Naslov
The effect of genetic polymorphisms in the organic cation transporters OCT1, OCT2 and OCT3 on the renal clearance of metformin

Autori
Tzvetkov, V. Mladen ; Vormfelde, V. Stefan ; Balen, Daniela ; Meineke, Ingolf ; Schmidt, Tobias ; Sehrt, Daniel ; Sabolić, Ivan ; Koepsell, Hermann ; Brockmoller, Jurgen

Izvornik
Clinical Pharmacology and Therapeutics (0009-9236) 86 (2009), 3; 299-306

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
genetic polymorphism; organic cation transporter; OCT1; OCT2; metformin; renal clearance; SNP; kidney tubulus

Sažetak
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 (r2 = 0.42, P < 0.0001), age (r2 = 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.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti, Kliničke medicinske znanosti, Farmacija

POVEZANOST RADA