Investigation Of The Role Of Organic Cation Transporter 2 (Oct2) In The Renal Transport Of Guanfacine, A Selective Alpha(2a)-Adrenoreceptor Agonist

1. Guanfacine is a selective alpha(2A)-adrenoreceptor agonist primarily excreted as its unchanged form through urine in human. This study was to investigate the involvement of organic cation transporter 2 (OCT2) in the renal tubular secretion of guanfacine.2. Transport of guanfacine was characterized using human embryonic kidney (HEK293) cells expressing human OCT2 (hOCT2). The inhibitory effect of cimetidine on guanfacine uptake was also examined. In addition, in vivo pharmacokinetic study was conducted in rats to assess the effects of cimetidine on the pharmacokinetics of guanfacine.3. The accumulation of guanfacine in hOCT2-transfected HEK293 cells was both time- and concentration-dependent, and markedly higher than that in mock cells. The apparent K-m and V-max values of guanfacine uptake by hOCT2 were 96.19 +/- 7.49 mu M and 13.03 +/- 0.49 nmol/mg protein/min, respectively. Guanfacine transport mediated by hOCT2 was significantly inhibited by a typical OCT2 inhibitor cimetidine with an IC50 value of 93.82 +/- 1.13 mu M. Co-administration of cimetidine significantly decreased the plasma clearance (CLp) as well as the renal clearance (CLr) of guanfacine in rats in a dose-dependent manner, resulting in a noticeable increase in the systemic exposure of guanfacine.4. These results indicated that OCT2 may be involved in the renal disposition of guanfacine.