Abstract
Drug transporters play an important role in the absorption, distribution, and elimination of drugs and their metabolites. Drug transporters can be subdivided into solute carrier (SLC) and ATP-binding cassette (ABC) family. SLC transporters are secondary active transporters that work as uptake transporters, whereas ABC transporters are primary active transporters that work as efflux transporters. Knockout animal models that lack a specific transporter gene(s) are excellent tools to study the function of a drug transporter. In recent times, various gene knockout animal models have been developed that have significantly contributed in defining the roles of these transporters in vivo; for example, the roles of multidrug resistance protein, breast cancer resistance protein, multidrug resistance–related proteins, organic anionic transporters, organic cationic transporters, and organic anion transporting polypeptides have received great attention after their knockout models were generated. In this review, we aim to summarize the in vivo roles of drug transporters based on studies using knockout animal models.
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References
Adachi M, Reid G, Schuetz JD (2002) Therapeutic and biological importance of getting nucleotides out of cells: a case for the ABC transporters, MRP4 and 5. Adv Drug Deliv Rev 54(10):1333–1342
Agarwal S, Sane R, Ohlfest JR, Elmquist WF (2011) The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. J Pharmacol Exp Ther 336(1):223–233
Agarwal S, Uchida Y, Mittapalli RK, Sane R, Terasaki T, Elmquist WF (2012) Quantitative proteomics of transporter expression in brain capillary endothelial cells isolated from P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and P-gp/Bcrp knockout mice. Drug Metab Dispos 40(6):1164–1169
Alvarez AI, Vallejo F, Barrera B, Merino G, Prieto JG, Tomas-Barberan F, Espin JC (2011) Bioavailability of the glucuronide and sulfate conjugates of genistein and daidzein in breast cancer resistance protein 1 knockout mice. Drug Metab Dispos 39(11):2008–2012
Belinsky MG, Guo P, Lee K, Zhou F, Kotova E, Grinberg A, Westphal H, Shchaveleva I, Klein-Szanto A, Gallo JM, Kruh GD (2007) Multidrug resistance protein 4 protects bone marrow, thymus, spleen, and intestine from nucleotide analogue-induced damage. Cancer Res 67(1):262–268
Brouwer KL, Keppler D, Hoffmaster KA, Bow DA, Cheng Y, Lai Y, Palm JE, Stieger B, Evers R (2013) In vitro methods to support transporter evaluation in drug discovery and development. Clin Pharmacol Ther 94(1):95–112
Brown SM, Campbell SD, Crafford A, Regina KJ, Holtzman MJ, Kharasch ED (2012) P-glycoprotein is a major determinant of norbuprenorphine brain exposure and antinociception. J Pharmacol Exp Ther 343(1):53–61
Chen C, Pollack GM (1998) Altered disposition and antinociception of [D-penicillamine(2,5)] enkephalin in mdr1a-gene-deficient mice. J Pharmacol Exp Ther 287(2):545–552
Choi MK, Song IS (2012) Involvement of multidrug resistance proteins (MRPs) in the efflux of vardenafil. J Pharm Investig 42(2):65–70
Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B, Pavenstadt H, Lanvers-Kaminsky C, am Zehnhoff-Dinnesen A, Schinkel AH, Koepsell H, Jurgens H, Schlatter E (2010) Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol 176(3):1169–1180
Ciarimboli G, Lancaster CS, Schlatter E, Franke RM, Sprowl JA, Pavenstadt H, Massmann V, Guckel D, Mathijssen RH, Yang W, Pui CH, Relling MV, Herrmann E, Sparreboom A (2012) Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. Clin Cancer Res 18(4):1101–1108
Cisternino S, Rousselle C, Lorico A, Rappa G, Scherrmann JM (2003) Apparent lack of Mrp1-mediated efflux at the luminal side of mouse blood–brain barrier endothelial cells. Pharm Res 20(6):904–909
Cisternino S, Mercier C, Bourasset F, Roux F, Scherrmann JM (2004) Expression, up-regulation, and transport activity of the multidrug-resistance protein Abcg2 at the mouse blood–brain barrier. Cancer Res 64(9):3296–3301
Cox DS, Scott KR, Gao H, Raje S, Eddington ND (2001) Influence of multidrug resistance (MDR) proteins at the blood–brain barrier on the transport and brain distribution of enaminone anticonvulsants. J Pharm Sci 90(10):1540–1552
Csanaky IL, Lu H, Zhang Y, Ogura K, Choudhuri S, Klaassen CD (2011) Organic anion-transporting polypeptide 1b2 (Oatp1b2) is important for the hepatic uptake of unconjugated bile acids: studies in Oatp1b2-null mice. Hepatology 53(1):272–281
Dagenais C, Ducharme J, Pollack GM (2002) Interaction of nonpeptidic delta agonists with P-glycoprotein by in situ mouse brain perfusion: liquid chromatography–mass spectrometry analysis and internal standard strategy. J Pharm Sci 91(1):244–252
Daniel H, Kottra G (2004) The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pflugers Arch 447(5):610–618
de Lange EC, de Bock G, Schinkel AH, de Boer AG, Breimer DD (1998) BBB transport and P-glycoprotein functionality using MDR1A (-/-) and wild-type mice. Total brain versus microdialysis concentration profiles of rhodamine-123. Pharm Res 15(11):1657–1665
de Vries NA, Buckle T, Zhao J, Beijnen JH, Schellens JH, van Tellingen O (2012) Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. Invest New Drugs 30(2):443–449
Deeken JF, Loscher W (2007) The blood–brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 13(6):1663–1674
Eisenblatter T, Galla HJ (2002) A new multidrug resistance protein at the blood–brain barrier. Biochem Biophys Res Commun 293(4):1273–1278
Eisner C, Faulhaber-Walter R, Wang Y, Leelahavanichkul A, Yuen PS, Mizel D, Star RA, Briggs JP, Levine M, Schnermann J (2010) Major contribution of tubular secretion to creatinine clearance in mice. Kidney Int 77(6):519–526
Elmquist WF, Miller DW (2001) The use of transgenic mice in pharmacokinetic and pharmacodynamic studies. J Pharm Sci 90(4):422–435
Emslie D, D’Costa K, Hasbold J, Metcalf D, Takatsu K, Hodgkin PO, Corcoran LM (2008) Oct2 enhances antibody-secreting cell differentiation through regulation of IL-5 receptor alpha chain expression on activated B cells. J Exp Med 205(2):409–421
Enokizono J, Kusuhara H, Sugiyama Y (2007) Effect of breast cancer resistance protein (Bcrp/Abcg2) on the disposition of phytoestrogens. Mol Pharmacol 72(4):967–975
Eraly SA, Vallon V, Vaughn DA, Gangoiti JA, Richter K, Nagle M, Monte JC, Rieg T, Truong DM, Long JM, Barshop BA, Kaler G, Nigam SK (2006) Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J Biol Chem 281(8):5072–5083
Estudante M, Morais JG, Soveral G, Benet LZ (2013) Intestinal drug transporters: an overview. Adv Drug Deliv Rev 65(10):1340–1356
Foucaud-Vignault M, Soayfane Z, Menez C, Bertrand-Michel J, Martin PG, Guillou H, Collet X, Lespine A (2011) P-glycoprotein dysfunction contributes to hepatic steatosis and obesity in mice. PLoS One 6(9):e23614
Franke RM, Kosloske AM, Lancaster CS, Filipski KK, Hu C, Zolk O, Mathijssen RH, Sparreboom A (2010) Influence of Oct1/Oct2-deficiency on cisplatin-induced changes in urinary N-acetyl-beta-d-glucosaminidase. Clin Cancer Res 16(16):4198–4206
Gao B, Stieger B, Noe B, Fritschy JM, Meier PJ (1999) Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. J Histochem Cytochem 47(10):1255–1264
Higgins JW, Bao JQ, Ke AB, Manro JR, Fallon JK, Smith PC, Zamek-Gliszczynski MJ (2014) Utility of Oatp1a/1b-knockout and OATP1B1/3-humanized mice in the study of OATP-mediated pharmacokinetics and tissue distribution: case studies with pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein. Drug Metab Dispos 42(1):182–192
Hirrlinger J, Konig J, Dringen R (2002) Expression of mRNAs of multidrug resistance proteins (Mrps) in cultured rat astrocytes, oligodendrocytes, microglial cells and neurones. J Neurochem 82(3):716–719
Hopper-Borge EA, Churchill T, Paulose C, Nicolas E, Jacobs JD, Ngo O, Kuang Y, Grinberg A, Westphal H, Chen ZS, Klein-Szanto AJ, Belinsky MG, Kruh GD (2011) Contribution of Abcc10 (Mrp7) to in vivo paclitaxel resistance as assessed in Abcc10(-/-) mice. Cancer Res 71(10):3649–3657
Hosten B, Boisgard R, Jacob A, Goutal S, Saubamea B, Dolle F, Scherrmann JM, Cisternino S, Tournier N (2013) [(1)(1)C]befloxatone brain kinetics is not influenced by Bcrp function at the blood–brain barrier: a PET study using Bcrp TGEM knockout rats. Eur J Pharm Sci 50(3–4):520–525
Hu Y, Smith DE, Ma K, Jappar D, Thomas W, Hillgren KM (2008) Targeted disruption of peptide transporter Pept1 gene in mice significantly reduces dipeptide absorption in intestine. Mol Pharm 5(6):1122–1130
Huang L, Be X, Tchaparian EH, Colletti AE, Roberts J, Langley M, Ling Y, Wong BK, Jin L (2012) Deletion of Abcg2 has differential effects on excretion and pharmacokinetics of probe substrates in rats. J Pharmacol Exp Ther 343(2):316–324
Imaoka T, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y (2007) Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Mol Pharmacol 71(2):619–627
International Transporter Consortium (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9(3):215–236
Irie M, Terada T, Okuda M, Inui K (2004) Efflux properties of basolateral peptide transporter in human intestinal cell line Caco-2. Pflugers Arch 449(2):186–194
Jappar D, Wu SP, Hu Y, Smith DE (2010) Significance and regional dependency of peptide transporter (PEPT) 1 in the intestinal permeability of glycylsarcosine: in situ single-pass perfusion studies in wild-type and Pept1 knockout mice. Drug Metab Dispos 38(10):1740–1746
Johnson DR, Finch RA, Lin ZP, Zeiss CJ, Sartorelli AC (2001) The pharmacological phenotype of combined multidrug-resistance mdr1a/1b- and mrp1-deficient mice. Cancer Res 61(4):1469–1476
Jonker JW, Wagenaar E, Mol CA, Buitelaar M, Koepsell H, Smit JW, Schinkel AH (2001) Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol Cell Biol 21(16):5471–5477
Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, Plosch T, Kuipers F, Elferink RP, Rosing H, Beijnen JH, Schinkel AH (2002) The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci USA 99(24):15649–15654
Jonker JW, Wagenaar E, Van Eijl S, Schinkel AH (2003) Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol 23(21):7902–7908
Kannan P, Telu S, Shukla S, Ambudkar SV, Pike VW, Halldin C, Gottesman MM, Innis RB, Hall MD (2011) The “specific” P-glycoprotein inhibitor Tariquidar is also a substrate and an inhibitor for breast cancer resistance protein (BCRP/ABCG2). ACS Chem Neurosci 2(2):82–89
Karssen AM, Meijer OC, van der Sandt IC, De Boer AG, De Lange EC, De Kloet ER (2002) The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone. J Endocrinol 175(1):251–260
Kawahara M, Sakata A, Miyashita T, Tamai I, Tsuji A (1999) Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice. J Pharm Sci 88(12):1281–1287
Kayouka M, Houze P, Baud FJ, Cisternino S, Debray M, Risede P, Schinkel AH, Warnet JM (2011) Does modulation of organic cation transporters improve pralidoxime activity in an animal model of organophosphate poisoning? Crit Care Med 39(4):803–811
Kido Y, Tamai I, Ohnari A, Sai Y, Kagami T, Nezu J, Nikaido H, Hashimoto N, Asano M, Tsuji A (2001) Functional relevance of carnitine transporter OCTN2 to brain distribution of L-carnitine and acetyl-L-carnitine across the blood–brain barrier. J Neurochem 79(5):959–969
Kikuchi T, Okamura T, Wakizaka H, Okada M, Odaka K, Yui J, Tsuji AB, Fukumura T, Zhang MR (2014) OAT3-mediated extrusion of the 99mTc-ECD metabolite in the mouse brain. J Cereb Blood Flow Metab 34(4):585–588
Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, Wilkinson GR (1998) The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 101(2):289–294
Kohler JJ, Hosseini SH, Green E, Abuin A, Ludaway T, Russ R, Santoianni R, Lewis W (2011) Tenofovir renal proximal tubular toxicity is regulated by OAT1 and MRP4 transporters. Lab Invest 91(6):852–858
Kwei GY, Alvaro RF, Chen Q, Jenkins HJ, Hop CE, Keohane CA, Ly VT, Strauss JR, Wang RW, Wang Z, Pippert TR, Umbenhauer DR (1999) Disposition of ivermectin and cyclosporin A in CF-1 mice deficient in mdr1a P-glycoprotein. Drug Metab Dispos 27(5):581–587
Lagas JS, Fan L, Wagenaar E, Vlaming ML, van Tellingen O, Beijnen JH, Schinkel AH (2010) P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 determine the pharmacokinetics of etoposide. Clin Cancer Res 16(1):130–140
Lancaster CS, Hu C, Franke RM, Filipski KK, Orwick SJ, Chen Z, Zuo Z, Loos WJ, Sparreboom A (2010) Cisplatin-induced downregulation of OCTN2 affects carnitine wasting. Clin Cancer Res 16(19):4789–4799
Lee YJ, Kusuhara H, Sugiyama Y (2004) Do multidrug resistance-associated protein-1 and -2 play any role in the elimination of estradiol-17 beta-glucuronide and 2,4-dinitrophenyl-S-glutathione across the blood–cerebrospinal fluid barrier? J Pharm Sci 93(1):99–107
Lee YJ, Kusuhara H, Jonker JW, Schinkel AH, Sugiyama Y (2005) Investigation of efflux transport of dehydroepiandrosterone sulfate and mitoxantrone at the mouse blood–brain barrier: a minor role of breast cancer resistance protein. J Pharmacol Exp Ther 312(1):44–52
Lin F, Marchetti S, Pluim D, Iusuf D, Mazzanti R, Schellens JH, Beijnen JH, van Tellingen O (2013) Abcc4 together with abcb1 and abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues. Clin Cancer Res 19(8):2084–2095
Lu H, Choudhuri S, Ogura K, Csanaky IL, Lei X, Cheng X, Song PZ, Klaassen CD (2008) Characterization of organic anion transporting polypeptide 1b2-null mice: essential role in hepatic uptake/toxicity of phalloidin and microcystin-LR. Toxicol Sci 103(1):35–45
Marchetti S, de Vries NA, Buckle T, Bolijn MJ, van Eijndhoven MA, Beijnen JH, Mazzanti R, van Tellingen O, Schellens JH (2008) Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice. Mol Cancer Ther 7(8):2280–2287
Meijer OC, de Lange EC, Breimer DD, de Boer AG, Workel JO, de Kloet ER (1998) Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 139(4):1789–1793
Minich T, Riemer J, Schulz JB, Wielinga P, Wijnholds J, Dringen R (2006) The multidrug resistance protein 1 (Mrp1), but not Mrp5, mediates export of glutathione and glutathione disulfide from brain astrocytes. J Neurochem 97(2):373–384
Mittapalli RK, Vaidhyanathan S, Sane R, Elmquist WF (2012) Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032). J Pharmacol Exp Ther 342(1):33–40
Miyajima M, Kusuhara H, Fujishima M, Adachi Y, Sugiyama Y (2011) Organic anion transporter 3 mediates the efflux transport of an amphipathic organic anion, dehydroepiandrosterone sulfate, across the blood–brain barrier in mice. Drug Metab Dispos 39(5):814–819
Miyama T, Takanaga H, Matsuo H, Yamano K, Yamamoto K, Iga T, Naito M, Tsuruo T, Ishizuka H, Kawahara Y, Sawada Y (1998) P-glycoprotein-mediated transport of itraconazole across the blood–brain barrier. Antimicrob Agents Chemother 42(7):1738–1744
Mizuno N, Suzuki M, Kusuhara H, Suzuki H, Takeuchi K, Niwa T, Jonker JW, Sugiyama Y (2004) Impaired renal excretion of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) sulfate in breast cancer resistance protein (BCRP1/ABCG2) knockout mice. Drug Metab Dispos 32(9):898–901
Morimoto K, Nakakariya M, Shirasaka Y, Kakinuma C, Fujita T, Tamai I, Ogihara T (2008) Oseltamivir (Tamiflu) efflux transport at the blood–brain barrier via P-glycoprotein. Drug Metab Dispos 36(1):6–9
Morrissey KM, Wen CC, Johns SJ, Zhang L, Huang SM, Giacomini KM (2012) The UCSF-FDA TransPortal: a public drug transporter database. Clin Pharmacol Ther 92(5):545–546
Muller MB, Keck ME, Binder EB, Kresse AE, Hagemeyer TP, Landgraf R, Holsboer F, Uhr M (2003) ABCB1 (MDR1)-type P-glycoproteins at the blood–brain barrier modulate the activity of the hypothalamic-pituitary-adrenocortical system: implications for affective disorder. Neuropsychopharmacology 28(11):1991–1999
Naba H, Kuwayama C, Kakinuma C, Ohnishi S, Ogihara T (2004) Eisai hyperbilirubinemic rat (EHBR) as an animal model affording high drug-exposure in toxicity studies on organic anions. Drug Metab Pharmacokinet 19(5):339–351
Nagle MA, Wu W, Eraly SA, Nigam SK (2013) Organic anion transport pathways in antiviral handling in choroid plexus in Oat1 (Slc22a6) and Oat3 (Slc22a8) deficient tissue. Neurosci Lett 534:133–138
Nakamura T, Satoh T, Horie T, Sagami F, Tagaya O (1989) Strain differences of rat liver carboxylesterase activities related to the phenotype difference of esterase-3 (egasyn). Res Commun Chem Pathol Pharmacol 66(3):451–459
Nishino J, Suzuki H, Sugiyama D, Kitazawa T, Ito K, Hanano M, Sugiyama Y (1999) Transepithelial transport of organic anions across the choroid plexus: possible involvement of organic anion transporter and multidrug resistance-associated protein. J Pharmacol Exp Ther 290(1):289–294
Ocheltree SM, Shen H, Hu Y, Keep RF, Smith DE (2005) Role and relevance of peptide transporter 2 (PEPT2) in the kidney and choroid plexus: in vivo studies with glycylsarcosine in wild-type and PEPT2 knockout mice. J Pharmacol Exp Ther 315(1):240–247
Ose A, Kusuhara H, Endo C, Tohyama K, Miyajima M, Kitamura S, Sugiyama Y (2010) Functional characterization of mouse organic anion transporting peptide 1a4 in the uptake and efflux of drugs across the blood–brain barrier. Drug Metab Dispos 38(1):168–176
Oude Elferink RP, Meijer DK, Kuipers F, Jansen PL, Groen AK, Groothuis GM (1995) Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport. Biochim Biophys Acta 1241(2):215–268
Polli JW, Olson KL, Chism JP, John-Williams LS, Yeager RL, Woodard SM, Otto V, Castellino S, Demby VE (2009) An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos 37(2):439–442
Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC, Piwnica-Worms D (1999) Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood–cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A 96(7):3900–3905
Rappa G, Finch RA, Sartorelli AC, Lorico A (1999) New insights into the biology and pharmacology of the multidrug resistance protein (MRP) from gene knockout models. Biochem Pharmacol 58(4):557–562
Romermann K, Wanek T, Bankstahl M, Bankstahl JP, Fedrowitz M, Muller M, Loscher W, Kuntner C, Langer O (2013) (R)-[(11)C]verapamil is selectively transported by murine and human P-glycoprotein at the blood–brain barrier, and not by MRP1 and BCRP. Nucl Med Biol 40(7):873–878
Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CA, van der Valk MA, Robanus-Maandag EC, te Riele HP et al (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77(4):491–502
Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P (1995) Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 96(4):1698–1705
Schinkel AH, Wagenaar E, Mol CA, van Deemter L (1996) P-glycoprotein in the blood–brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97(11):2517–2524
Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, van der Valk MA, Voordouw AC, Spits H, van Tellingen O, Zijlmans JM, Fibbe WE, Borst P (1997) Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci U S A 94(8):4028–4033
Shen H, Ocheltree SM, Hu Y, Keep RF, Smith DE (2007) Impact of genetic knockout of PEPT2 on cefadroxil pharmacokinetics, renal tubular reabsorption, and brain penetration in mice. Drug Metab Dispos 35(7):1209–1216
Shin YJ, Lee JH, Oh JH, Lee YJ (2013) Low-dose probenecid selectively inhibits urinary excretion of phenolsulfonphthalein in rats without affecting biliary excretion. J Appl Toxicol 33(6):511–515
Shitara Y, Maeda K, Ikejiri K, Yoshida K, Horie T, Sugiyama Y (2013) Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos 34(1):45–78
Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, Yue L, Lo JC, Burchard EG, Brett CM, Giacomini KM (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117(5):1422–1431
Shukla S, Zaher H, Hartz A, Bauer B, Ware JA, Ambudkar SV (2009) Curcumin inhibits the activity of ABCG2/BCRP1, a multidrug resistance-linked ABC drug transporter in mice. Pharm Res 26(2):480–487
Smith BJ, Doran AC, McLean S, Tingley FD 3rd, O’Neill BT, Kajiji SM (2001) P-glycoprotein efflux at the blood–brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists. J Pharmacol Exp Ther 298(3):1252–1259
Sprowl JA, Ciarimboli G, Lancaster CS, Giovinazzo H, Gibson AA, Du G, Janke LJ, Cavaletti G, Shields AF, Sparreboom A (2013) Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proc Natl Acad Sci U S A 110(27):11199–11204
Swain MD, Orzechowski KL, Swaim HL, Jones YL, Robl MG, Tinaza CA, Myers MJ, Jhingory MV, Buckely LE, Lancaster VA, Yancy HF (2013) P-gp substrate-induced neurotoxicity in an Abcb1a knock-in/Abcb1b knock-out mouse model with a mutated canine ABCB1 targeted insertion. Res Vet Sci 94(3):656–661
Sweeney DE, Vallon V, Rieg T, Wu W, Gallegos TF, Nigam SK (2011) Functional maturation of drug transporters in the developing, neonatal, and postnatal kidney. Mol Pharmacol 80(1):147–154
Sweet DH, Miller DS, Pritchard JB, Fujiwara Y, Beier DR, Nigam SK (2002) Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J Biol Chem 277(30):26934–26943
Tahara H, Kusuhara H, Fuse E, Sugiyama Y (2005) P-glycoprotein plays a major role in the efflux of fexofenadine in the small intestine and blood–brain barrier, but only a limited role in its biliary excretion. Drug Metab Dispos 33(7):963–968
Takenaka K, Morgan JA, Scheffer GL, Adachi M, Stewart CF, Sun D, Leggas M, Ejendal KF, Hrycyna CA, Schuetz JD (2007) Substrate overlap between Mrp4 and Abcg2/Bcrp affects purine analogue drug cytotoxicity and tissue distribution. Cancer Res 67(14):6965–6972
Tang SC, Hendrikx JJ, Beijnen JH, Schinkel AH (2013) Genetically modified mouse models for oral drug absorption and disposition. Curr Opin Pharmacol 13(6):853–858
Tian X, Swift B, Zamek-Gliszczynski MJ, Belinsky MG, Kruh GD, Brouwer KL (2008) Impact of basolateral multidrug resistance-associated protein (Mrp) 3 and Mrp4 on the hepatobiliary disposition of fexofenadine in perfused mouse livers. Drug Metab Dispos 36(5):911–915
Torres AM, Dnyanmote AV, Bush KT, Wu W, Nigam SK (2011) Deletion of multispecific organic anion transporter Oat1/Slc22a6 protects against mercury-induced kidney injury. J Biol Chem 286(30):26391–26395
Toyama K, Yonezawa A, Masuda S, Osawa R, Hosokawa M, Fujimoto S, Inagaki N, Inui K, Katsura T (2012) Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis. Br J Pharmacol 166(3):1183–1191
Tsuda M, Terada T, Mizuno T, Katsura T, Shimakura J, Inui K (2009) Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. Mol Pharmacol 75(6):1280–1286
Vallon V, Eraly SA, Wikoff WR, Rieg T, Kaler G, Truong DM, Ahn SY, Mahapatra NR, Mahata SK, Gangoiti JA, Wu W, Barshop BA, Siuzdak G, Nigam SK (2008a) Organic anion transporter 3 contributes to the regulation of blood pressure. J Am Soc Nephrol 19(9):1732–1740
Vallon V, Rieg T, Ahn SY, Wu W, Eraly SA, Nigam SK (2008b) Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol Renal Physiol 294(4):F867–F873
Vallon V, Eraly SA, Rao SR, Gerasimova M, Rose M, Nagle M, Anzai N, Smith T, Sharma K, Nigam SK, Rieg T (2012) A role for the organic anion transporter OAT3 in renal creatinine secretion in mice. Am J Physiol Renal Physiol 302(10):F1293–F1299
van Asperen J, van Tellingen O, Schinkel AH, Beijnen JH (1999) Comparative pharmacokinetics of vinblastine after a 96-hour continuous infusion in wild-type mice and mice lacking mdr1a P-glycoprotein. J Pharmacol Exp Ther 289(1):329–333
van de Steeg E, Wagenaar E, van der Kruijssen CM, Burggraaff JE, de Waart DR, Elferink RP, Kenworthy KE, Schinkel AH (2010) Organic anion transporting polypeptide 1a/1b-knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs. J Clin Invest 120(8):2942–2952
van de Steeg E, van Esch A, Wagenaar E, Kenworthy KE, Schinkel AH (2013) Influence of human OATP1B1, OATP1B3, and OATP1A2 on the pharmacokinetics of methotrexate and paclitaxel in humanized transgenic mice. Clin Pharmacol Ther 19(4):821–832
van der Deen M, Timens W, Timmer-Bosscha H, van der Strate BW, Scheper RJ, Postma DS, de Vries EG, Kerstjens HA (2007) Reduced inflammatory response in cigarette smoke exposed Mrp1/Mdr1a/1b deficient mice. Respir Res 8:49
Vanwert AL, Bailey RM, Sweet DH (2007) Organic anion transporter 3 (Oat3/Slc22a8) knockout mice exhibit altered clearance and distribution of penicillin G. Am J Physiol Renal Physiol 293(4):F1332–F1341
Vanwert AL, Srimaroeng C, Sweet DH (2008) Organic anion transporter 3 (oat3/slc22a8) interacts with carboxyfluoroquinolones, and deletion increases systemic exposure to ciprofloxacin. Mol Pharmacol 74(1):122–131
Vialou V, Amphoux A, Zwart R, Giros B, Gautron S (2004) Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation. J Neurosci 24(11):2846–2851
Vialou V, Balasse L, Callebert J, Launay JM, Giros B, Gautron S (2008) Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J Neurochem 106(3):1471–1482
Vlaming ML, Mohrmann K, Wagenaar E, de Waart DR, Elferink RP, Lagas JS, van Tellingen O, Vainchtein LD, Rosing H, Beijnen JH, Schellens JH, Schinkel AH (2006) Carcinogen and anticancer drug transport by Mrp2 in vivo: studies using Mrp2 (Abcc2) knockout mice. J Pharmacol Exp Ther 318(1):319–327
Walker AL, Lancaster CS, Finkelstein D, Ware RE, Sparreboom A (2013) Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics. Am J Physiol Cell Physiol 305(12):C1223–C1229
Walters HC, Craddock AL, Fusegawa H, Willingham MC, Dawson PA (2000) Expression, transport properties, and chromosomal location of organic anion transporter subtype 3. Am J Physiol Gastrointest Liver Physiol 279(6):G1188–G1200
Watanabe S, Tsuda M, Terada T, Katsura T, Inui K (2010) Reduced renal clearance of a zwitterionic substrate cephalexin in MATE1-deficient mice. J Pharmacol Exp Ther 334(2):651–656
Wijnholds J, deLange EC, Scheffer GL, van den Berg DJ, Mol CA, van der Valk M, Schinkel AH, Scheper RJ, Breimer DD, Borst P (2000a) Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood–cerebrospinal fluid barrier. J Clin Invest 105(3):279–285
Wijnholds J, Mol CA, van Deemter L, de Haas M, Scheffer GL, Baas F, Beijnen JH, Scheper RJ, Hatse S, De Clercq E, Balzarini J, Borst P (2000b) Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci U S A 97(13):7476–7481
Wikoff WR, Nagle MA, Kouznetsova VL, Tsigelny IF, Nigam SK (2011) Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1). J Proteome Res 10(6):2842–2851
Wu SP, Smith DE (2013) Impact of intestinal PepT1 on the kinetics and dynamics of N-formyl-methionyl-leucyl-phenylalanine, a bacterially-produced chemotactic peptide. Mol Pharm 10(2):677–684
Xue X, Gong LK, Maeda K, Luan Y, Qi XM, Sugiyama Y, Ren J (2011) Critical role of organic anion transporters 1 and 3 in kidney accumulation and toxicity of aristolochic acid I. Mol Pharm 8(6):2183–2192
Yang B, Smith DE (2013) Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild-type and PepT1 knockout mice. Drug Metab Dispos 41(3):608–614
Yang Z, Zhu W, Gao S, Yin T, Jiang W, Hu M (2012) Breast cancer resistance protein (ABCG2) determines distribution of genistein phase II metabolites: reevaluation of the roles of ABCG2 in the disposition of genistein. Drug Metab Dispos 40(10):1883–1893
You G, Morris ME (2007) Drug transporters : molecular characterization and role in drug disposition. Wiley, Hoboken
Zaher H, Khan AA, Palandra J, Brayman TG, Yu L, Ware JA (2006) Breast cancer resistance protein (Bcrp/abcg2) is a major determinant of sulfasalazine absorption and elimination in the mouse. Mol Pharm 3(1):55–61
Zaher H, Meyer zu Schwabedissen HE, Tirona RG, Cox ML, Obert LA, Agrawal N, Palandra J, Stock JL, Kim RB, Ware JA (2008) Targeted disruption of murine organic anion-transporting polypeptide 1b2 (Oatp1b2/Slco1b2) significantly alters disposition of prototypical drug substrates pravastatin and rifampin. Mol Pharmacol 74(2):320–329
Zamek-Gliszczynski MJ, Nezasa K, Tian X, Bridges AS, Lee K, Belinsky MG, Kruh GD, Brouwer KL (2006a) Evaluation of the role of multidrug resistance-associated protein (Mrp) 3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3-/- and Abcc4-/- mice. J Pharmacol Exp Ther 319(3):1485–1491
Zamek-Gliszczynski MJ, Nezasa K, Tian X, Kalvass JC, Patel NJ, Raub TJ, Brouwer KL (2006b) The important role of Bcrp (Abcg2) in the biliary excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in mice. Mol Pharmacol 70(6):2127–2133
Zhang Y, Han H, Elmquist WF, Miller DW (2000) Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells. Brain Res 876(1–2):148–153
Zhang Y, Csanaky IL, Lehman-McKeeman LD, Klaassen CD (2011) Loss of organic anion transporting polypeptide 1a1 increases deoxycholic acid absorption in mice by increasing intestinal permeability. Toxicol Sci 124(2):251–260
Zhang Y, Limaye PB, Lehman-McKeeman LD, Klaassen CD (2012) Dysfunction of organic anion transporting polypeptide 1a1 alters intestinal bacteria and bile acid metabolism in mice. PLoS ONE 7(4):e34522
Zhang Y, Csanaky IL, Selwyn FP, Lehman-McKeeman LD, Klaassen CD (2013) Organic anion-transporting polypeptide 1a4 (Oatp1a4) is important for secondary bile acid metabolism. Biochem Pharmacol 86(3):437–445
Zhao R, Raub TJ, Sawada GA, Kasper SC, Bacon JA, Bridges AS, Pollack GM (2009) Breast cancer resistance protein interacts with various compounds in vitro, but plays a minor role in substrate efflux at the blood–brain barrier. Drug Metab Dispos 37(6):1251–1258
Zhu P, Hata R, Ogasawara M, Cao F, Kameda K, Yamauchi K, Schinkel AH, Maeyama K, Sakanaka M (2012) Targeted disruption of organic cation transporter 3 (Oct3) ameliorates ischemic brain damage through modulating histamine and regulatory T cells. J Cereb Blood Flow Metab 32(10):1897–1908
Zolk O, Fromm MF (2011) Transporter-mediated drug uptake and efflux: important determinants of adverse drug reactions. Clin Pharmacol Ther 89(6):798–805
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All authors (N. Shin, J.-H. Oh, and Y.-J. Lee) declare that they have no conflict of interest. This work was supported by a Grant from the Kyung Hee University (KHU-20090598).
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Shin, N., Oh, JH. & Lee, YJ. Role of drug transporters: an overview based on knockout animal model studies. Journal of Pharmaceutical Investigation 45, 101–114 (2015). https://doi.org/10.1007/s40005-015-0178-z
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DOI: https://doi.org/10.1007/s40005-015-0178-z