamivudine showed no difference among subjects with different ABCG2 genotypes; 2480 ± 502, 2207 ± 1019, 2422 ± 239, 2552 ± 698 ng h −1 ml −1 for wild type, K141/K141, Q126/Stop126 and M12/M12 genotype, respectively ( P = 0.85). The estimated 95% confidence intervals for the mean difference between K141/K141, Q126/Stop126, M12/M12 and wild as reference were (−1053, 507), (−555, 439) and (−552, 696), respectively. No other pharmacokinetic parameters were estimated to be significantly different among four different ABCG2 genotypes tested. Conclusions Lamivudine appeared to be a substrate of ABCG2 in vitro , but the disposition of lamivudine was not significantly influenced by known in vitro functional variants of ABCG2, Q141K, V12M and Q126X in healthy subjects.