Transport of the dopamine D2 agonist pramipexole by rat organic cation transporters OCT1 and OCT2 in kidney.
We investigated the mechanism of renal tubular secretion of the dopamine D2 receptor agonist pramipexole in rats, focusing on organic cation transporters 1 and 2. The uptake of [14C]pramipexole by Xenopus oocytes injected with complementary RNA of either rat organic cation transporter (rOCT) 1 or rOCT2 was significantly higher than that by water-injected oocytes: the kinetic parameters, K(m) and V(max), of pramipexole uptake were 49.5 muM and 234 pmol/60 min/oocyte for rOCT1, and 16.9 microM and 12.8 pmol/60 min/oocyte for rOCT2. Pramipexole was taken up into kidney slices in a time- and concentration-dependent manner, and Eadie-Hofstee plots revealed the involvement of two saturable components. The kinetic parameters, K(m1) and V(max1), of the high-affinity component were 12.9 microM and 10.7 nmol/15 min/g kidney, respectively. The uptake of [14C]pramipexole by rOCT1, rOCT2, and kidney slices was inhibited by procainamide and corticosterone, which are selective inhibitors of rOCT1 and rOCT2, respectively. The IC50 values of procainamide and corticosterone for the uptake of [14C]pramipexole by rOCT1, rOCT2, and kidney slices were 7.7, 167.0, and 47.0 microM and 163.7, 10.7, and 47.7 microM, respectively. These results demonstrate that both rOCT1 and rOCT2 are involved in the renal uptake of pramipexole across the basolateral membrane of the proximal tubular epithelial cells.
Ishiguro
Naoki
N
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan.
Saito
Asami
A
Yokoyama
Kazutoshi
K
Morikawa
Makoto
M
Igarashi
Takashi
T
Tamai
Ikumi
I
D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D052160:Benzothiazoles; D003345:Corticosterone / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D009865:Oocytes / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D000077487:Pramipexole; D011342:Procainamide / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013844:Thiazoles / Q000493:pharmacokinetics*; D014982:Xenopus laevis
D052160:Benzothiazoles; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D020033:Protein Isoforms; D017448:Receptors, Dopamine D2; C100590:Slc22a2 protein, rat; D013844:Thiazoles; D000077487:Pramipexole; D000547:Amantadine; D011342:Procainamide; D003345:Corticosterone