Abstract
After uptake into liver cells, the antiemetic drugs tropisetron and ondansetron undergo metabolic inactivation by cytochrome P450 2D6 (CYP2D6). We investigated whether the hepatic organic cation transporter 1 (OCT1; SLC22A1) mediates cellular uptake and whether common OCT1 loss-of-function polymorphisms affect pharmacokinetics and efficacy of both drugs. Both tropisetron and ondansetron inhibited ASP+ uptake in OCT1-overexpressing HEK293 cells. Overexpression of wild-type, but not OCT1 loss-of-function variants, significantly increased tropisetron uptake. Correspondingly, patients with two loss-of-function OCT1 alleles had higher tropisetron plasma concentrations (n=59, P<0.04) and higher clinical efficacy (n=91, P=0.009) compared with carriers of fully active OCT1. Overexpression of OCT1 did not increase ondansetron uptake. Nevertheless, OCT1 genotypes correlated with pharmacokinetics (n=45, P<0.05) and clinical efficacy (n=222, P<0.02) of ondansetron, the effect size of OCT1 genotypes on pharmacokinetics and efficacy was greater for tropisetron than for ondansetron. In conclusion, in addition to the known effects of CYP2D6, OCT1 deficiency may increase efficacy of tropisetron and potentially of ondansetron by limiting their hepatic uptake.
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References
Roila F, Hesketh PJ, Herrstedt J . Prevention of chemotherapy- and radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol 2006; 17: 20–28.
Aapro M . 5-HT(3)-receptor antagonists in the management of nausea and vomiting in cancer and cancer treatment. Oncology 2005; 69: 97–109.
Hesketh PJ . Chemotherapy-induced nausea and vomiting. N Engl J Med 2008; 358: 2482–2494.
Kaiser R, Sezer O, Papies A, Bauer S, Schelenz C, Tremblay PB et al. Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 2002; 20: 2805–2811.
Hilgendorf C, Ahlin G, Seithel A, Artursson P, Ungell AL, Karlsson J . Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metab Dispos 2007; 35: 1333–1340.
Nies AT, Herrmann E, Brom M, Keppler D . Vectorial transport of the plant alkaloid berberine by double-transfected cells expressing the human organic cation transporter 1 (OCT1, SLC22A1) and the efflux pump MDR1 P-glycoprotein (ABCB1). Naunyn Schmiedebergs Arch Pharmacol 2008; 376: 449–461.
Tzvetkov MV, Vormfelde SV, Balen D, Meineke I, Schmidt T, Sehrt D et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther 2009; 86: 299–306.
Kerb R, Brinkmann U, Chatskaia N, Gorbunov D, Gorboulev V, Mornhinweg E et al. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics 2002; 12: 591–595.
Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, Stryke D et al. Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci USA 2003; 100: 5902–5907.
Bauer S, Stömer E, Kaiser R, Tremblay PB, Brockmöller J, Roots I . Simultaneous determination of ondansetron and tropisetron in human plasma using HPLC with UV detection. Biomed Chromatogr 2002; 16: 187–190.
Tzvetkov MV, Meineke I, Sehrt D, Vormfelde SV, Brockmöller J . Amelogenin-based sex identification as a strategy to control the identity of DNA samples in genetic-association studies. Pharmacogenomics 2010; 11: 449–457.
Stephens M, Donnelly P . A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.
Koepsell H, Lips K, Volk C . Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 2007; 24: 1227–1251.
Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P et al. Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1. J Med Chem 2008; 51: 5932–5942.
Brockmöller J, Kirchheiner J, Meisel C, Roots I . Pharmacogenetic diagnostics of cytochrome P450 polymorphisms in clinical drug development and in drug treatment. Pharmacogenomics 2000; 1: 125–151.
Ingelman-Sundberg M . Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci 2004; 25: 193–200.
Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med 2008; 359: 789–799.
Romaine SP, Bailey KM, Hall AS, Balmforth AJ . The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharmacogenomics J 10: 1–11.
Vormfelde SV, Toliat MR, Schirmer M, Meineke I, Nürnberg P, Brockmoller J . The polymorphisms Asn130Asp and Val174Ala in OATP1B1 and the CYP2C9 allele *3 independently affect torsemide pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2008; 83: 815–817.
Werner D, Werner U, Meybaum A, Schmidt B, Umbreen S, Grosch A et al. Determinants of steady-state torasemide pharmacokinetics: impact of pharmacogenetic factors, gender and angiotensin II receptor blockers. Clin Pharmacokinet 2008; 47: 323–332.
Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007; 117: 1422–1431.
Ciarimboli G, Koepsell H, Iordanova M, Gorboulev V, Durner B, Lang D et al. Individual PKC-phosphorylation sites in organic cation transporter 1 determine substrate selectivity and transport regulation. J Am Soc Nephrol 2005; 16: 1562–1570.
Horton R . Lotronex and the FDA: a fatal erosion of integrity. Lancet 2001; 357: 1544–1545.
Candiotti KA, Birnbach DJ, Lubarsky DA, Nhuch F, Kamat A, Koch WH et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology 2005; 102: 543–549.
Janicki PK, Schuler HG, Jarzembowski TM, Rossi M 2nd . Prevention of postoperative nausea and vomiting with granisetron and dolasetron in relation to CYP 2D6 genotype. Anesth Analg 2006; 102: 1127–1133.
Yonezawa A, Masuda S, Yokoo S, Katsura T, Inui K . Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family). J Pharmacol Exp Ther 2006; 319: 879–886.
Zhang S, Lovejoy KS, Shima JE, Lagpacan LL, Shu Y, Lapuk A et al. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res 2006; 66: 8847–8857.
Chen JJ, Li Z, Pan H, Murphy DL, Tamir H, Koepsell H et al. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter: abnormal intestinal motility and the expression of cation transporters. J Neurosci 2001; 21: 6348–6361.
Mashru RC, Sutariya VB, Sankalia MG, Sankalia JM . Effect of pH on in vitro permeation of ondansetron hydrochloride across porcine buccal mucosa. Pharm Dev Technol 2005; 10: 241–247.
Acknowledgements
We are grateful to Herman Koepsell and Valentin Gorboulev for kindly providing the initial OCT1-expressing construct and Rene Niehus for his help with the genotyping. In addition, we thank all patients who participated in the clinical investigation. This project was financially supported by DFG grant GRK1034/2 to MVT and ARS.
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Tzvetkov, M., Saadatmand, A., Bokelmann, K. et al. Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT3 antagonists tropisetron and ondansetron. Pharmacogenomics J 12, 22–29 (2012). https://doi.org/10.1038/tpj.2010.75
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DOI: https://doi.org/10.1038/tpj.2010.75
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