Drug-transporter interaction testing in drug discovery and development

Table 1 Characteristics of transporters on the shortlists of regulatory

Transporter	Expression (tissue/cell type/localization)	Physiological substrates	Select drug substrates	Guidance
P-gp	Brain/endothelial cell/apical	Phospholipids, cytokines, steroids	Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, indinavir, itraconazole, lapatinib, maraviroc, nilotinib, paclitaxel, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan, vinca alkaloids	FDA/ EMA
	Kidney/epithelial cell/apical
	Liver/hepatocyte/canalicular
	Small intestine/enterocyte/apical
	(colon)
BCRP	Brain/endothelial cell/apical	Vitamins (riboflavin, biotin), porphyrins, estrogen sulfate conjugates	Methotrexate, mitoxantrone, daunorubicin, doxorubicin, imatinib, irrinotecan, lapatinib, rosuvastatin, pitavastatin, provastatin, sulfasalazine, topotecan	FDA/ EMA
	Liver/hepatocyte/canalicular
	Small intestine/enterocyte/apical
	Kidney/epithelial cell/apical
	Placenta/syncytiotrophoblast/apical (maternal)
BSEP	Liver/hepatocyte/canalicular	Taurocholate, glycocholate	Pravastatin, paclitaxel, vinblastine	EMA
OATP1B1	Liver/hepatocyte/basolateral	Bilirubin and its conjugates, thyroxin, triiodothyronine, bile acids, eicosanoids (thromboxane B2, prostaglandin E2, leukotriene C4), dehydroepiandrosterone sulfate, estradiol 17β-glucuronide, estrone 3-sulfate, glycocholate	Atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, methotrexate, olmesartan, pitavastatin, pravastatin, repaglinide, rifampin, rosuvastatin, simvastatin acid, SN-38 (active metabolite of irinotecan), valsartan	FDA/ EMA
OATP1B3	Liver/hepatocyte/basolateral	Estradiol 17β-glucuronide, taurocholate, estrone 3-sulfate, dehydroepiandrosterone sulfate, thyoxin	Atorvastatin, bosentan, digoxin, methotrexate, olmesartan, paclitaxel, pitavastatin, rosuvastatin, telmisartan, valsartan	FDA/ EMA
OAT1	Kidney/proximal tubular cell/basolateral	Para-aminohippuric acid, homocysteine, Cysteine,dicarboxylates, prostaglandine E2, urate, estrone-3-sulfate	Adefovir, captopril, cidofovir, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, zalcitabine, zidovudine	FDA/ EMA
OAT3	Kidney/proximal tubular cell/basolateral	Estrone 3-sulfate, estradiol 17β-glucoronide, cAMP, taurocholate, cortisol, dehydroepiandrosterone sulfate, prostaglandine E2, urate, succinate, para-aminohippuric acid	Acyclovir, bumetanide, ciprofloxacin, famotidine, furosemide, methotrexate, oseltamivir acid, (the active metabolite of oseltamivir), penicillin G, pravastatin, rosuvastatin, sitagliptin, valacyclovir, zidovudine	FDA/ EMA
1-Oct	Liver/hepatocyte/basolateral	Corticosterone, β-oestradiol, progesterone, testosterone, choline, creatinine, guanidine, L-carnitine, thiamine, thyramine, acetylcholine, dopamine	Acyclovir, amantadine, gancyclovir, imatinib, lamivudin, metformin, oxaliplatin, quinidine, quinine, ranitidine, zalcitabine	EMA
	Small intestine/enterocyte/basolateral
2-Oct	Kidney/epithelial cell/ basolateral	β-oestradiol, progesterone, testosterone, choline, creatinine, guanidine, L-carnitine, acetylcholine, dopamine, epinephrine, norepinephrine, histamin, serotonin, choline, dopamine, prostagladine E2	Amantadine, amilorid, cimetidine, cisplatin, dofetilide, famotidine, lamivudin, metformin, oxaliplatin, pindolol, procainamide, ranitidine, zalcitabine	FDA/ EMA
MATE1	Kidney/epithelial cell/apical	Choline, creatinine, guanidine, corticosterone, estrone 3-sulfate, thiamine	Acyclovir, cimetidine, fexofenadine, gancyclovir, metformin, procainamide, topotecan	EMA
	Liver/hepatocyte/canalicular
MATE2/MATE2K	Kidney/epithelial cell/apical	Choline, creatinine, guanidine, corticosterone, estrone 3-sulfate, thiamine	Acyclovir, cimetidine, gancyclovir, metformin, procainamide, topotecan	EMA

FDA: Food and Drug Administration; P-gp: P-glycoprotein; EMA: European Medicines Agency; BCRP: Breast cancer resistance protein; OAT: Organic anion transporter; OCT: Organic cation transporter; MATE1: Multidrug and toxin extrusion protein 1.