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In Vivo Characterization of Interactions on Transporters

  • Hiroyuki Kusuhara
  • Kenta Yoshida
  • Yuichi Sugiyama
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 7)

Abstract

Drug transporters play indispensable roles in the disposition of drugs in the body; e.g., in hepatic and renal eliminations, intestinal absorption, and in transport across active barriers, and consequently, in the response to drugs. Importance of the solute carrier family, such as OATP/SLCO, OCT/SLC22, OAT/SLC22, and MATE/SLC47, and the ATP-binding cassette transporters, such as P-glycoprotein/ABCB1, MRPs/ABCC, and BCRP/ABCG2, are well recognized in drug discovery and clinical situations. To date, it is however a great challenge to identify in vivo probe substrates and inhibitors applicable for investigating the impact of drug transporters in humans. This chapter has summarized the relevant clinical drug–drug interaction and pharmagenomic studies on drug transporters in humans, as well as some in vitro studies on transporters, in order to suggest applicable probe substrates and inhibitors for drug transporters. In addition to the drugs at the market, some endogenous and food-derived metabolites are probes for drug transporters. This chapter also highlights the impact of drug transporters on such compounds.

Keywords

Drug Transporter Breast Cancer Resistance Protein Probe Substrate Clearance Ratio Positron Emission Tomography Probe 
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.

Abbreviations

ABC

ATP-binding cassette

AUC

Area under the plasma concentration–time curve

BBB

Blood–brain barrier

BCRP

Breast cancer resistance protein

CLoverall

Overall intrinsic clearance

CLr

Renal clearance

CLT

Total body clearance

CNS

Central nervous system

CR

Clearance ratio (ratio of renal clearance to the glomerular filtration)

DDI

Drug–drug interaction

Fh

Hepatic availability

fp

Unbound fraction in plasma

GFR

Glomerular filtration rate

MATE

Mutlidrug and toxic compound extrusion

MRP

Multidrug-resistant associated protein

NMN

N-methylnicotinamide

NTCP

Sodium bile acid co-transporting polypeptide

OAT

Organic anion transporter

OATP

Organic anion transporting polypeptide

OCT

Organic cation transporter

PET

Positron emission tomography

P-gp

P-glycoprotein

PSeff

The clearance for the back flux

PSinf

The clearance for the influx

RAF

Relative activity factor

SLC

Solute carrier

SNP

Single nucleotide polymorphism

SPECT

Single photon emission computed tomography

TEA

Tetraethyl ammonium

TIC

(15R)-16-m-tolyl-17, 18, 19, 20-tetranorisocarbacyclin

Notes

Acknowledgement

The authors would like to thank Dr. Mari Miyajiam and Sumito Ito for their kind support.

References

  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 49:64–71PubMedCentralPubMedGoogle Scholar
  2. Akamine Y, Miura M, Sunagawa S, Kagaya H, Yasui-Furukori N, Uno T (2010) Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers. Xenobiotica 40:782–789PubMedGoogle Scholar
  3. Arakawa R, Ito H, Okumura M, Morimoto T, Seki C, Takahashi H, Takano A, Suhara T (2010) No inhibitory effect on P-glycoprotein function at blood–brain barrier by clinical dose of clarithromycin: a human PET study with [(1)(1)C]verapamil. Ann Nucl Med 24:83–87PubMedGoogle Scholar
  4. Azadkhan AK, Truelove SC, Aronson JK (1982) The disposition and metabolism of sulphasalazine (salicylazosulphapyridine) in man. Br J Clin Pharmacol 13:523–528PubMedCentralPubMedGoogle Scholar
  5. Backman JT, Luurila H, Neuvonen M, Neuvonen PJ (2005) Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther 78:154–167PubMedGoogle Scholar
  6. Bailey DG, Dresser GK, Leake BF, Kim RB (2007) Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther 81:495–502PubMedGoogle Scholar
  7. Bartels AL, van Berckel BN, Lubberink M, Luurtsema G, Lammertsma AA, Leenders KL (2008a) Blood–brain barrier P-glycoprotein function is not impaired in early Parkinson’s disease. Parkinsonism Relat Disord 14:505–508PubMedGoogle Scholar
  8. Bartels AL, Willemsen AT, Kortekaas R, de Jong BM, de Vries R, de Klerk O, van Oostrom JC, Portman A, Leenders KL (2008b) Decreased blood–brain barrier P-glycoprotein function in the progression of Parkinson’s disease, PSP and MSA. J Neural Transm 115:1001–1009PubMedCentralPubMedGoogle Scholar
  9. Bauer M, Karch R, Neumann F, Wagner CC, Kletter K, Muller M, Loscher W, Zeitlinger M, Langer O (2010) Assessment of regional differences in tariquidar-induced P-glycoprotein modulation at the human blood–brain barrier. J Cereb Blood Flow Metab 30:510–515PubMedCentralPubMedGoogle Scholar
  10. Breimer DD, Schellens JH (1990) A ‘cocktail’ strategy to assess in vivo oxidative drug metabolism in humans. Trends Pharmacol Sci 11:223–225PubMedGoogle Scholar
  11. Bronger H, Konig J, Kopplow K, Steiner HH, Ahmadi R, Herold-Mende C, Keppler D, Nies AT (2005) ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Res 65:11419–11428PubMedGoogle Scholar
  12. Burckhardt G, Burckhardt BC (2011) In vitro and in vivo evidence of the importance of organic anion transporters (OATs) in drug therapy. Handb Exp Pharmacol 201:29–104PubMedGoogle Scholar
  13. Chen C, Mireles RJ, Campbell SD, Lin J, Mills JB, Xu JJ, Smolarek TA (2005) Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos 33:537–546PubMedGoogle Scholar
  14. Chew SC, Singh O, Chen X, Ramasamy RD, Kulkarni T, Lee EJ, Tan EH, Lim WT, Chowbay B (2011) The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of docetaxel in nasopharyngeal carcinoma patients. Cancer Chemother Pharmacol 67:1471–1478PubMedGoogle Scholar
  15. Choi MK, Shin HJ, Choi YL, Deng JW, Shin JG, Song IS (2011) Differential effect of genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide 1B1 (OATP1B1) on the uptake of HMG-CoA reductase inhibitors. Xenobiotica 41:24–34PubMedGoogle Scholar
  16. Christian CD Jr, Meredith CG, Speeg KV Jr (1984) Cimetidine inhibits renal procainamide clearance. Clin Pharmacol Ther 36:221–227PubMedGoogle Scholar
  17. Ci L, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y (2007) Involvement of MRP4 (ABCC4) in the luminal efflux of ceftizoxime and cefazolin in the kidney. Mol Pharmacol 71:1591–1597PubMedGoogle Scholar
  18. Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP (2007) Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 132:272–281PubMedGoogle Scholar
  19. de Jong FA, Scott-Horton TJ, Kroetz DL, McLeod HL, Friberg LE, Mathijssen RH, Verweij J, Marsh S, Sparreboom A (2007) Irinotecan-induced diarrhea: functional significance of the polymorphic ABCC2 transporter protein. Clin Pharmacol Ther 81:42–49PubMedGoogle Scholar
  20. de Klerk OL, Willemsen AT, Roosink M, Bartels AL, Hendrikse NH, Bosker FJ, den Boer JA (2009) Locally increased P-glycoprotein function in major depression: a PET study with [11C]verapamil as a probe for P-glycoprotein function in the blood–brain barrier. Int J Neuropsychopharmacol 12:895–904PubMedGoogle Scholar
  21. de Klerk OL, Willemsen AT, Bosker FJ, Bartels AL, Hendrikse NH, den Boer JA, Dierckx RA (2010) Regional increase in P-glycoprotein function in the blood–brain barrier of patients with chronic schizophrenia: a PET study with [(11)C]verapamil as a probe for P-glycoprotein function. Psychiatry Res 183:151–156PubMedGoogle Scholar
  22. 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 281:5072–5083PubMedGoogle Scholar
  23. Eyal S, Ke B, Muzi M, Link JM, Mankoff DA, Collier AC, Unadkat JD (2010) Regional P-glycoprotein activity and inhibition at the human blood–brain barrier as imaged by positron emission tomography. Clin Pharmacol Ther 87:579–585PubMedCentralPubMedGoogle Scholar
  24. Feng B, Obach RS, Burstein AH, Clark DJ, de Morais SM, Faessel HM (2008) Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: an in vitro-in vivo study. Clin Pharmacol Ther 83:567–576PubMedGoogle Scholar
  25. Fish DN, Chow AT (1997) The clinical pharmacokinetics of levofloxacin. Clin Pharmacokinet 32:101–119PubMedGoogle Scholar
  26. Fletcher CV, Henry WK, Noormohamed SE, Rhame FS, Balfour HH Jr (1995) The effect of cimetidine and ranitidine administration with zidovudine. Pharmacotherapy 15:701–708PubMedGoogle Scholar
  27. Fuhr U, Jetter A, Kirchheiner J (2007) Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the “cocktail” approach. Clin Pharmacol Ther 81:270–283PubMedGoogle Scholar
  28. Fujino H, Saito T, Ogawa S, Kojima J (2005) Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase. J Pharm Pharmacol 57:1305–1311PubMedGoogle Scholar
  29. Gedeon C, Behravan J, Koren G, Piquette-Miller M (2006) Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta 27:1096–1102PubMedGoogle Scholar
  30. Ghibellini G, Leslie EM, Pollack GM, Brouwer KL (2008) Use of tc-99m mebrofenin as a clinical probe to assess altered hepatobiliary transport: integration of in vitro, pharmacokinetic modeling, and simulation studies. Pharm Res 25:1851–1860PubMedCentralPubMedGoogle Scholar
  31. Giacomini KM, Sugiyama Y (2005) Membrane transporters and drug response. In: Brunton LL, Lazo JS, Parker KL, Goodman LS, Gilman AG (eds) Goodman & Gilman’s the pharmacological basis of therapeutics, 11th edn. McGraw-Hill, New York, pp 41–70Google Scholar
  32. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236PubMedGoogle Scholar
  33. Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, von Richter O, Zundler J, Kroemer HK (1999) The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 104:147–153PubMedCentralPubMedGoogle Scholar
  34. Guhlmann A, Krauss K, Oberdorfer F, Siegel T, Scheuber PH, Muller J, Csuk-Glanzer B, Ziegler S, Ostertag H, Keppler D (1995) Noninvasive assessment of hepatobiliary and renal elimination of cysteinyl leukotrienes by positron emission tomography. Hepatology 21:1568–1575PubMedGoogle Scholar
  35. Haenisch S, May K, Wegner D, Caliebe A, Cascorbi I, Siegmund W (2008) Influence of genetic polymorphisms on intestinal expression and rifampicin-type induction of ABCC2 and on bioavailability of talinolol. Pharmacogenet Genomics 18:357–365PubMedGoogle Scholar
  36. Hasannejad H, Takeda M, Taki K, Shin HJ, Babu E, Jutabha P, Khamdang S, Aleboyeh M, Onozato ML, Tojo A, Enomoto A, Anzai N, Narikawa S, Huang XL, Niwa T, Endou H (2004) Interactions of human organic anion transporters with diuretics. J Pharmacol Exp Ther 308:1021–1029PubMedGoogle Scholar
  37. Hasegawa M, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y (2007) Multidrug resistance-associated protein 4 is involved in the urinary excretion of hydrochlorothiazide and furosemide. J Am Soc Nephrol 18:37–45PubMedGoogle Scholar
  38. He YJ, Zhang W, Chen Y, Guo D, Tu JH, Xu LY, Tan ZR, Chen BL, Li Z, Zhou G, Yu BN, Kirchheiner J, Zhou HH (2009) Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism. Clin Chim Acta 405:49–52PubMedGoogle Scholar
  39. 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 30:13–19PubMedGoogle Scholar
  40. Hirano M, Maeda K, Shitara Y, Sugiyama Y (2004) Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther 311:139–146PubMedGoogle Scholar
  41. Hirano M, Maeda K, Matsushima S, Nozaki Y, Kusuhara H, Sugiyama Y (2005) Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin. Mol Pharmacol 68:800–807PubMedGoogle Scholar
  42. Ho ES, Lin DC, Mendel DB, Cihlar T (2000) Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J Am Soc Nephrol 11:383–393PubMedGoogle Scholar
  43. Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, Wang Y, Kim RB (2006) Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130:1793–1806PubMedGoogle Scholar
  44. Horikiri Y, Suzuki T, Mizobe M (1998) Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci 87:289–294PubMedGoogle Scholar
  45. Ieiri I, Suzuki H, Kimura M, Takane H, Nishizato Y, Irie S, Urae A, Kawabata K, Higuchi S, Otsubo K, Sugiyama Y (2004) Influence of common variants in the pharmacokinetic genes (OATP-C, UGT1A1, and MRP2) on serum bilirubin levels in healthy subjects. Hepatol Res 30:91–95PubMedGoogle Scholar
  46. Ieiri I, Suwannakul S, Maeda K, Uchimaru H, Hashimoto K, Kimura M, Fujino H, Hirano M, Kusuhara H, Irie S, Higuchi S, Sugiyama Y (2007) SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 82:541–547PubMedGoogle Scholar
  47. Ieiri I, Higuchi S, Sugiyama Y (2009) Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Expert Opin Drug Metab Toxicol 5:703–729PubMedGoogle Scholar
  48. Imamura Y, Murayama N, Okudaira N, Kurihara A, Okazaki O, Izumi T, Inoue K, Yuasa H, Kusuhara H, Sugiyama Y (2011) Prediction of fluoroquinolone-induced elevation in serum creatinine levels: a case of drug-endogenous substance interaction involving the inhibition of renal secretion. Clin Pharmacol Ther 89:81–88PubMedGoogle Scholar
  49. Imanaga J, Kotegawa T, Imai H, Tsutsumi K, Yoshizato T, Ohyama T, Shirasaka Y, Tamai I, Tateishi T, Ohashi K (2011) The effects of the SLCO2B1 c.1457C>T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans. Pharmacogenet Genomics 21:84–93PubMedGoogle Scholar
  50. 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 71:619–627PubMedGoogle Scholar
  51. Ito S, Kusuhara H, Kuroiwa Y, Wu C, Moriyama Y, Inoue K, Kondo T, Yuasa H, Nakayama H, Horita S, Sugiyama Y (2010) Potent and specific inhibition of mMate1-mediated efflux of type i organic cations in the liver and kidney by pyrimethamine. J Pharmacol Exp Ther 333:341–350PubMedGoogle Scholar
  52. Ito S, Kusuhara H, Yokochi M, Toyoshima J, Inoue K, Yuasa H, Sugiyama Y (2012a) Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther 340:393–403PubMedGoogle Scholar
  53. Ito S, Kusuhara H, Kumagai Y, Moriyama Y, Inoue K, Kondo T, Nakayama H, Horita H, Tanabe K, Yuasa H, Sugiyama Y (2012b) N-Methylnicotinamide is an endogenous probe for evaluation of drug-drug interactions involving multidrug and toxin extrusions (MATE1 and MATE2-K). Clin Pharmacol Ther 92(5):635–641PubMedGoogle Scholar
  54. Ji C, Tschantz WR, Pfeifer ND, Ullah M, Sadagopan N (2012) Development of a multiplex UPLC-MRM MS method for quantification of human membrane transport proteins OATP1B1, OATP1B3 and OATP2B1 in in vitro systems and tissues. Anal Chim Acta 717:67–76PubMedGoogle Scholar
  55. Jonker JW, Wagenaar E, van Deemter L, Gottschlich R, Bender HM, Dasenbrock J, Schinkel AH (1999) Role of blood–brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimadoline, a peripherally acting analgaesic drug. Br J Pharmacol 127:43–50PubMedCentralPubMedGoogle Scholar
  56. Kabat-Koperska J, Motyl W, Domanski L, Safranow K, Golembiewska E, Kedzierska K, Ciechanowski K (2004) Methods of GFR determination–creatinine clearance after cimetidine administration in clinical practice. Acta Med Austriaca 31:51–55PubMedGoogle Scholar
  57. Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT (2005) Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin Pharmacol Toxicol 97:249–256PubMedGoogle Scholar
  58. Kalliokoski A, Niemi M (2009) Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 158:693–705PubMedCentralPubMedGoogle Scholar
  59. Kato Y, Miyazaki T, Kano T, Sugiura T, Kubo Y, Tsuji A (2009) Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol. J Pharm Sci 98:2529–2539PubMedGoogle Scholar
  60. Kato K, Kusuhara H, Kumagai Y, Ieiri I, Moria H, Ito S, Nakaia Y, Maeda K, Sugiyama Y (2012) Association of MRP2 SNP rs12762549 with the basal plasma levels of phase II metabolites of isoflavonoids in healthy Japanese subjects. Pharmacogenet Genomics 22(5):344–354PubMedGoogle Scholar
  61. Kawamura K, Yamasaki T, Yui J, Hatori A, Konno F, Kumata K, Irie T, Fukumura T, Suzuki K, Kanno I, Zhang MR (2009) In vivo evaluation of P-glycoprotein and breast cancer resistance protein modulation in the brain using [(11)C]gefitinib. Nucl Med Biol 36:239–246PubMedGoogle Scholar
  62. Kawamura K, Konno F, Yui J, Yamasaki T, Hatori A, Yanamoto K, Wakizaka H, Takei M, Nengaki N, Fukumura T, Zhang MR (2010) Synthesis and evaluation of [11C]XR9576 to assess the function of drug efflux transporters using PET. Ann Nucl Med 24:403–412PubMedGoogle Scholar
  63. Kawamura K, Yamasaki T, Konno F, Yui J, Hatori A, Yanamoto K, Wakizaka H, Takei M, Kimura Y, Fukumura T, Zhang MR (2011) Evaluation of limiting brain penetration related to P-glycoprotein and breast cancer resistance protein using [(11)C]GF120918 by PET in mice. Mol Imaging Biol 13:152–160PubMedGoogle Scholar
  64. Keskitalo JE, Kurkinen KJ, Neuvoneni PJ, Niemi M (2008) ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin. Clin Pharmacol Ther 84:457–461PubMedGoogle Scholar
  65. Keskitalo JE, Pasanen MK, Neuvonen PJ, Niemi M (2009a) Different effects of the ABCG2 c.421C>A SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin. Pharmacogenomics 10:1617–1624PubMedGoogle Scholar
  66. Keskitalo JE, Zolk O, Fromm MF, Kurkinen KJ, Neuvonen PJ, Niemi M (2009b) ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 86:197–203PubMedGoogle Scholar
  67. Kirch W, Rose I, Klingmann I, Pabst J, Ohnhaus EE (1986) Interaction of bisoprolol with cimetidine and rifampicin. Eur J Clin Pharmacol 31:59–62PubMedGoogle Scholar
  68. Kirchheiner J, Kudlicz D, Meisel C, Bauer S, Meineke I, Roots I, Brockmoller J (2003) Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (−)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers. Clin Pharmacol Ther 74:186–194PubMedGoogle Scholar
  69. Kirchheiner J, Meineke I, Muller G, Bauer S, Rohde W, Meisel C, Roots I, Brockmoller J (2004) Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers. Clin Pharmacokinet 43:267–278PubMedGoogle Scholar
  70. Kitamura S, Maeda K, Wang Y, Sugiyama Y (2008) Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos 36(10):2014–2023PubMedGoogle Scholar
  71. Kitazawa E, Tamura N, Iwabuchi H, Uchiyama M, Muramatsu S, Takahagi H, Tanaka M (1993) Biotransformation of pravastatin sodium (I). Mechanisms of enzymic transformation and epimerization of an allylic hydroxy group of pravastatin sodium. Biochem Biophys Res Commun 192:597–602PubMedGoogle Scholar
  72. Kiyotani K, Mushiroda T, Kubo M, Zembutsu H, Sugiyama Y, Nakamura Y (2008) Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia. Cancer Sci 99:967–972PubMedGoogle Scholar
  73. Kondo C, Suzuki H, Itoda M, Ozawa S, Sawada J, Kobayashi D, Ieiri I, Mine K, Ohtsubo K, Sugiyama Y (2004) Functional analysis of SNPs variants of BCRP/ABCG2. Pharm Res 21:1895–1903PubMedGoogle Scholar
  74. Kreisl WC, Liow JS, Kimura N, Seneca N, Zoghbi SS, Morse CL, Herscovitch P, Pike VW, Innis RB (2010) P-glycoprotein function at the blood–brain barrier in humans can be quantified with the substrate radiotracer 11C-N-desmethyl-loperamide. J Nucl Med 51:559–566PubMedCentralPubMedGoogle Scholar
  75. Krumpochova P, Sapthu S, Brouwers JF, de Haas M, de Vos R, Borst P, van de Wetering K (2012) Transportomics: screening for substrates of ABC transporters in body fluids using vesicular transport assays. FASEB J 26:738–747PubMedGoogle Scholar
  76. Kumata K, Ogawa M, Takei M, Fujinaga M, Yoshida Y, Nengaki N, Fukumura T, Suzuki K, Zhang MR (2012) Radiosynthesis of [13N]dantrolene, a positron emission tomography probe for breast cancer resistant protein, using no-carrier-added [13N]ammonia. Bioorg Med Chem 20:305–310PubMedGoogle Scholar
  77. Kuppens IE, Witteveen EO, Jewell RC, Radema SA, Paul EM, Mangum SG, Beijnen JH, Voest EE, Schellens JH (2007) A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in cancer patients. Clin Cancer Res 13:3276–3285PubMedGoogle Scholar
  78. Kusuhara H, Sugiyama Y (2009) In vitro-in vivo extrapolation of transporter-mediated clearance in the liver and kidney. Drug Metab Pharmacokinet 24:37–52PubMedGoogle Scholar
  79. 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 89:837–844PubMedGoogle Scholar
  80. Kusuhara H, Furuie H, Inano A, Sunagawa A, Yamada S, Wu C, Fukizawa S, Morimoto N, Ieiri I, Morishita M, Sumita K, Mayahara H, Fujita T, Maeda K, Sugiyama Y (2012) Pharmacokinetic interaction study of sulfasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP. Br J Pharmacol 166(6):1793–1803PubMedCentralPubMedGoogle Scholar
  81. Lai MY, Jiang FM, Chung CH, Chen HC, Chao PD (1988) Dose dependent effect of cimetidine on procainamide disposition in man. Int J Clin Pharmacol Ther Toxicol 26:118–121PubMedGoogle Scholar
  82. Langer O, Bauer M, Hammers A, Karch R, Pataraia E, Koepp MJ, Abrahim A, Luurtsema G, Brunner M, Sunder-Plassmann R, Zimprich F, Joukhadar C, Gentzsch S, Dudczak R, Kletter K, Muller M, Baumgartner C (2007) Pharmacoresistance in epilepsy: a pilot PET study with the P-glycoprotein substrate R-[(11)C]verapamil. Epilepsia 48:1774–1784PubMedGoogle Scholar
  83. Lau YY, Okochi H, Huang Y, Benet LZ (2006) Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites: application of in vitro and ex situ systems. J Pharmacol Exp Ther 316:762–771PubMedGoogle Scholar
  84. Lau YY, Huang Y, Frassetto L, Benet LZ (2007) Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther 81:194–204PubMedGoogle Scholar
  85. Levey AS, Perrone RD, Madias NE (1988) Serum creatinine and renal function. Annu Rev Med 39:465–490PubMedGoogle Scholar
  86. Lilja JJ, Backman JT, Laitila J, Luurila H, Neuvonen PJ (2003) Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol. Clin Pharmacol Ther 73:192–198PubMedGoogle Scholar
  87. Lilja JJ, Raaska K, Neuvonen PJ (2005a) Effects of orange juice on the pharmacokinetics of atenolol. Eur J Clin Pharmacol 61:337–340PubMedGoogle Scholar
  88. Lilja JJ, Raaska K, Neuvonen PJ (2005b) Effects of grapefruit juice on the pharmacokinetics of acebutolol. Br J Clin Pharmacol 60:659–663PubMedCentralPubMedGoogle Scholar
  89. Maeda K, Sugiyama Y (2008) Impact of genetic polymorphisms of transporters on the pharmacokinetic, pharmacodynamic and toxicological properties of anionic drugs. Drug Metab Pharmacokinet 23:223–235PubMedGoogle Scholar
  90. Maeda K, Ieiri I, Yasuda K, Fujino A, Fujiwara H, Otsubo K, Hirano M, Watanabe T, Kitamura Y, Kusuhara H, Sugiyama Y (2006) Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril. Clin Pharmacol Ther 79:427–439PubMedGoogle Scholar
  91. Maeda K, Ikeda Y, Fujita T, Yoshida K, Azuma Y, Haruyama Y, Yamane N, Kumagai Y, Sugiyama Y (2011) Identification of the rate-determining process in the hepatic clearance of atorvastatin in a clinical cassette microdosing study. Clin Pharmacol Ther 90:575–581PubMedGoogle Scholar
  92. Mairinger S, Langer O, Kuntner C, Wanek T, Bankstahl JP, Bankstahl M, Stanek J, Dorner B, Bauer F, Baumgartner C, Loscher W, Erker T, Muller M (2010) Synthesis and in vivo evaluation of the putative breast cancer resistance protein inhibitor [11C]methyl 4-((4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl)phenyl)amino-carbonyl)-2-(quinoline-2-carbonylamino)benzoate. Nucl Med Biol 37:637–644PubMedCentralPubMedGoogle Scholar
  93. Martin PD, Warwick MJ, Dane AL, Hill SJ, Giles PB, Phillips PJ, Lenz E (2003) Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther 25:2822–2835PubMedGoogle Scholar
  94. Masereeuw R, Russel FG (2010) Therapeutic implications of renal anionic drug transporters. Pharmacol Ther 126:200–216PubMedGoogle Scholar
  95. Masuda S, Terada T, Yonezawa A, Tanihara Y, Kishimoto K, Katsura T, Ogawa O, Inui K (2006) Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol 17:2127–2135PubMedGoogle Scholar
  96. Matsushima S, Maeda K, Ishiguro N, Igarashi T, Sugiyama Y (2008) Investigation of the inhibitory effects of various drugs on the hepatic uptake of fexofenadine in humans. Drug Metab Dispos 36:663–669PubMedGoogle Scholar
  97. Matsushima S, Maeda K, Inoue K, Ohta KY, Yuasa H, Kondo T, Nakayama H, Horita S, Kusuhara H, Sugiyama Y (2009) The inhibition of human multidrug and toxin extrusion 1 is involved in the drug-drug interaction caused by cimetidine. Drug Metab Dispos 37:555–559PubMedGoogle Scholar
  98. Merino G, van Herwaarden AE, Wagenaar E, Jonker JW, Schinkel AH (2005) Sex-dependent expression and activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP/ABCG2) in liver. Mol Pharmacol 67:1765–1771PubMedGoogle Scholar
  99. Mougey EB, Feng H, Castro M, Irvin CG, Lima JJ (2009) Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenet Genomics 19:129–138PubMedCentralPubMedGoogle Scholar
  100. Muirhead MR, Somogyi AA, Rolan PE, Bochner F (1986) Effect of cimetidine on renal and hepatic drug elimination: studies with triamterene. Clin Pharmacol Ther 40:400–407PubMedGoogle Scholar
  101. Muzi M, Mankoff DA, Link JM, Shoner S, Collier AC, Sasongko L, Unadkat JD (2009) Imaging of cyclosporine inhibition of P-glycoprotein activity using 11C-verapamil in the brain: studies of healthy humans. J Nucl Med 50:1267–1275PubMedCentralPubMedGoogle Scholar
  102. Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y (2006) Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 82:1074–1084PubMedGoogle Scholar
  103. Nakai D, Nakagomi R, Furuta Y, Tokui T, Abe T, Ikeda T, Nishimura K (2001) Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J Pharmacol Exp Ther 297:861–867PubMedGoogle Scholar
  104. Nakamura T, Yonezawa A, Hashimoto S, Katsura T, Inui K (2010) Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. Biochem Pharmacol 80:1762–1767PubMedGoogle Scholar
  105. Nakanishi T, Tamai I (2012) Genetic polymorphisms of OATP transporters and their impact on intestinal absorption and hepatic disposition of drugs. Drug Metab Pharmacokinet 27:106–121PubMedGoogle Scholar
  106. Naritomi Y, Terashita S, Kagayama A (2004) Identification and relative contributions of human cytochrome P450 isoforms involved in the metabolism of glibenclamide and lansoprazole: evaluation of an approach based on the in vitro substrate disappearance rate. Xenobiotica 34:415–427PubMedGoogle Scholar
  107. Niemi M, Cascorbi I, Timm R, Kroemer HK, Neuvonen PJ, Kivisto KT (2002) Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther 72:326–332PubMedGoogle Scholar
  108. Niemi M, Arnold KA, Backman JT, Pasanen MK, Godtel-Armbrust U, Wojnowski L, Zanger UM, Neuvonen PJ, Eichelbaum M, Kivisto KT, Lang T (2006) Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics. Pharmacogenet Genomics 16:801–808PubMedGoogle Scholar
  109. Niemi M, Pasanen MK, Neuvonen PJ (2011) Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 63:157–181PubMedGoogle Scholar
  110. Nierenerg DW (1987) Drug inhibition of penicillin tubular secretion: concordance between in vitro and clinical findings. J Pharmacol Exp Ther 240:712–716Google Scholar
  111. 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 321:362–369PubMedGoogle Scholar
  112. Opravil M, Keusch G, Luthy R (1993) Pyrimethamine inhibits renal secretion of creatinine. Antimicrob Agents Chemother 37:1056–1060PubMedCentralPubMedGoogle Scholar
  113. Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y (2005) A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci USA 102:17923–17928PubMedCentralPubMedGoogle Scholar
  114. Ranganathan P, Culverhouse R, Marsh S, Mody A, Scott-Horton TJ, Brasington R, Joseph A, Reddy V, Eisen S, McLeod HL (2008) Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J Rheumatol 35:572–579PubMedGoogle Scholar
  115. Rau T, Erney B, Gores R, Eschenhagen T, Beck J, Langer T (2006) High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. Clin Pharmacol Ther 80:468–476PubMedGoogle Scholar
  116. Riedmaier S, Klein K, Hofmann U, Keskitalo JE, Neuvonen PJ, Schwab M, Niemi M, Zanger UM (2010) UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo. Clin Pharmacol Ther 87:65–73PubMedGoogle Scholar
  117. Rodvold KA, Paloucek FP, Jung D, Gallastegui J (1987) Interaction of steady-state procainamide with H2-receptor antagonists cimetidine and ranitidine. Ther Drug Monit 9:378–383PubMedGoogle Scholar
  118. Sadeque AJ, Wandel C, He H, Shah S, Wood AJ (2000) Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 68:231–237PubMedGoogle Scholar
  119. Sarapa N, Wickremasingha P, Ge N, Weitzman R, Fuellhart M, Yen C, Lloyd-Parks J (2007) Lack of effect of DX-619, a novel des-fluoro(6)-quinolone, on glomerular filtration rate measured by serum clearance of cold iohexol. Antimicrob Agents Chemother 51:1912–1917PubMedCentralPubMedGoogle Scholar
  120. 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 77:491–502PubMedGoogle Scholar
  121. Schwarz UI, Seemann D, Oertel R, Miehlke S, Kuhlisch E, Fromm MF, Kim RB, Bailey DG, Kirch W (2005) Grapefruit juice ingestion significantly reduces talinolol bioavailability. Clin Pharmacol Ther 77:291–301PubMedGoogle Scholar
  122. 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 67:222–228PubMedGoogle Scholar
  123. Shimizu K, Takashima T, Yamane T, Sasaki M, Kageyama H, Hashizume Y, Maeda K, Sugiyama Y, Watanabe Y, Senda M (2012) Whole-body distribution and radiation dosimetry of [(11)C]telmisartan as a biomarker for hepatic organic anion transporting polypeptide (OATP) 1B3. Nucl Med Biol 39(6):847–853PubMedGoogle Scholar
  124. Shirasaka Y, Kuraoka E, Spahn-Langguth H, Nakanishi T, Langguth P, Tamai I (2010) Species difference in the effect of grapefruit juice on intestinal absorption of talinolol between human and rat. J Pharmacol Exp Ther 332:181–189PubMedGoogle Scholar
  125. Shitara Y, Itoh T, Sato H, Li AP, Sugiyama Y (2003) Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. J Pharmacol Exp Ther 304:610–616PubMedGoogle Scholar
  126. Shitara Y, Horie T, Sugiyama Y (2006) Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci 27:425–446PubMedGoogle Scholar
  127. Shitara Y, Nagamatsu Y, Wada S, Sugiyama Y, Horie T (2009) Long-lasting inhibition of the transporter-mediated hepatic uptake of sulfobromophthalein by cyclosporin a in rats. Drug Metab Dispos 37:1172–1178PubMedGoogle Scholar
  128. 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 117:1422–1431PubMedCentralPubMedGoogle Scholar
  129. Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, Sheardown SA, Yue L, Burchard EG, Brett CM, Giacomini KM (2008) Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 83:273–280PubMedCentralPubMedGoogle Scholar
  130. 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 26:480–487PubMedCentralPubMedGoogle Scholar
  131. Sinhvi SM, Duchin KL, Willard DA, McKinstry DN, Migdalof BH (1982) Renal handling of captopril: effect of probenecid. Clin Pharmacol Ther 32:182–189PubMedGoogle Scholar
  132. 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 25:339–345PubMedGoogle Scholar
  133. 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 23:545–551PubMedCentralPubMedGoogle Scholar
  134. Somogyi AA, Hovens CM, Muirhead MR, Bochner F (1989) Renal tubular secretion of amiloride and its inhibition by cimetidine in humans and in an animal model. Drug Metab Dispos 17:190–196PubMedGoogle Scholar
  135. Somogyi AA, Bochner F, Sallustio BC (1992) Stereoselective inhibition of pindolol renal clearance by cimetidine in humans. Clin Pharmacol Ther 51:379–387PubMedGoogle Scholar
  136. Sorgel F, Kinzig M (1993) Pharmacokinetics of gyrase inhibitors, part 2: renal and hepatic elimination pathways and drug interactions. Am J Med 94:56S–69SPubMedGoogle Scholar
  137. Spahn H, Reuter K, Mutschler E, Gerok W, Knauf H (1987) Pharmacokinetics of amiloride in renal and hepatic disease. Eur J Clin Pharmacol 33:493–498PubMedGoogle Scholar
  138. Tachibana T, Kato M, Watanabe T, Mitsui T, Sugiyama Y (2009) Method for predicting the risk of drug-drug interactions involving inhibition of intestinal CYP3A4 and P-glycoprotein. Xenobiotica 39:430–443PubMedGoogle Scholar
  139. Tahara H, Kusuhara H, Endou H, Koepsell H, Imaoka T, Fuse E, Sugiyama Y (2005) A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters. J Pharmacol Exp Ther 315:337–345PubMedGoogle Scholar
  140. Takashima T, Kitamura S, Wada Y, Tanaka M, Shigihara Y, Ishii H, Ijuin R, Shiomi S, Nakae T, Cui Y, Doi H, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y,Watanabe Y (2012) PET imaging-based evaluation of hepatobiliary transport in humans with (15R)–11C-TIC-Me. J Nucl Med. 2012 May;53(5):741–748. doi: 10.2967/jnumed.111.098681. Epub 2012 Apr 12.Google Scholar
  141. Takashima T, Nagata H, Nakae T, Cui Y, Wada Y, Kitamura S, Doi H, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y, Watanabe Y (2010) Positron emission tomography studies using (15R)-16-m-[11C]tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester for the evaluation of hepatobiliary transport. J Pharmacol Exp Ther 335:314–323PubMedGoogle Scholar
  142. Takashima-Hirano M, Takashima T, Katayama Y, Wada Y, Sugiyama Y, Watanabe Y, Doi H, Suzuki M (2011) Efficient sequential synthesis of PET Probes of the COX-2 inhibitor [11C]celecoxib and its major metabolite [11C]SC-62807 and in vivo PET evaluation. Bioorg Med Chem 19:2997–3004PubMedGoogle Scholar
  143. Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K (2007) Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol 74:359–371PubMedGoogle Scholar
  144. Tomalik-Scharte D, Fuhr U, Hellmich M, Frank D, Doroshyenko O, Jetter A, Stingl JC (2011) Effect of the CYP2C8 genotype on the pharmacokinetics and pharmacodynamics of repaglinide. Drug Metab Dispos 39:927–932PubMedGoogle Scholar
  145. Tournier N, Valette H, Peyronneau MA, Saba W, Goutal S, Kuhnast B, Dolle F, Scherrmann JM, Cisternino S, Bottlaender M (2011) Transport of selected PET radiotracers by human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2): an in vitro screening. J Nucl Med 52:415–423PubMedGoogle Scholar
  146. Tsuda M, Terada T, Ueba M, Sato T, Masuda S, Katsura T, Inui K (2009) Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J Pharmacol Exp Ther 329:185–191PubMedGoogle Scholar
  147. Urakami Y, Kimura N, Okuda M, Inui K (2004) Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney. Pharm Res 21:976–981PubMedGoogle Scholar
  148. Uwai Y, Ida H, Tsuji Y, Katsura T, Inui K (2007) Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm Res 24:811–815PubMedGoogle Scholar
  149. 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–F873PubMedGoogle Scholar
  150. van Crugten J, Bochner F, Keal J, Somogyi A (1986) Selectivity of the cimetidine-induced alterations in the renal handling of organic substrates in humans. Studies with anionic, cationic and zwitterionic drugs. J Pharmacol Exp Ther 236:481–487PubMedGoogle Scholar
  151. van de Steeg E, Stranecky V, Hartmannova H, Noskova L, Hrebicek M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, Kenworthy KE, Sticova E, al-Edreesi M, Knisely AS, Kmoch S, Jirsa M, Schinkel AH (2012) Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 122:519–528PubMedCentralPubMedGoogle Scholar
  152. 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 74:122–131PubMedCentralPubMedGoogle Scholar
  153. Wagner CC, Bauer M, Karch R, Feurstein T, Kopp S, Chiba P, Kletter K, Loscher W, Muller M, Zeitlinger M, Langer O (2009) A pilot study to assess the efficacy of tariquidar to inhibit P-glycoprotein at the human blood–brain barrier with (R)-11C-verapamil and PET. J Nucl Med 50:1954–1961PubMedCentralPubMedGoogle Scholar
  154. Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, Sugiyama Y (2003) Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol 63:844–848PubMedGoogle Scholar
  155. Wang ZJ, Yin OQ, Tomlinson B, Chow MS (2008) OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine. Pharmacogenet Genomics 18:637–645PubMedGoogle Scholar
  156. Watanabe T, Kusuhara H, Maeda K, Shitara Y, Sugiyama Y (2009a) Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans. J Pharmacol Exp Ther 328:652–662PubMedGoogle Scholar
  157. Watanabe T, Maeda K, Kondo T, Nakayama H, Horita S, Kusuhara H, Sugiyama Y (2009b) Prediction of the hepatic and renal clearance of transporter substrates in rats using in vitro uptake experiments. Drug Metab Dispos 37:1471–1479PubMedGoogle Scholar
  158. Watanabe T, Kusuhara H, Maeda K, Kanamaru H, Saito Y, Hu ZH, Sugiyama Y (2010a) Investigation of the rate-determining process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans. Drug Metab Dispos 38:215–222PubMedGoogle Scholar
  159. Watanabe T, Kusuhara H, Sugiyama Y (2010b) Application of physiologically based pharmacokinetic modeling and clearance concept to drugs showing transporter-mediated distribution and clearance in humans. J Pharmacokinet Pharmacodyn 37:575–590PubMedGoogle Scholar
  160. Weaver ML, Orwig BA, Rodriguez LC, Graham ED, Chin JA, Shapiro MJ, McLeod JF, Mangold JB (2001) Pharmacokinetics and metabolism of nateglinide in humans. Drug Metab Dispos 29:415–421PubMedGoogle Scholar
  161. Windass AS, Lowes S, Wang Y, Brown CD (2007) The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. J Pharmacol Exp Ther 322:1221–1227PubMedGoogle Scholar
  162. Xiang X, Han Y, Neuvonen M, Pasanen MK, Kalliokoski A, Backman JT, Laitila J, Neuvonen PJ, Niemi M (2009) Effect of SLCO1B1 polymorphism on the plasma concentrations of bile acids and bile acid synthesis marker in humans. Pharmacogenet Genomics 19:447–457PubMedGoogle Scholar
  163. Yamada A, Maeda K, Ishiguro N, Tsuda Y, Igarashi T, Ebner T, Roth W, Ikushiro S, Sugiyama Y (2011) The impact of pharmacogenetics of metabolic enzymes and transporters on the pharmacokinetics of telmisartan in healthy volunteers. Pharmacogenet Genomics 21:523–530PubMedGoogle Scholar
  164. Yamasaki Y, Ieiri I, Kusuhara H, Sasaki T, Kimura M, Tabuchi H, Ando Y, Irie S, Ware J, Nakai Y, Higuchi S, Sugiyama Y (2008) Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans. Clin Pharmacol Ther 84:95–103PubMedGoogle Scholar
  165. 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 77:17–23PubMedGoogle Scholar
  166. Yoshida K, Maeda K, Sugiyama Y (2012) Transporter-mediated drug-drug interactions involving OATP substrates: predictions based on in vitro inhibition studies. Clin Pharmacol Ther 91(6):1053–1064PubMedGoogle Scholar
  167. Zhang W, Yu BN, He YJ, Fan L, Li Q, Liu ZQ, Wang A, Liu YL, Tan ZR, Fen J, Huang YF, Zhou HH (2006) Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta 373:99–103PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Hiroyuki Kusuhara
    • 1
  • Kenta Yoshida
    • 1
  • Yuichi Sugiyama
    • 1
    • 2
  1. 1.Graduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
  2. 2.Sugiyama LaboratoryRIKEN Innovation Center, RIKEN Research Cluster for Innovation, RIKENTsurumi-ku, YokohamaJapan

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