title: Investigation of the role of organic cation transporter 2 (OCT2) in the renal transport of guanfacine, a selective α2A-adrenoreceptor agonist.
abstract: 1. Guanfacine is a selective α2A-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 Km and Vmax values of guanfacine uptake by hOCT2 were 96.19 ± 7.49 μM 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 μM. 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.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing, Jiangsu , China and.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Li
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Sun
authors.forename: Jiayin
authors.initials: J
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Wang
authors.forename: Junxiu
authors.initials: J
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000378:metabolism*; D000818:Animals; D002927:Cimetidine; D016316:Guanfacine / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D019789:Tetraethylammonium
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; D016316:Guanfacine; D019789:Tetraethylammonium; D002927:Cimetidine
keywords: Drug–drug interactions; guanfacine; organic cation transporter 2; renal disposition