Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin.
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 (CL(R)) and the net secretion (SrCL(R)) 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 CL(R) and SrCL(R) of metformin (P<0.01).


CONCLUSIONS
We conclude that genetic variation in OCT2 plays an important role in the CL(R) and SrCL(R) of metformin in healthy volunteers.
Chen
Ying
Y
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158, USA.
Li
Shuanglian
S
Brown
Chaline
C
Cheatham
Stephen
S
Castro
Richard A
RA
Leabman
Maya K
MK
Urban
Thomas J
TJ
Chen
Ligong
L
Yee
Sook Wah
SW
Choi
Ji Ha
JH
Huang
Yong
Y
Brett
Claire M
CM
Burchard
Esteban G
EG
Giacomini
Kathleen M
KM
D001692:Biological Transport; D002460:Cell Line; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008687:Metformin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D050505:Mutant Proteins / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013997:Time Factors
D050505:Mutant Proteins; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; D008687:Metformin