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Endocrine and Metabolic Regulation of Transporters for Organic Cations

  • Lauren M. AleksunesEmail author
Chapter

Abstract

The disposition of organic cations in the liver and kidneys are under a dynamic regulation by the endocrine and metabolic systems of the body. Researchers have demonstrated the ability of steroids, sex hormones, and physiological states such as pregnancy to alter the expresion and function of transporter proteins that mediate the uptake and efflux of organic cations. This chapter reviews the endocrine and metabolic pathways that influence the pharmacokinetics as well as the toxicity of organic cations.

Keywords

Diabetes Estradiol Gender Obesity Testosterone Glucocorticoid 

References

  1. 1.
    Lickteig AJ, Cheng X, Augustine LM, Klaassen CD, Cherrington NJ. Tissue distribution, ontogeny and induction of the transporters multidrug and toxin extrusion (MATE) 1 and MATE2 mRNA expression levels in mice. Life Sci. 2008;83:59–64.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Slitt AL, Cherrington NJ, Hartley DP, Leazer TM, Klaassen CD. Tissue distribution and renal developmental changes in rat organic cation transporter mRNA levels. Drug Metab Dispos. 2002;30:212–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Alnouti Y, Petrick JS, Klaassen CD. Tissue distribution and ontogeny of organic cation transporters in mice. Drug Metab Dispos. 2006;34:477–82.PubMedGoogle Scholar
  4. 4.
    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. Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol. 2010;176:1169–80.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Filipski KK, Loos WJ, Verweij J, Sparreboom A. Interaction of Cisplatin with the human organic cation transporter 2. Clin Cancer Res. 2008;14:3875–80.PubMedCrossRefGoogle Scholar
  6. 6.
    Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther. 2009;86:396–402.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Nakamura T, Yonezawa A, Hashimoto S, Katsura T, Inui K. Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. Biochem Pharmacol. 2010;80:1762–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Bowman HM, Hook JB. Sex differences in organic ion transport by rat kidney. Proc Soc Exp Biol Med. 1972;141:258–62.PubMedCrossRefGoogle Scholar
  9. 9.
    Urakami Y, Nakamura N, Takahashi K, Okuda M, Saito H, Hashimoto Y, Inui K. Gender differences in expression of organic cation transporter OCT2 in rat kidney. FEBS Lett. 1999;461:339–42.PubMedCrossRefGoogle Scholar
  10. 10.
    Yonezawa A, Masuda S, Nishihara K, Yano I, Katsura T, Inui K. Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat. Biochem Pharmacol. 2005;70:1823–31.PubMedCrossRefGoogle Scholar
  11. 11.
    Groves CE, Suhre WB, Cherrington NJ, Wright SH. Sex differences in the mRNA, protein, and functional expression of organic anion transporter (Oat) 1, Oat3, and organic cation transporter (Oct) 2 in rabbit renal proximal tubules. J Pharmacol Exp Ther. 2006;316:743–52.PubMedCrossRefGoogle Scholar
  12. 12.
    Schlatter E, Klassen P, Massmann V, Holle SK, Guckel D, Edemir B, Pavenstadt H, Ciarimboli G. Mouse organic cation transporter 1 determines properties and regulation of basolateral organic cation transport in renal proximal tubules. Pflugers Arch. 2014;466:1581–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, Zanger UM, Keppler D, Schwab M, Schaeffeler E. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009;50:1227–40.PubMedCrossRefGoogle Scholar
  14. 14.
    Wilde S, Schlatter E, Koepsell H, Edemir B, Reuter S, Pavenstadt H, Neugebauer U, Schroter R, Brast S, Ciarimboli G. Calmodulin-associated post-translational regulation of rat organic cation transporter 2 in the kidney is gender dependent. Cell Mol Life Sci. 2009;66:1729–40.PubMedCrossRefGoogle Scholar
  15. 15.
    Harvey AM, Malvin RL. The effect of androgenic hormones on creatinine secretion in the rat. J Physiol. 1966;184:883–8.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    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. Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. Clin Cancer Res. 2012;18:1101–8.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Harvey AM, Malvin RL. Comparison of creatinine and inulin clearances in male and female rats. Am J Physiol. 1965;209:849–52.PubMedGoogle Scholar
  18. 18.
    Shu Y, Bello CL, Mangravite LM, Feng B, Giacomini KM. Functional characteristics and steroid hormone-mediated regulation of an organic cation transporter in Madin-Darby canine kidney cells. J Pharmacol Exp Ther. 2001;299:392–8.PubMedGoogle Scholar
  19. 19.
    Urakami Y, Okuda M, Saito H, Inui K. Hormonal regulation of organic cation transporter OCT2 expression in rat kidney. FEBS Lett. 2000;473:173–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Asaka J, Terada T, Okuda M, Katsura T, Inui K. Androgen receptor is responsible for rat organic cation transporter 2 gene regulation but not for rOCT1 and rOCT3. Pharm Res. 2006;23:697–704.PubMedCrossRefGoogle Scholar
  21. 21.
    Meetam P, Srimaroeng C, Soodvilai S, Chatsudthipong V. Role of estrogen in renal handling of organic cation, tetraethylammonium: in vivo and in vitro studies. Biol Pharm Bull. 2009;32:1968–72.PubMedCrossRefGoogle Scholar
  22. 22.
    Pelis RM, Hartman RC, Wright SH, Wunz TM, Groves CE. Influence of estrogen and xenoestrogens on basolateral uptake of tetraethylammonium by opossum kidney cells in culture. J Pharmacol Exp Ther. 2007;323:555–61.PubMedCrossRefGoogle Scholar
  23. 23.
    Maeda T, Yotsumoto T, Oyabu M, Tamai I. Effect of glucocorticoid receptor ligand dexamethasone on the expression of organic cation transporter in rat liver. Drug Metab Pharmacokinet. 2008;23:67–72.PubMedCrossRefGoogle Scholar
  24. 24.
    Maeda T, Oyabu M, Yotsumoto T, Higashi R, Nagata K, Yamazoe Y, Tamai I. Effect of pregnane X receptor ligand on pharmacokinetics of substrates of organic cation transporter Oct1 in rats. Drug Metab Dispos. 2007;35:1580–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Rulcova A, Krausova L, Smutny T, Vrzal R, Dvorak Z, Jover R, Pavek P. Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4alpha upregulation in primary human hepatocytes. Pharmacol Rep. 2013;65:1322–35.PubMedCrossRefGoogle Scholar
  26. 26.
    Saborowski M, Kullak-Ublick GA, Eloranta JJ. The human organic cation transporter-1 gene is transactivated by hepatocyte nuclear factor-4alpha. J Pharmacol Exp Ther. 2006;317:778–85.PubMedCrossRefGoogle Scholar
  27. 27.
    Yacovino LL, Gibson CJ, Aleksunes LM. Down-regulation of brush border efflux transporter expression in the kidneys of pregnant mice. Drug Metab Dispos. 2013;41:320–5.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Aleksunes LM, Yeager RL, Wen X, Cui JY, Klaassen CD. Repression of hepatobiliary transporters and differential regulation of classic and alternative bile acid pathways in mice during pregnancy. Toxicol Sci. 2012;130:257–68.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C, Arndt P, Ulzheimer JC, Sonders MS, Baumann C, Waldegger S, Lang F, Koepsell H. Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol. 1998;54:342–52.PubMedGoogle Scholar
  30. 30.
    Noetzli M, Guidi M, Ebbing K, Eyer S, Wilhelm L, Michon A, Thomazic V, Alnawaqil AM, Maurer S, Zumbach S, Giannakopoulos P, von Gunten A, Csajka C, Eap CB. Population pharmacokinetic study of memantine: effects of clinical and genetic factors. Clin Pharmacokinet. 2013;52:211–23.PubMedCrossRefGoogle Scholar
  31. 31.
    Gaudry SE, Sitar DS, Smyth DD, McKenzie JK, Aoki FY. Gender and age as factors in the inhibition of renal clearance of amantadine by quinine and quinidine. Clin Pharmacol Ther. 1993;54:23–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Wong LT, Escobar MR, Smyth DD, Sitar DS. Gender-associated differences in rat renal tubular amantadine transport and absence of stereoselective transport inhibition by quinine and quinidine in distal tubules. J Pharmacol Exp Ther. 1993;267:1440–4.PubMedGoogle Scholar
  33. 33.
    Wong LT, Sitar DS, Aoki FY. Chronic tobacco smoking and gender as variables affecting amantadine disposition in healthy subjects. Br J Clin Pharmacol. 1995;39:81–4.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Bastian G, Barrail A, Urien S. Population pharmacokinetics of oxaliplatin in patients with metastatic cancer. Anticancer Drugs. 2003;14:817–24.PubMedCrossRefGoogle Scholar
  35. 35.
    Harvey AM, Malvin RL, Vander AJ. Comparison of creatinine secretion in men and women. Nephron. 1966;3:201–5.PubMedCrossRefGoogle Scholar
  36. 36.
    James GD, Sealey JE, Alderman M, Ljungman S, Mueller FB, Pecker MS, Laragh JH. A longitudinal study of urinary creatinine and creatinine clearance in normal subjects. Race, sex, and age differences. Am J Hypertens. 1988;1:124–31.PubMedCrossRefGoogle Scholar
  37. 37.
    Sambol NC, Chiang J, O'Conner M, Liu CY, Lin ET, Goodman AM, Benet LZ, Karam JH. Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus. J Clin Pharmacol. 1996;36:1012–21.PubMedCrossRefGoogle Scholar
  38. 38.
    Ravva P, Gastonguay MR, Tensfeldt TG, Faessel HM. Population pharmacokinetic analysis of varenicline in adult smokers. Br J Clin Pharmacol. 2009;68:669–81.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    de Jongh FE, Gallo JM, Shen M, Verweij J, Sparreboom A. Population pharmacokinetics of cisplatin in adult cancer patients. Cancer Chemother Pharmacol. 2004;54:105–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Grover B, Auberger C, Sarangarajan R, Cacini W. Functional impairment of renal organic cation transport in experimental diabetes. Pharmacol Toxicol. 2002;90:181–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Thomas MC, Tikellis C, Kantharidis P, Burns WC, Cooper ME, Forbes JM. The role of advanced glycation in reduced organic cation transport associated with experimental diabetes. J Pharmacol Exp Ther. 2004;311:456–66.PubMedCrossRefGoogle Scholar
  42. 42.
    Grover B, Buckley D, Buckley AR, Cacini W. Reduced expression of organic cation transporters rOCT1 and rOCT2 in experimental diabetes. J Pharmacol Exp Ther. 2004;308:949–56.PubMedCrossRefGoogle Scholar
  43. 43.
    Thomas MC, Tikellis C, Burns WC, Thallas V, Forbes JM, Cao Z, Osicka TM, Russo LM, Jerums G, Ghabrial H, Cooper ME, Kantharidis P. Reduced tubular cation transport in diabetes: prevented by ACE inhibition. Kidney Int. 2003;63:2152–61.PubMedCrossRefGoogle Scholar
  44. 44.
    Nowicki MT, Aleksunes LM, Sawant SP, Dnyanmote AV, Mehendale HM, Manautou JE. Renal and hepatic transporter expression in type 2 diabetic rats. Drug Metab Lett. 2008;2:11–7.PubMedCrossRefGoogle Scholar
  45. 45.
    More VR, Wen X, Thomas PE, Aleksunes LM, Slitt AL. Severe diabetes and leptin resistance cause differential hepatic and renal transporter expression in mice. Comp Hepatol. 2012;11:1.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    More VR, Slitt AL. Alteration of hepatic but not renal transporter expression in diet-induced obese mice. Drug Metab Dispos. 2011;39:992–9.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Jang EH, Kim HK, Park CS, Kang JH. Increased expression of hepatic organic cation transporter 1 and hepatic distribution of metformin in high-fat diet-induced obese mice. Drug Metab Pharmacokinet. 2010;25:392–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Moreno-Navarrete JM, Ortega FJ, Rodriguez-Hermosa JI, Sabater M, Pardo G, Ricart W, Fernandez-Real JM. OCT1 expression in adipocytes could contribute to increased metformin action in obese subjects. Diabetes. 2011;60:168–76.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Thomas MC, Jerums G, Tsalamandris C, Macisaac R, Panagiotopoulos S, Cooper ME, MDNSG Study Group. Increased tubular organic ion clearance following chronic ACE inhibition in patients with type 1 diabetes. Kidney Int. 2005;67:2494–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Bardin C, Nobecourt E, Larger E, Chast F, Treluyer JM, Urien S. Population pharmacokinetics of metformin in obese and non-obese patients with type 2 diabetes mellitus. Eur J Clin Pharmacol. 2012;68:961–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Tarasova L, Kalnina I, Geldnere K, Bumbure A, Ritenberga R, Nikitina-Zake L, Fridmanis D, Vaivade I, Pirags V, Klovins J. Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients. Pharmacogenet Genomics. 2012;22:659–66.PubMedCrossRefGoogle Scholar
  52. 52.
    Christensen MM, Brasch-Andersen C, Green H, Nielsen F, Damkier P, Beck-Nielsen H, Brosen K. The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenet Genomics. 2011;21:837–50.PubMedCrossRefGoogle Scholar
  53. 53.
    Stocker SL, Morrissey KM, Yee SW, Castro RA, Xu L, Dahlin A, Ramirez AH, Roden DM, Wilke RA, McCarty CA, Davis RL, Brett CM, Giacomini KM. The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther. 2013;93:186–94.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Toyama K, Yonezawa A, Masuda S, Osawa R, Hosokawa M, Fujimoto S, Inagaki N, Inui K, Katsura T. Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis. Br J Pharmacol. 2012;166:1183–91.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Toyama K, Yonezawa A, Tsuda M, Masuda S, Yano I, Terada T, Osawa R, Katsura T, Hosokawa M, Fujimoto S, Inagaki N, Inui K. Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients. Pharmacogenet Genomics. 2010;20:135–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Scott LA, Madan E, Valentovic MA. Influence of streptozotocin (STZ)-induced diabetes, dextrose diuresis and acetone on cisplatin nephrotoxicity in Fischer 344 (F344) rats. Toxicology. 1990;60:109–25.PubMedCrossRefGoogle Scholar
  57. 57.
    Scott LA, Madan E, Valentovic MA. Attenuation of cisplatin nephrotoxicity by streptozotocin-induced diabetes. Fundam Appl Toxicol. 1989;12:530–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Sarangarajan R, Cacini W. Effect of route of administration and dose on diabetes-induced protection against cisplatin nephrotoxicity. Proc Soc Exp Biol Med. 1996;212:362–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Valentovic MA, Scott LA, Madan E, Yokel RA. Renal accumulation and urinary excretion of cisplatin in diabetic rats. Toxicology. 1991;70:151–62.PubMedCrossRefGoogle Scholar
  60. 60.
    Ormond PM, Basinger MA, Jones MM, Hande KR. Association between increased atrial natriuretic peptide and reduced cisplatin nephrotoxicity in rats. J Pharmacol Exp Ther. 1992;262:246–51.PubMedGoogle Scholar
  61. 61.
    Sarangarajan R, Cacini W. Early onset of cisplatin-induced nephrotoxicity in streptozotocin-diabetic rats treated with insulin. Basic Clin Pharmacol Toxicol. 2004;95:66–71.PubMedCrossRefGoogle Scholar
  62. 62.
    Sarangarajan R, Cacini W. Normalization of hyperglycaemia by oral vanadyl sulfate does not reverse diabetes-induced protection against cisplatin nephrotoxicity in streptozotocin-diabetic rats. Pharmacol Toxicol. 1999;85:169–73.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyRutgers University, Ernest Mario School of PharmacyPiscatawayUSA
  2. 2.Environmental and Occupational Health Sciences InstituteRutgers UniversityPiscatawayUSA

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