Organic Cation Transporter
OCT1 (SLC22A1) and OCT2 (SLC22A2) Transporters are validated, stable and robust cell-based assays
OCT: What and Where
The organic cation transporter (OCT) family of SLC22 transporters are expressed ubiquitously throughout the body. Of the different subtypes of this greater family of transporters, the passive diffusion organic cation transporters, OCT1 and OCT2, have been most identified as clinically relevant and to play a role in drug-drug interactions (DDIs). Human OCT1 (hOCT1, the product of the SLC22A1 gene) is mainly expressed in the liver while expression of human OCT2 (hOCT2, the product of the SLC22A2 gene) is mainly localized to the kidney proximal tubules. The substrate profiles of these transporters tend to be low molecular weight, hydrophilic, cationic compounds.1 OCTs play a major role in disposition and excretion of many drug and endogenous compounds.
OCT Clinical Importance
In both the kidney and liver, OCTs are expressed in the sinusoidal (blood) membrane, where they play a role in distribution of organic cations into these tissues. Often times, OCTs also work in tangent with efflux transporters, such as MATE, to aid in excretion. As a result, inhibition of OCT transporters can lead to increased exposure to drug substances which are OCT substrates, as well as accumulation of endogenous compounds. OCTs’ important physiological functions make them prime candidates to play a major role in clinically significant DDIs.
OCT Regulatory Significance
In both the European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions (effective: Jan 2013) and the US Food and Drug Administration (FDA) Guidance for the Industry: Drug Interactions Studies (issued: Feb 2012), OCT2 is named specifically as a clinically relevant transporter, and it is “recommended” to investigate OCT2 inhibitor potential of a new drug. Additionally, the EMA states that OCT1 should “also be considered.” With regard to substrate potential, both agencies indicate that the route of elimination from the body should be considered. That is to say if the “active secretion by the kidney is more than or equal to 25% of total clearance”2 or if “≥25% of the elimination”3 is due to hepatic or renal secretion, OCT substrate potential should be assessed.
Clinically Relevant Probe Substrates and Inhibitors
|tetraethylammonium (TEA), N-methyloyridinium, metformin*, oxaliplatin, 1-methyl-4-phenylpyridine (MPP+)*||quinine‡, quinidine‡, disopyramide, repaglinide‡|
|Amantadine, amiloride, cimetidine, dopamine, famotidine, memamtine, metformin*, pindolol, procainamide, ranitidine, verenicline, oxaliplatin, 1-methyl-4-phenylpyridine (MPP+)*||cimetidine‡, quinidine‡, pilsicainidine, cetirizine, testosterone, imipramine‡|
|*Probe substrate validated by Absorption Systems
‡Inhibitor validated by Absorption Systems
OCT In Vitro Model
We have stably transfected HEK293 cells separately with hOCT1 and hOCT2, and have validated a clonally-selected, robust cell-based assay in which transporter function and expression has been well characterized.
1. Giacomini KM, et al. (2010) Membrane transporters in drug development. Nature Reviews Drug Disc. 9(3):215-236
2. US Food and Drug Administration (Feb 2012) Draft Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing and Labeling Recommendations
3. European Medicines Agency (Jun 2012) Guideline on the Investigation of Drug Interactions