The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine.
OBJECTIVE
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 3H-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 Km and Vmax were 216.5 +/- 58 microm 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.
Kim
Ho-Sook
HS
Department of Pharmacology and Pharmacogenomics Research Centre, Inje University College of Medicine, Busan, Korea.
Sunwoo
Yu Eun
YE
Ryu
Ji Young
JY
Kang
Ho-Jin
HJ
Jung
Hye-Eun
HE
Song
Im-Sook
IS
Kim
Eun-Young
EY
Shim
Joo-Cheol
JC
Shon
Ji-Hong
JH
Shin
Jae-Gook
JG
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000493:pharmacokinetics; D000328:Adult; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006801:Humans; D019259:Lamivudine / Q000493:pharmacokinetics*; D009363:Neoplasm Proteins; D020641:Polymorphism, Single Nucleotide; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics*; D016896:Treatment Outcome
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine