Investigation of the role of organic cation transporter 2 (OCT2) in the renal transport of guanfacine, a selective α_2A-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.

Role of organic cation transporters in drug–drug interaction

“…The inhibitor concentration in the systemic blood is relevant for inhibitory effects on hOCT2-mediated drug excretion in the kidney, for hOCT1 and/or hOCT2 mediated transfer of drugs across the blood-brain barrier, and for hOCT1-mediated drug uptake into cells of peripheral tissues e.g., fat cells [85]. Drug concentration in the portal vein, which may be up to 100-fold higher compared to the concentration in the systemic blood for orally applied drugs [86], is relevant for [80], hOCT2 [80] a1-adrenoreceptor blocker, voiding dysfunction Terazosin hOCT1 [80], hOCT2 [80] a2-adrenoreceptor agonist, ADHS Guanfacine hOCT2 [84] Anesthetic, local Lidocaine hOCT3 [2] Antiarrhythmic Amiodarone hOCT2 [80] Antiarrhythmic Disopyramide hOCT1 [80] Antiarrhythmic Procainamide hOCT1 [80], hOCT2 [80] Antiarrhythmic Quinidine hOCT3 [2] Antibiotic Trimethoprim hOCT1 [80], hOCT2 [80] Anticholinergic, bradycardia Atropin hOCT1 [80], hOCT2 [80] Anticholinergic, gastric ulcer Clidinium hOCT1 [80] Anticholinergic, Glycopyrrolate hOCT1 [80], hOCT2 [80] Anticholinergic, gastric ulcer Mepenzolate hOCT1 [80] Anticholinergic, gastric ulcer Oxyphonium hOCT1 [80], hOCT2 [80] Anticholinergic (muscarinic), bronchospasmolyticum Ipratropium hOCT1 [80], hOCT2 [80] Anticholinergic (muscarinic), bronchospasmolyticum Tiotropium hOCT1 [80], hOCT2 [80] Anticholinergic (nicotinic), nicotine addiction Varenicline hOCT1 [80], hOCT2 [ [80], hOCT2 [80] b-2-sympathicomimetic, antiasthmatic Fenoterol hOCT1 [80], hOCT2 [80] b-2-sympathicomimetic, antiasthmatic Formoterol hOCT1 [80] b-2-sympathicomimetic, obstructive lung disease Indacaterol hOCT1 [80] b-2-sympathicomimetic, antiasthmatic Salbutamol hOCT1 …”

The effects of ketoconazole and cimetidine on the pharmacokinetics of oral tramadol in greyhound dogs

“…Ketoconazole is an inhibitor of the p‐glycoprotein efflux pump (Coelho et al., ), and cimetidine is an inhibitor of the organic cation transporter (Li et al., ). Therefore, it is possible that the increased tramadol bioavailability was due to inhibition of efflux transporters in the gastrointestinal tract, and the increased bioavailability was independent of altered first‐pass metabolism.…”

The role of organic cation transporter 2 inhibitor cimetidine, experimental diabetes mellitus and metformin on gabapentin pharmacokinetics in rats

“…The pharmacokinetic parameters AUC 0−∞ , T max , C max , Cl T /F, t 1,2 , Cl r , and Fe were not changed after the coadministration of GAB and cimetidine, a known Oct2 inhibitor [8,14,15,17] or the Oct2 substrate metformin [24,25]. Nadai et al, [14] used cimetidine to evaluate the contribution of Oct2 in the Cl r of 3-methylxanthine and enprofylline in rats.…”

“…Cimetidine was characterized as an OCT2/Oct2 inhibitor drug by in vitro, in vivo, and clinical studies [8,10,14,15] and there are no differences between human and rats in terms of the affinity of cimetidine for OCT2/Oct2 [16]. Cimetidine is recommended as OCT2/Oct2 inhibitor by The International Transporter Consortium, which developed organograms for drug-drug interaction studies [17].…”