The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin.
Organic cation transporters (OCTs) can mediate metformin transmembrane transport. We explored metformin pharmacokinetics in relation to genetic variations in OCT1, OCT2, OCT3, OCTN1, and MATE1 in 103 healthy male Caucasians. Renal clearance varied 3.8-fold and was significantly dependent on creatinine clearance (r(2) = 0.42, P < 0.0001), age (r(2) = 0.09, P = 0.002), and OCT1 polymorphisms. Carriers of zero, one, and two low-activity OCT1 alleles (Arg61Cys, Gly401Ser, 420del, or Gly465Arg) had mean renal clearances of 30.6, 33.1, and 37.1 l/h, respectively (P = 0.04, after adjustment for creatinine clearance and age). Immunohistochemical staining of human kidneys demonstrated OCT1 expression on the apical side of proximal and distal tubules. Increased renal clearance, in parallel with the known decreased hepatic uptake, may contribute to reduced metformin efficacy in low-activity genotypes. Renal OCT1 expression may be important not only in relation to metformin but with respect to other drugs as well.
Tzvetkov
M V
MV
Department of Clinical Pharmacology, University Medical Center, University of Göttingen, Göttingen, Germany.
Vormfelde
S V
SV
Balen
D
D
Meineke
I
I
Schmidt
T
T
Sehrt
D
D
Sabolić
I
I
Koepsell
H
H
Brockmöller
J
J
D000328:Adult; D000375:Aging / Q000502:physiology; D015992:Body Mass Index; D003404:Creatinine / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics*; D050811:Octamer Transcription Factor-1 / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D027981:Symporters; D013739:Testosterone / Q000097:blood; D000099254:Organic Cation Transporter 3
D003404:Creatinine; D007004:Hypoglycemic Agents; D008687:Metformin; D050811:Octamer Transcription Factor-1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D027981:Symporters; D013739:Testosterone; D000099254:Organic Cation Transporter 3; C494165:POU2F1 protein, human; C491013:SLC22A2 protein, human; C109807:SLC22A4 protein, human; C521869:SLC47A1 protein, human