Why evaluate the substrate and inhibitor potential of the investigational drug for specific transporters and why do the FDA and EMA care?
Membrane transporters can have clinically relevant effects on the pharmacokinetics and pharmacodynamics of a drug in various organs and tissues by controlling its absorption, distribution, and elimination. Transporter-mediated uptake or efflux of drugs and endogenous compounds may impact the efficacy and safety of the investigational drug and potential concomitant medications. Several key transporters have the potential to interact with drugs in clinical use and the FDA recommends determining if the investigational drug is a substrate and/or an inhibitor of those key transporters.
Why use in vitro assays?
In vitro studies are part of an integrated approach to reduce unnecessary clinical studies. Negative in vitro results can preclude the need for clinical drug-drug interaction (DDI) studies; in some cases it is also possible to waive clinical studies for compounds that do interact with P-gp and/or BCRP (find more information on biowaivers on page 42). If clinical DDI studies are required, then in vitro results may serve as the basis for design of those studies. Similarly, the results of clinical DDI studies help to explain and refine predictive in vitro models or tools.
Timing of in vitro evaluation
Because it is recommended to evaluate all investigational drugs as inhibitors of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1 and MATE2-K, and as substrates of P-gp and BCRP, it is suggested to investigate these transporters relatively early in drug development. Furthermore, knowing if the investigational drug is a potential substrate or inhibitor of one of these transporters can help with potential clinical studies down the road.
Bile Salt Export Pump (BSEP)
Breast Cancer Resistance Protein (BCRP)
Multidrug and Toxin Extrusion (MATE)
Multidrug Resistance-Associated Protein (MDR)
Organic Anion Transporter (OAT)
Organic Anion Transporter Polypeptides (OATP)
Organic Cation Transporter (OCT)
CellPort Test Systems
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Transporter Evaluation Systems
|NTCP-HEK293||PepT1 (C2BBe1)||Custom Development|
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Off-the-shelf and custom designs for maximum utility at every stage of development
|Substrate||Single Concentration||Multiple Concentrations, Inhibitor Challenge, Km/Vmax|
|Inhibition||Single Concentration||Multiple Concentrations, IC50|
Extensively characterized test systems using the most clinically-relevant substrates and inhibitors for complete regulatory confidence.
|MDR1||Digoxin , Etoposide, Fexofenadine, Amprenavir, Talinolol, Loperamide||Valspodar, Cyclosporin A, Vinblastin, Ketoconazole, Loperamide|
|BCRP||Cladribine, Topotecan, Prazosin, Cimetidine, Sulfasalazine, Mitoxantrone, Actinomycin D, Doxorubicin, Estrone-3-Sulfate, Etoposide, Irinotecen, Rosuvastatin, Daunorubicin, SN-38, Fexofenadine||Ko143, Elacridar, FTC|
|OCT1||MPP+, Amantadine, Amiloride, Metformin, Pindolol, Procainamide, Propanolol, Ranitidine||Repaglinide, Disopyramide, Quinine, Quinidine, Cimetidine, Rosiglitazone, Triethylamine, Metformin|
|OCT2||MPP+, Pindolol, Ranitidine, Procainamide, Amiloride, Amantadine||Imipramine, TPA, Verapamil, Quinidine, Cimetidine, Metformin, Dopamine, Triethylamine|
|OAT1||PAH, Adefovir, Cidofovir, Furosemide, Lamivudine, Tenofovir, Zidovudine||Probenecid, Bumetanide, Novobiocin, Quinaprilat, TEA, Methotrexate, Lamivudine|
|OAT3||Furosemide, Bumetanide, Cefaclor, Quinaprilat||Probenecid, Bumetanide, Novobiocin, Quinaprilat, Rosuvastatin, Naproxen|
|OATP1B1||Atorvastatin, Rosuvastatin, Pitavastatin||Rifamycin SV, Atenolol, Cyclosporin A, Digoxin, Estrone-3-Sulfate, Estradiol-17β Glucuronide, Ketoconazole, Propranolol, Rifampicin, Ritonavir, Rosuvastatin, Taurocholic Acid, Tolbutamide, Verapamil|
|OATP1B3||Atorvastatin, Pitavastatin, Rosuvastatin||Rifamycin SV, Rifampicin, Rosuvastatin, Taurocholic Acid, Ritonavir, Cyclosporin A, Estradiol-17β Glucuronide, Estrone-3-Sulfate, Atenolol, Propranolol, Digoxin|
|MATE1||Metformin, MPP+, Cimetidine, Amiloride||Cimetidine, Atenolol, Triethylamine, Amantadine, Imipramine, Disopyramide, MPP+, Verapamil, Quinidine, Ritonavir|
|MATE2K||Metformin, MPP+, Cimetidine, Amiloride||Pyrimethamine, Ondansetron, Quinidine|
|BSEP||[3H] Taurocholic acid||Cyclosporin A, Troglitazone|