Accounting for Transporters in Renal Clearance: Towards a Mechanistic Kidney Model (Mech KiM)

  • Sibylle NeuhoffEmail author
  • Lu Gaohua
  • Howard Burt
  • Masoud Jamei
  • Linzhong Li
  • Geoffrey T. Tucker
  • Amin Rostami-Hodjegan
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 7)


The impact of transporters in modulating the disposition of drugs in the liver and their passage across the gut wall has received much more attention than their role in renal excretion, despite the fact that 25–30 % of drugs are cleared predominantly by renal clearance and renal transporters contribute significantly to this process. Thus there is a need to improve the ability to predict changes in renal clearance arising from genetic variability, the impact of disease and interactions related to renal transporters. Such changes may also influence the accumulation of xenobiotics within the kidney cell leading to nephrotoxicity. Attempts to develop mechanistic, physiologically based models of renal drug elimination have been limited. This chapter outlines the features and application of a new model (Mech KiM) that links drug characteristics to knowledge of renal physiology in predicting the contributions of glomerular filtration, active and passive secretion, active and passive reabsorption and metabolism to renal elimination.


Proximal Tubule Renal Clearance Distal Tubule Quantitative Structure Activity Relationship Model Proximal Tubular Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Passive diffusion clearance


Cytochrome P450


Glomerular filtration rate


Inter-system extrapolation factor for transporters


In vitro–in vivo extrapolation


Multidrug and toxin extruder


Modification of diet in renal disease


Physiologically based pharmacokinetics


Proximal tubular cells per gram of kidney


Quantitative structure activity relationship


Relative activity factor


Relative expression factor


Transporter-mediated drug–drug interaction


Uridine glucuronosyltransferase


  1. Abel S, Nichols DJ, Brearley CJ, Eve MD (2000) Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide. Br J Clin Pharmacol 49:64–71PubMedCentralPubMedCrossRefGoogle Scholar
  2. Anzai N, Endou H (2007) Renal drug transporters and nephrotoxicity. AATEX 14:447–452Google Scholar
  3. Baldelli S, Merlini S, Perico N, Nicastri A, Cortinovis M, Gotti E, Remuzzi G, Cattaneo D (2007) C-440T/T-331C polymorphisms in the UGT1A9 gene affect the pharmacokinetics of mycophenolic acid in kidney transplantation. Pharmacogenomics 8:1127–1141PubMedCrossRefGoogle Scholar
  4. Bauer LA, Black DJ, Lill JS, Garrison J, Raisys VA, Hooton TM (2005) Levofloxacin and ciprofloxacin decrease procainamide and N-acetylprocainamide renal clearances. Antimicrob Agents Chemother 49:1649–1651PubMedCentralPubMedCrossRefGoogle Scholar
  5. Berndt WO (1989) Potential involvement of renal transport mechanisms in nephrotoxicity. Toxicol Lett 46:77–82PubMedCrossRefGoogle Scholar
  6. Bhatnagar V, Xu G, Hamilton BA, Truong DM, Eraly SA, Wu W, Nigam SK (2006) Analyses of 5′ regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3). J Hum Genet 51:575–580PubMedCrossRefGoogle Scholar
  7. Brightman FA, Leahy DE, Searle GE, Thomas S (2006a) Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in human plasma. Drug Metab Dispos 34:94–101PubMedCrossRefGoogle Scholar
  8. Brightman FA, Leahy DE, Searle GE, Thomas S (2006b) Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in rat plasma. Drug Metab Dispos 34:84–93PubMedCrossRefGoogle Scholar
  9. Broer S (2008) Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev 88:249–286PubMedCrossRefGoogle Scholar
  10. Burnell JM, Kirby WM (1951) Effectiveness of a new compound, benemid, in elevating serum penicillin concentrations. J Clin Invest 30:697–700PubMedCentralPubMedCrossRefGoogle Scholar
  11. Cheng Y, Vapurcuyan A, Shahidullah M, Aleksunes LM, Pelis RM (2012) Expression of organic anion transporter 2 in the human kidney and its potential role in the tubular secretion of guanine-containing antiviral drugs. Drug Metab Dispos 40:617–624PubMedCrossRefGoogle Scholar
  12. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41PubMedCrossRefGoogle Scholar
  13. Cummings BS, Lasker JM, Lash LH (2000) Expression of glutathione-dependent enzymes and cytochrome P450s in freshly isolated and primary cultures of proximal tubular cells from human kidney. J Pharmacol Exp Ther 293:677–685PubMedGoogle Scholar
  14. Cundy KC, Petty BG, Flaherty J, Fisher PE, Polis MA, Wachsman M, Lietman PS, Lalezari JP, Hitchcock MJ, Jaffe HS (1995) Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 39:1247–1252PubMedCentralPubMedCrossRefGoogle Scholar
  15. De Lannoy IA, Koren G, Klein J, Charuk J, Silverman M (1992) Cyclosporin and quinidine inhibition of renal digoxin excretion: evidence for luminal secretion of digoxin. Am J Physiol 263:F613–F622PubMedGoogle Scholar
  16. Ding R, Tayrouz Y, Riedel KD, Burhenne J, Weiss J, Mikus G, Haefeli WE (2004) Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers. Clin Pharmacol Ther 76:73–84PubMedCrossRefGoogle Scholar
  17. Doddareddy MR, Cho YS, Koh HY, Kim DH, Pae AN (2006) In silico renal clearance model using classical volsurf approach. J Chem Inf Model 46:1312–1320PubMedCrossRefGoogle Scholar
  18. Eaton DC, Pooler J (2009) Vander’s renal physiology. McGraw-Hill, New YorkGoogle Scholar
  19. El-Sheikh AA, van den Heuvel JJ, Koenderink JB, Russel FG (2007) Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport. J Pharmacol Exp Ther 320:229–235PubMedCrossRefGoogle Scholar
  20. Guyton AC (1992) Human physiology and mechanisms of disease. W.B. Saunders, PhiladelphiaGoogle Scholar
  21. Hager WD, Fenster P, Mayersohn M, Perrier D, Graves P, Marcus FI, Goldman S (1979) Digoxin-quinidine interaction pharmacokinetic evaluation. N Engl J Med 300:1238–1241PubMedCrossRefGoogle Scholar
  22. Hall S, Rowland M (1984) Relationship between renal clearance, protein binding and urine flow for digitoxin, a compound of low clearance in the isolated perfused rat kidney. J Pharmacol Exp Ther 228:174–179PubMedGoogle Scholar
  23. Harbourt DE, Fallon JK, Ito S, Baba T, Ritter JK, Glish GL, Smith PC (2012) Quantification of human uridine-diphosphate glucuronosyl transferase 1A isoforms in liver, intestine, and kidney using nanobore liquid chromatography-tandem mass spectrometry. Anal Chem 84:98–105PubMedCentralPubMedCrossRefGoogle Scholar
  24. Hill G, Cihlar T, Oo C, Ho ES, Prior K, Wiltshire H, Barrett J, Liu B, Ward P (2002) The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos 30:13–19PubMedCrossRefGoogle Scholar
  25. Honari J, Blair AD, Cutler RE (1977) Effects of probenecid on furosemide kinetics and natriuresis in man. Clin Pharmacol Ther 22:395–401PubMedGoogle Scholar
  26. Howe JL, Back DJ, Colbert J (1992) Extrahepatic metabolism of zidovudine. Br J Clin Pharmacol 33:190–192PubMedCentralPubMedCrossRefGoogle Scholar
  27. Inotsume N, Nishimura M, Nakano M, Fujiyama S, Sato T (1990) The inhibitory effect of probenecid on renal excretion of famotidine in young, healthy volunteers. J Clin Pharmacol 30:50–56PubMedCrossRefGoogle Scholar
  28. Jalava KM, Partanen J, Neuvonen PJ (1997) Itraconazole decreases renal clearance of digoxin. Ther Drug Monit 19:609–613PubMedCrossRefGoogle Scholar
  29. Jamei M, Marciniak S, Feng K, Barnett A, Tucker G, Rostami-Hodjegan A (2009) The Simcyp population-based ADME simulator. Expert Opin Drug Metab Toxicol 5:211–223PubMedCrossRefGoogle Scholar
  30. Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C, Madhusudan Rao Y (2002) Effect of cephalexin on the pharmacokinetics of metformin in healthy human volunteers. Drug Metabol Drug Interact 19:41–48PubMedCrossRefGoogle Scholar
  31. Kaloyanides GJ (1991) Metabolic interactions between drugs and renal tubulointerstitial cells: role in nephrotoxicity. Kidney Int 39:531–540PubMedCrossRefGoogle Scholar
  32. Karyekar CS, Eddington ND, Briglia A, Gubbins PO, Dowling TC (2004) Renal interaction between itraconazole and cimetidine. J Clin Pharmacol 44:919–927PubMedCrossRefGoogle Scholar
  33. Katayama K, Ohtani H, Kawabe T, Mizuno H, Endoh M, Kakemi M, Koizumi T (1990) Kinetic studies on drug disposition in rabbits. I. Renal excretion of iodopyracet and sulfamethizole. J Pharmacobiodyn 13:97–107PubMedCrossRefGoogle Scholar
  34. Kiser JJ, Carten ML, Aquilante CL, Anderson PL, Wolfe P, King TM, Delahunty T, Bushman LR, Fletcher CV (2008) The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther 83:265–272PubMedCrossRefGoogle Scholar
  35. Knauf H, Mutschler E (1992) Diuretika: Prinzipien der klinischen Anwendung. Urban and Schwarzenberg, MünchenGoogle Scholar
  36. Ko H, Cathcart KS, Griffith DL, Peters GR, Adams WJ (1989) Pharmacokinetics of intravenously administered cefmetazole and cefoxitin and effects of probenecid on cefmetazole elimination. Antimicrob Agents Chemother 33:356–361PubMedCentralPubMedCrossRefGoogle Scholar
  37. Kojima S, Shida M, Tanaka K, Takano H, Yokoyama H, Kuramochi M (2001) Renal macrostructure and cortical circulation in hypertension assessed by dynamic computed tomography. Am J Hypertens 14:516–523PubMedCrossRefGoogle Scholar
  38. Komiya I (1986) Urine flow dependence of renal clearance and interrelation of renal reabsorption and physicochemical properties of drugs. Drug Metab Dispos 14:239–245PubMedGoogle Scholar
  39. Komiya I (1987) Urine flow-dependence and interspecies variation of the renal reabsorption of sulfanilamide. J Pharmacobiodyn 10:1–7PubMedCrossRefGoogle Scholar
  40. Kosoglou T, Rocci ML Jr, Vlasses PH (1988) Trimethoprim alters the disposition of procainamide and N-acetylprocainamide. Clin Pharmacol Ther 44:467–477PubMedCrossRefGoogle Scholar
  41. Kremer JM, Hamilton RA (1995) The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg. J Rheumatol 22:2072–2077PubMedGoogle Scholar
  42. Kusuhara H, Ito S, Kumagai Y, Jiang M, Shiroshita T, Moriyama Y, Inoue K, Yuasa H, Sugiyama Y (2011) Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. Clin Pharmacol Ther 89:837–844PubMedCrossRefGoogle Scholar
  43. Lash LH, Putt DA, Cai H (2008) Drug metabolism enzyme expression and activity in primary cultures of human proximal tubular cells. Toxicology 244:56–65PubMedCentralPubMedCrossRefGoogle Scholar
  44. Laskin OL, de Miranda P, King DH, Page DA, Longstreth JA, Rocco L, Lietman PS (1982) Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans. Antimicrob Agents Chemother 21:804–807PubMedCentralPubMedCrossRefGoogle Scholar
  45. Lavé T, Chapman K, Goldsmith P, Rowland M (2009) Human clearance prediction: shifting the paradigm. Expert Opin Drug Metab Toxicol 5:1039–1048PubMedCrossRefGoogle Scholar
  46. Ma L, Sun J, Peng Y, Zhang R, Shao F, Hu X, Zhu J, Wang X, Cheng X, Zhu Y, Wan P, Feng D, Wu H, Wang G (2012) Glucuronidation of edaravone by human liver and kidney microsomes: biphasic kinetics and identification of UGT1A9 as the major UDP-glucuronosyltransferase isoform. Drug Metab Dispos 40:734–741PubMedCrossRefGoogle Scholar
  47. Mahmood I (1998) Interspecies scaling of renally secreted drugs. Life Sci 63:2365–2371PubMedCrossRefGoogle Scholar
  48. Mahmood I (2009) Role of fixed coefficients and exponents in the prediction of human drug clearance: how accurate are the predictions from one or two species? J Pharm Sci 98:2472–2493PubMedCrossRefGoogle Scholar
  49. Manga NDJ, Rowe PH, Cromin MTD (2003) A hierarchical QSAR model for urinary excretion of drugs in humans as a predictive tool for biotransformation. QSAR Comb Sci 22:263–273CrossRefGoogle Scholar
  50. Martin DE, Shen J, Griener J, Raasch R, Patterson JH, Cascio W (1996) Effects of ofloxacin on the pharmacokinetics and pharmacodynamics of procainamide. J Clin Pharmacol 36:85–91PubMedCrossRefGoogle Scholar
  51. Mayer JM, Hall SD, Rowland M (1988) Relationship between lipophilicity and tubular reabsorption for a series of 5-alkyl-5-ethylbarbituric acids in the isolated perfused rat kidney preparation. J Pharm Sci 77:359–364PubMedCrossRefGoogle Scholar
  52. Milne MD, Scribner BH, Crawford MA (1958) Non-ionic diffusion and the excretion of weak acids and bases. Am J Med 24:709–729PubMedCrossRefGoogle Scholar
  53. Milne AM, Burchell B, Coughtrie MW (2011) A novel method for the immunoquantification of UDP-glucuronosyltransferases in human tissue. Drug Metab Dispos 39:2258–2263PubMedCrossRefGoogle Scholar
  54. Motohashi H, Sakurai Y, Saito H, Masuda S, Urakami Y, Goto M, Fukatsu A, Ogawa O, Inui K (2002) Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 13:866–874PubMedGoogle Scholar
  55. Muller F, Konig J, Glaeser H, Schmidt I, Zolk O, Fromm MF, Maas R (2011) Molecular mechanism of renal tubular secretion of the antimalarial drug chloroquine. Antimicrob Agents Chemother 55:3091–3098PubMedCentralPubMedCrossRefGoogle Scholar
  56. Nozaki Y, Kusuhara H, Kondo T, Hasegawa M, Shiroyanagi Y, Nakazawa H, Okano T, Sugiyama Y (2007) Characterization of the uptake of organic anion transporter (OAT) 1 and OAT3 substrates by human kidney slices. J Pharmacol Exp Ther 321:362–369PubMedCrossRefGoogle Scholar
  57. Nyengaard JR, Bendtsen TF (1992) Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec 232:194–201PubMedCrossRefGoogle Scholar
  58. Ogasawara K, Terada T, Motohashi H, Asaka J, Aoki M, Katsura T, Kamba T, Ogawa O, Inui K (2008) Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney. J Hum Genet 53:607–614PubMedCrossRefGoogle Scholar
  59. Paine SW, Ménochet K, Denton R, McGinnity DF, Riley RJ (2011) Prediction of human renal clearance from preclinical species for a diverse set of drugs that exhibit both active secretion and net reabsorption. Drug Metab Dispos 39:1008–1013PubMedCrossRefGoogle Scholar
  60. Pedersen KE, Dorph-Pedersen A, Hvidt S, Klitgaard NA, Pedersen KK (1982) The long-term effect of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects. Eur J Clin Pharmacol 22:123–127PubMedCrossRefGoogle Scholar
  61. Pitts RF (1974) Physiology of the kidney and body fluids. Year Book Medical Publishers, ChicagoGoogle Scholar
  62. Proctor NJ, Tucker GT, Rostami-Hodjegan A (2004) Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica 34:151–178PubMedCrossRefGoogle Scholar
  63. Proctor WR, Bourdet DL, Thakker DR (2008) Mechanisms underlying saturable intestinal absorption of metformin. Drug Metab Dispos 36:1650–1658PubMedCrossRefGoogle Scholar
  64. Qi W, Johnson DW, Vesey DA, Pollock CA, Chen X (2007) Isolation, propagation and characterization of primary tubule cell culture from human kidney. Nephrology (Carlton) 12:155–159CrossRefGoogle Scholar
  65. Ring BJ, Chien JY, Adkison KK, Jones HM, Rowland M, Jones RD, Yates JW, Ku MS, Gibson CR, He H, Vuppugalla R, Marathe P, Fischer V, Dutta S, Sinha VK, Bjornsson T, Lave T, Poulin P (2011) PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: comparative assessement of prediction methods of human clearance. J Pharm Sci 100: 4090–4110Google Scholar
  66. Rodgers T, Rowland M (2006) Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci 95:1238–1257PubMedCrossRefGoogle Scholar
  67. Rodgers T, Leahy D, Rowland M (2005) Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci 94:1259–1276PubMedCrossRefGoogle Scholar
  68. Russel FG, Wouterse AC, Hekman P, Grutters GJ, van Ginneken CA (1987a) Quantitative urine collection in renal clearance studies in the dog. J Pharmacol Methods 17:125–136PubMedCrossRefGoogle Scholar
  69. Russel FG, Wouterse AC, van Ginneken CA (1987b) Physiologically based pharmacokinetic model for the renal clearance of phenolsulfonphthalein and the interaction with probenecid and salicyluric acid in the dog. J Pharmacokinet Biopharm 15:349–368PubMedCrossRefGoogle Scholar
  70. Russel FG, Wouterse AC, van Ginneken CA (1987c) Physiologically based pharmacokinetic model for the renal clearance of salicyluric acid and the interaction with phenolsulfonphthalein in the dog. Drug Metab Dispos 15:695–701PubMedGoogle Scholar
  71. Sakurai Y, Motohashi H, Ueo H, Masuda S, Saito H, Okuda M, Mori N, Matsuura M, Doi T, Fukatsu A, Ogawa O, Inui K (2004) Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseases. Pharm Res 21:61–67PubMedCrossRefGoogle Scholar
  72. Shiga T, Hashiguchi M, Urae A, Kasanuki H, Rikihisa T (2000) Effect of cimetidine and probenecid on pilsicainide renal clearance in humans. Clin Pharmacol Ther 67:222–228PubMedCrossRefGoogle Scholar
  73. Shitara Y, Horie T, Sugiyama Y (2006) Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci 27:425–446PubMedCrossRefGoogle Scholar
  74. Smith DE, Pavlova A, Berger UV, Hediger MA, Yang T, Huang YG, Schnermann JB (1998) Tubular localization and tissue distribution of peptide transporters in rat kidney. Pharm Res 15:1244–1249PubMedCrossRefGoogle Scholar
  75. Somogyi A, McLean A, Heinzow B (1983) Cimetidine-procainamide pharmacokinetic interaction in man: evidence of competition for tubular secretion of basic drugs. Eur J Clin Pharmacol 25:339–345PubMedCrossRefGoogle Scholar
  76. Somogyi A, Stockley C, Keal J, Rolan P, Bochner F (1987) Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol 23:545–551PubMedCentralPubMedCrossRefGoogle Scholar
  77. Somogyi AA, Bochner F, Sallustio BC (1992) Stereoselective inhibition of pindolol renal clearance by cimetidine in humans. Clin Pharmacol Ther 51:379–387PubMedCrossRefGoogle Scholar
  78. Spruill WJ, Wade WE, Cobb HH III (2007) Estimating glomerular filtration rate with a modification of diet in renal disease equation: implications for pharmacy. Am J Health Syst Pharm 64:652–660PubMedCrossRefGoogle Scholar
  79. Tachibana T, Kitamura S, Kato M, Mitsui T, Shirasaka Y, Yamashita S, Sugiyama Y (2010) Model analysis of the concentration-dependent permeability of P-gp substrates. Pharm Res 27:442–446PubMedCrossRefGoogle Scholar
  80. Tang H, Hussain A, Leal M, Mayersohn M, Fluhler E (2007) Interspecies prediction of human drug clearance based on scaling data from one or two animal species. Drug Metab Dispos 35:1886–1893PubMedCrossRefGoogle Scholar
  81. Tang-Liu DD, Tozer TN, Riegelman S (1983) Dependence of renal clearance on urine flow: a mathematical model and its application. J Pharm Sci 72:154–158PubMedCrossRefGoogle Scholar
  82. Trifillis AL (1999) Isolation, culture and characterization of human renal proximal tubule and collecting duct cells. Exp Nephrol 7:353–359PubMedCrossRefGoogle Scholar
  83. Tsuruoka S, Ioka T, Wakaumi M, Sakamoto K, Ookami H, Fujimura A (2006) Severe arrhythmia as a result of the interaction of cetirizine and pilsicainide in a patient with renal insufficiency: first case presentation showing competition for excretion via renal multidrug resistance protein 1 and organic cation transporter 2. Clin Pharmacol Ther 79:389–396PubMedCrossRefGoogle Scholar
  84. Vallon V, Rieg T, Ahn SY, Wu W, Eraly SA, Nigam SK (2008) 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:F867–F873PubMedCrossRefGoogle Scholar
  85. Varma MV, Feng B, Obach RS, Troutman MD, Chupka J, Miller HR, El-Kattan A (2009) Physicochemical determinants of human renal clearance. J Med Chem 52:4844–4852PubMedCrossRefGoogle Scholar
  86. Watanabe T, Kusuhara H, Maeda K, Kanamaru H, Saito Y, Hu Z, Sugiyama Y (2010) Investigation of the rate-determining process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans. Drug Metab Dispos 38:215–222PubMedCrossRefGoogle Scholar
  87. Watanabe T, Kusuhara H, Debori Y, Maeda K, Kondo T, Nakayama H, Horita S, Ogilvie BW, Parkinson A, Hu Z, Sugiyama Y (2011) Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug–drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments. Drug Metab Dispos 39:1031–1038PubMedCrossRefGoogle Scholar
  88. Wilmer MJ, Saleem MA, Masereeuw R, Ni L, van der Velden TJ, Russel FG, Mathieson PW, Monnens LA, van den Heuvel LP, Levtchenko EN (2010) Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters. Cell Tissue Res 339:449–457PubMedCentralPubMedCrossRefGoogle Scholar
  89. Yasui-Furukori N, Uno T, Sugawara K, Tateishi T (2005) Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics. Clin Pharmacol Ther 77:17–23PubMedCrossRefGoogle Scholar
  90. Yee SW, Chen L, Giacomini KM (2010) Pharmacogenomics of membrane transporters: past, present and future. Pharmacogenomics 11:475–479PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Sibylle Neuhoff
    • 1
    Email author
  • Lu Gaohua
    • 1
  • Howard Burt
    • 1
  • Masoud Jamei
    • 1
  • Linzhong Li
    • 1
  • Geoffrey T. Tucker
    • 1
    • 2
  • Amin Rostami-Hodjegan
    • 1
    • 3
  1. 1.Simcyp Limited, Blades Enterprise CentreSheffieldUK
  2. 2.Clinical Pharmacology, School of Medicine and Biomedical SciencesUniversity of SheffieldSheffieldUK
  3. 3.Faculty of Medical and Human Sciences, School of Pharmacy and Pharmaceutical SciencesUniversity of Manchester StopfordManchesterUK

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