TY - JOUR
T1 - Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin
AU - Chen, Ying
AU - Li, Shuanglian
AU - Brown, Chaline
AU - Cheatham, Stephen
AU - Castro, Richard A.
AU - Leabman, Maya K.
AU - Urban, Thomas J.
AU - Chen, Ligong
AU - Yee, Sook Wah
AU - Choi, Ji Ha
AU - Huang, Yong
AU - Brett, Claire M.
AU - Burchard, Esteban G.
AU - Giacomini, Kathleen M.
PY - 2009/7/1
Y1 - 2009/7/1
N2 - OBJECTIVE: The goal of this study was to determine the effect of a genetic variant in the organic cation transporter 2 (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the antidiabetic drug, metformin. METHODS: The uptake of metformin was performed in stably transfected HEK-293 cells expressing the empty vector (MOCK), the reference OCT2-808G, and the variant OCT2-808T. Healthy individuals with known OCT2 genotypes [14 homozygous for the OCT2 reference allele (808G/G) and nine heterozygous for the variant allele (808G/T, *3D)] were recruited to this study. Metformin concentrations in plasma and urine were measured by liquid chromatography-tandem mass spectrometry method. Creatinine levels were also measured in plasma and urine. Pharmacokinetic parameters were evaluated for both the groups. RESULTS: We observed that in HEK-293 stably transfected cells, OCT2-808T had a greater capacity to transport metformin than did the reference OCT2. Metformin pharmacokinetics was characterized in 23 healthy volunteers of Caucasian and African-American ancestries. We observed that the renal clearance (CLR) and the net secretion (SrCLR) of metformin were significantly different between the volunteers heterozygous for the variant allele (808G/T), and the volunteers homozygous for the reference allele (808G/G) (P<0.005). Multivariate analysis revealed that OCT2 genotype was a significant predictor of CLR and SrCLR of metformin (P<0.01). CONCLUSION: We conclude that genetic variation in OCT2 plays an important role in the CLR and SrCLR of metformin in healthy volunteers.
AB - OBJECTIVE: The goal of this study was to determine the effect of a genetic variant in the organic cation transporter 2 (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the antidiabetic drug, metformin. METHODS: The uptake of metformin was performed in stably transfected HEK-293 cells expressing the empty vector (MOCK), the reference OCT2-808G, and the variant OCT2-808T. Healthy individuals with known OCT2 genotypes [14 homozygous for the OCT2 reference allele (808G/G) and nine heterozygous for the variant allele (808G/T, *3D)] were recruited to this study. Metformin concentrations in plasma and urine were measured by liquid chromatography-tandem mass spectrometry method. Creatinine levels were also measured in plasma and urine. Pharmacokinetic parameters were evaluated for both the groups. RESULTS: We observed that in HEK-293 stably transfected cells, OCT2-808T had a greater capacity to transport metformin than did the reference OCT2. Metformin pharmacokinetics was characterized in 23 healthy volunteers of Caucasian and African-American ancestries. We observed that the renal clearance (CLR) and the net secretion (SrCLR) of metformin were significantly different between the volunteers heterozygous for the variant allele (808G/T), and the volunteers homozygous for the reference allele (808G/G) (P<0.005). Multivariate analysis revealed that OCT2 genotype was a significant predictor of CLR and SrCLR of metformin (P<0.01). CONCLUSION: We conclude that genetic variation in OCT2 plays an important role in the CLR and SrCLR of metformin in healthy volunteers.
KW - Membrane transporter
KW - Metformin
KW - Organic cation transporter
KW - Pharmacogenetics
KW - Pharmacokinetics
KW - Single nucleotide polymorphism
UR - http://www.scopus.com/inward/record.url?scp=67651235787&partnerID=8YFLogxK
U2 - 10.1097/FPC.0b013e32832cc7e9
DO - 10.1097/FPC.0b013e32832cc7e9
M3 - Article
C2 - 19483665
AN - SCOPUS:67651235787
SN - 1744-6872
VL - 19
SP - 497
EP - 504
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
IS - 7
ER -