Organic Anion Transporter

OAT1 (SLC22A6) and OAT3 (SLC22A8) Transporters are validated, stable and robust cell-based assays

OAT: What and Where

OAT Drug Transporter

The organic anion transporters (OATs), part of the SLC22 superfamily of transporters, are expressed throughout the body.  However, the most clinically relevant members of this sub-family of transporters, OAT1 (gene: SLC22A6) and OAT3 (gene: SLC22A8), are mainly localized to the basolateral membrane of the renal proximal tubule cells. Here, they act to mediate entry into the cells, eventually leading to renal excretion. Substrates of these transporters tend to be small (>500 Da) organic anions; however, it has been demonstrated that OAT3 transports the positively charged drug, cimietidine1.

OAT Clinical Importance

OATs are critical to the entry of many drugs into the renal proximal tubules and, ultimately, for renal excretion. Thus, co-dosing a compound which is an OAT substrate with an OAT inhibitor can lead to reduced renal clearance, higher plasma levels, and increased negative side effects. As an example, the interaction between probenecid and methotrexate, which was first described4 in 1978, can now be identified as an OAT-based drug-drug interaction, with probenecid inhibiting the OAT1 and OAT3 transport of methotrexate.

OAT 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(issued: Feb 2012), OAT1 and OAT3 are named specifically as clinically relevant transporters, and it is “recommended” to investigate OAT1 and OAT3 inhibitor potential of all new drugs. 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 renal secretion, OAT substrate potential should be assessed.

Clinically Relevant Probe Substrates and Inhibitors

OAT1
Substrates Inhibitors
adefovir, captopril, furosemide, lamivudine, methotrexate*, para-aminohippurate (PAH)*, oseltamivir, tenofovir, zalcitabine, zidovudine probenecid‡
OAT3
Substrates Inhibitors
Acyclovir, bumetanide, ciprofloxacin, famotidine, furosemide*, methotrexate*, zidovudine, penicillin G, pravastatin, rosuvastatin, sitagliptin probenecid‡, cimetidine, diclofenac
*Probe substrate validated by Absorption Systems
‡Inhibitor validated by Absorption Systems

 

OAT In Vitro Model

We have stably transfected HEK293 cells separately with hOAT1 and hOAT3, and have validated a clonally-selected, robust cell-based assay that has been well-characterized for transporter function and expression.

References
1. Giacomini KM, et al. (2010) Membrane transporters in drug development. Nature Reviews Drug Disc. 9(3):215-236
2. European Medicines Agency (Jun 2012) Guideline on the Investigation of Drug Interactions
3. US Food and Drug Administration (Feb 2012) Draft Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing and Labeling Recommendations
4. Aherne GW, et al. (1978) Prolongation and enhancement of serum methotrexate concentrations by probenecid. Br Med J 1: 1097-1099