Substrates and Inhibitors of Organic Cation Transporters (OCTs) and Plasma Membrane Monoamine Transporter (PMAT) and Therapeutic Implications

Faster Serotonin Clearance in CA3 Region of Hippocampus and Antidepressant-like Effect of Decynium-22 in Juvenile Mice Are Putatively Linked to Increased Plasma Membrane Monoamine Transporter Function: Implications for Efficacy of Antidepressants in Juveniles

“…We did not evaluate a role for OCT1 in this study because its expression in brain is relatively low, monoamines are generally reported to be poor substrates for this transporter, and D22 has lower affinity for OCT1 than other OCTs or PMAT [ 18 , 35 ]. D22 has been reported to have lower affinity for OCT2 than OCT3 or PMAT (e.g., [ 19 ]), although other studies show it to have equivalent affinity (see [ 18 ]); thus, we cannot rule out a possible role for OCT2 in our present findings.…”

“…Furthermore, the therapeutic efficacy of SSRIs is also less in adolescents than in adults, warranting future investigations into the contribution of D22-sensitive transporters to serotonergic homeostasis in adolescents as well. Finally, it should be kept in mind that D22-sensitive transporters are capable of transporting monoamines other than serotonin, albeit with varying affinities (for reviews see [ 11 , 12 , 18 , 35 ]). Thus, blockade of these transporters would be expected to increase extracellular levels of all monoamines.…”

“…The goals of the present study were to evaluate the antidepressant-like effects of D22, assess functional clearance of serotonin in vivo and quantify expression of OCT3 and PMAT in juvenile P21 and adult (P90) mice. Although D22 has activity at all three OCT subtypes (OCT1, OCT2 and OCT3) and PMAT, we focused on OCT3 and PMAT, and not OCT1 or OCT2, because D22 is generally reported to have higher affinity for OCT3 and PMAT compared to OCT1 and OCT2, and monoamine uptake by OCT1 is very limited [ 18 , 19 ]. Importantly, D22 lacks affinity at SERT, the dopamine transporter (DAT) and the norepinephrine transporter (NET) [ 19 ].…”

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics

“…Once the expression of drug transporters changes, it binds to affect the pharmacokinetics of drugs. Therefore, the Food and Drug Administration and National Medical Products Administration of China have pointed out that eleven drug transporters in the kidneys, including organic anion transporter 1 (OAT1), organic anion transporter 1 (OAT3), organic anion transporter polypeptide 4C1 (OATP4C1), organic cation transporter (OCT2), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi-drug and toxin extrusion protein 1 (MATE1), multi-drug and toxin extrusion protein 2-K (MATE2-K), organic anion transporter 4 (OAT4), multidrug resistance-associated protein 2 (MRP2) and multidrug resistance-associated protein 4 (MRP4), need to be researched for drug applications [ 3 , 4 ].…”

High Affinity Decynium-22 Binding to Brain Membrane Homogenates and Reduced Dorsal Camouflaging after Acute Exposure to it in Zebrafish

“…In mammals, there are three isoforms: OCT1 is richly expressed in the liver, kidneys, and gut; OCT2 is widely found in the brain, kidneys, and to a lesser extent, in other peripheral organs; and OCT3 is predominant in the heart, lungs, adipose tissue, placenta, and brain, and also occurs in other peripheral organs ( Koepsell et al, 2007 ; Nies et al, 2011 ; Koepsell, 2020 ; Samodelov et al, 2020 ; Sweet, 2021 ). Substrates of mammalian OCTs include the biogenic amines serotonin, norepinephrine, dopamine, and histamine; antioxidants; vitamins such as choline and thiamine; metabolites such as guanidine or putrescine; xenobiotic compounds including drugs such as metformin; and cationic neurotoxins such as the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cation, 1-methyl-4-phenyl pyridinium (MPP+), or paraquat cations that are used to model Parkinson’s disease in rodents ( Cui et al, 2009 ; Rappold et al, 2011 ; Nies et al, 2011 ; Bönisch, 2021 ; Yee and Giacomini, 2021 ). The pseudoisocyanine 1-1′-diethyl-2,2′cyanine iodide (decynium-22 or D-22) blocks human and mouse OCTs at low nM concentrations, and because of this property, D-22 is a useful pharmacological tool in the studies of OCT functions ( Hayer et al, 1999 ; Hayer-Zillgen et al, 2002 ; Fraser-Spears et al, 2019 ; ; Bönisch, 2021 ).…”