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Effects of CYP2D6 and CYP3A5 genetic polymorphisms on steady-state pharmacokinetics and hemodynamic effects of tamsulosin in humans

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

Tamsulosin is one of the most potent drugs currently available to treat benign prostatic hyperplasia. Cytochrome P450 (CYP) 2D6 and CYP3A are the two major enzymes responsible for tamsulosin metabolism. The purpose of this study was to evaluate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on the pharmacokinetics and hemodynamic effects of tamsulosin in humans.

Methods

Twenty-nine male subjects were enrolled and their CYP2D6 (*2,*4,*5,*10,*14,*21,*41, and *xN) and CYP3A5 (*5) genotypes were screened. Tamsulosin was administered daily for 6 days to assess its steady-state pharmacokinetics and hemodynamic effects according to CYP2D6 and CYP3A5 genotypes.

Results

CYP2D6 group 3 (with genotype *10/*10 or *5/*10) exhibited higher plasma levels than CYP2D6 group 1 (with genotype *1/*1,*1/*2,*1/*2xN, or *2/*10xN) or CYP2D6 group 2 (with genotype *1/*10,*1/*41, or *2/*5) (trough concentrations for groups 1, 2, and 3: 1.3, 1.8, and 3.8 ng/mL, respectively [P < 0.001]; peak concentrations for groups 1, 2, 3: 8.3, 10.0, and 13.8 ng/mL, respectively [P < 0.005]). Similarly, CYP2D6 genotypes influenced the hemodynamic effects of tamsulosin based on systolic and diastolic blood pressures. However, the CYP3A5*3 polymorphism did not affect tamsulosin plasma levels and its hemodynamic effects.

Conclusion

The CYP2D6 but not the CYP3A5 genetic polymorphisms affected the pharmacokinetics and the hemodynamic effects of tamsulosin.

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References

  1. Roehrborn CG (2009) Efficacy of alpha-adrenergic receptor blockers in the treatment of male lower urinary tract symptoms. Rev Urol 11[Suppl 1]:S1–S8

    PubMed  PubMed Central  Google Scholar 

  2. Lyseng-Williamson KA, Jarvis B, Wagstaff AJ (2002) Tamsulosin: an update of its role in the management of lower urinary tract symptoms. Drugs 62(1):135–167

    Article  PubMed  CAS  Google Scholar 

  3. Troost J, Tatami S, Tsuda Y, Mattheus M, Mehlburger L, Wein M, Michel MC (2011) Effects of strong CYP2D6 and 3A4 inhibitors, paroxetine and ketoconazole, on the pharmacokinetics and cardiovascular safety of tamsulosin. Br J Clin Pharmacol 72(2):247–256. https://doi.org/10.1111/j.1365-2125.2011.03988.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Koiso K, Akaza H, Kikuchi K, Aoyagi K, Ohba S, Miyazaki M, Ito M, Sueyoshi T, Matsushima H, Kamimura H, Watanabe T, Higuchi S (1996) Pharmacokinetics of tamsulosin hydrochloride in patients with renal impairment: effects of alpha 1-acid glycoprotein. J Clin Pharmacol 36(11):1029–1038

    Article  PubMed  CAS  Google Scholar 

  5. Myrand SP, Sekiguchi K, Man MZ, Lin X, Tzeng RY, Teng CH, Hee B, Garrett M, Kikkawa H, Lin CY, Eddy SM, Dostalik J, Mount J, Azuma J, Fujio Y, Jang IJ, Shin SG, Bleavins MR, Williams JA, Paulauskis JD, Wilner KD (2008) Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther 84(3):347–361. https://doi.org/10.1038/sj.clpt.6100482

    Article  PubMed  CAS  Google Scholar 

  6. Taguchi K, Schafers RF, Michel MC (1998) Radioreceptor assay analysis of tamsulosin and terazosin pharmacokinetics. Br J Clin Pharmacol 45(1):49–55

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Soeishi Y, Matsushima H, Watanabe T, Higuchi S, Cornelissen K, Ward J (1996) Absorption, metabolism and excretion of tamsulosin hydrochloride in man. Xenobiotica 26(6):637–645

    Article  PubMed  CAS  Google Scholar 

  8. Kamimura H, Oishi S, Matsushima H, Watanabe T, Higuchi S, Hall M, Wood SG, Chasseaud LF (1998) Identification of cytochrome P450 isozymes involved in metabolism of the alpha1-adrenoceptor blocker tamsulosin in human liver microsomes. Xenobiotica 28(10):909–922. https://doi.org/10.1080/004982598238985

    Article  PubMed  CAS  Google Scholar 

  9. Haertter S (2013) Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6. Drug Metabol Drug Interact 28(4):209–216. https://doi.org/10.1515/dmdi-2013-0032

    Article  PubMed  CAS  Google Scholar 

  10. Meyer UA, Zanger UM (1997) Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol 37:269–296. https://doi.org/10.1146/annurev.pharmtox.37.1.269

    Article  PubMed  CAS  Google Scholar 

  11. Ingelman-Sundberg M, Oscarson M, McLellan RA (1999) Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci 20(8):342–349

    Article  PubMed  CAS  Google Scholar 

  12. Liu YT, Hao HP, Liu CX, Wang GJ, Xie HG (2007) Drugs as CYP3A probes, inducers, and inhibitors. Drug Metab Rev 39(4):699–721. https://doi.org/10.1080/03602530701690374

    Article  PubMed  CAS  Google Scholar 

  13. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27(4):383–391. https://doi.org/10.1038/86882

    Article  PubMed  CAS  Google Scholar 

  14. Hustert E, Haberl M, Burk O, Wolbold R, He YQ, Klein K, Nuessler AC, Neuhaus P, Klattig J, Eiselt R, Koch I, Zibat A, Brockmoller J, Halpert JR, Zanger UM, Wojnowski L (2001) The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 11(9):773–779

    Article  PubMed  CAS  Google Scholar 

  15. Park PW, Seo YH, Ahn JY, Kim KA, Park JY (2009) Effect of CYP3A5*3 genotype on serum carbamazepine concentrations at steady-state in Korean epileptic patients. J Clin Pharm Ther 34(5):569–574. https://doi.org/10.1111/j.1365-2710.2009.01057.x

    Article  PubMed  CAS  Google Scholar 

  16. Kim KA, Park PW, Lee OJ, Kang DK, Park JY (2007) Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects. J Clin Pharmacol 47(1):87–93. https://doi.org/10.1177/0091270006295063

    Article  PubMed  CAS  Google Scholar 

  17. Park JY, Kim KA, Park PW, Lee OJ, Kang DK, Shon JH, Liu KH, Shin JG (2006) Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects. Clin Pharmacol Ther 79(6):590–599. https://doi.org/10.1016/j.clpt.2006.02.008

    Article  PubMed  CAS  Google Scholar 

  18. Lowe FC (2005) Summary of clinical experiences with tamsulosin for the treatment of benign prostatic hyperplasia. Rev Urol 7[Suppl 4]:S13–S21

    PubMed  PubMed Central  Google Scholar 

  19. Bird ST, Delaney JA, Brophy JM, Etminan M, Skeldon SC, Hartzema AG (2013) Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology. BMJ 347:f6320. https://doi.org/10.1136/bmj.f6320

    Article  PubMed  PubMed Central  Google Scholar 

  20. Oelke M, Gericke A, Michel MC (2014) Cardiovascular and ocular safety of alpha1-adrenoceptor antagonists in the treatment of male lower urinary tract symptoms. Expert Opin Drug Saf 13(9):1187–1197. https://doi.org/10.1517/14740338.2014.936376

    Article  PubMed  CAS  Google Scholar 

  21. Park JY, Kim KA, Park PW, Lee OJ, Ryu JH, Lee GH, Ha MC, Kim JS, Kang SW, Lee KR (2006) Pharmacokinetic and pharmacodynamic characteristics of a new S-amlodipine formulation in healthy Korean male subjects: a randomized, open-label, two-period, comparative, crossover study. Clin Ther 28(11):1837–1847. https://doi.org/10.1016/j.clinthera.2006.11.008

    Article  PubMed  CAS  Google Scholar 

  22. Park JY, Kim KA, Lee GS, Park PW, Kim SL, Lee YS, Lee YW, Shin EK (2004) Randomized, open-label, two-period crossover comparison of the pharmacokinetic and pharmacodynamic properties of two amlodipine formulations in healthy adult male Korean subjects. Clin Ther 26(5):715–723

    Article  PubMed  CAS  Google Scholar 

  23. Lee SJ, Lee SS, Jung HJ, Kim HS, Park SJ, Yeo CW, Shin JG (2009) Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 37(7):1464–1470. https://doi.org/10.1124/dmd.108.022368

    Article  PubMed  CAS  Google Scholar 

  24. Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS (2017) Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med 19(1):69–76. https://doi.org/10.1038/gim.2016.80

    Article  PubMed  Google Scholar 

  25. Matsushima H, Takanuki KI, Kamimura H, Watanabe T, Higuchi S (1997) Highly sensitive method for the determination of tamsulosin hydrochloride in human plasma dialysate, plasma and urine by high-performance liquid chromatography-electrospray tandem mass spectrometry. J Chromatogr B Biomed Sci Appl 695(2):317–327

    Article  PubMed  CAS  Google Scholar 

  26. Keski-Rahkonen P, Parssinen O, Leppanen E, Mauriala T, Lehtonen M, Auriola S (2007) Determination of tamsulosin in human aqueous humor and serum by liquid chromatography-electrospray ionization tandem mass spectrometry. J Pharm Biomed Anal 43(2):606–612. https://doi.org/10.1016/j.jpba.2006.07.016

    Article  PubMed  CAS  Google Scholar 

  27. Choi CI, Bae JW, Jang CG, Lee SY (2012) Tamsulosin exposure is significantly increased by the CYP2D6*10/*10 genotype. J Clin Pharmacol 52(12):1934–1938. https://doi.org/10.1177/0091270011432168

    Article  PubMed  CAS  Google Scholar 

  28. Franco-Salinas G, de la Rosette JJ, Michel MC (2010) Pharmacokinetics and pharmacodynamics of tamsulosin in its modified-release and oral controlled absorption system formulations. Clin Pharmacokinet 49(3):177–188. https://doi.org/10.2165/11317580-000000000-00000

    Article  PubMed  CAS  Google Scholar 

  29. Boehringer Ingelheim GmbH (2016) Flomax (tamsulosin hydrochloride). Highlights of prescribing information. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Flomax+Caps/Flomax.pdf. Assessed 22 May 2018

  30. Roehrborn CG, Schwinn DA (2004) Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol 171(3):1029–1035. https://doi.org/10.1097/01.ju.0000097026.43866.cc

    Article  PubMed  CAS  Google Scholar 

  31. Michel MC, Korstanje C, Krauwinkel W (2005) Cardiovascular safety of Tamsulosin modified release in the fasted and fed state in elderly healthy subjects. Eur Urol Suppl 4(2):9–14

    Article  CAS  Google Scholar 

  32. Clarke TA, Waskell LA (2003) The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. Drug Metab Dispos 31(1):53–59

    Article  PubMed  CAS  Google Scholar 

  33. Fukuda T, Onishi S, Fukuen S, Ikenaga Y, Ohno M, Hoshino K, Matsumoto K, Maihara A, Momiyama K, Ito T, Fujio Y, Azuma J (2004) CYP3A5 genotype did not impact on nifedipine disposition in healthy volunteers. Pharmacogenomics J 4(1):34–39. https://doi.org/10.1038/sj.tpj.6500218

    Article  PubMed  CAS  Google Scholar 

  34. Hwang IC, Park JY, Ahn HY, Kim KK, Suh HS, Ko KD, Kim KA (2014) Effects of CYP3A5, CYP2C19, and CYP2B6 on the clinical efficacy and adverse outcomes of sibutramine therapy: a crucial role for the CYP2B6*6 allele. Clin Chim Acta 428:77–81. https://doi.org/10.1016/j.cca.2013.11.007

    Article  PubMed  CAS  Google Scholar 

  35. Kim KA, Park PW, Park JY (2008) Effect of CYP3A5*3 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects. Eur J Clin Pharmacol 64(6):589–597. https://doi.org/10.1007/s00228-008-0471-0

    Article  PubMed  CAS  Google Scholar 

  36. Werk AN, Cascorbi I (2014) Functional gene variants of CYP3A4. Clin Pharmacol Ther 96(3):340–348. https://doi.org/10.1038/clpt.2014.129

    Article  PubMed  CAS  Google Scholar 

  37. PharmVar. Cytochrome P450 family 2 subfamily D member 6. Pharmacogene Variation Consortium. https://www.pharmvar.org/gene/CYP2D6. Accessed 22 May 2018

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Acknowledgements

This study was supported by a Korea University Grant.

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  1. Department of Clinical Pharmacology & Toxicology, Anam Hospital, Korea University College of Medicine, 126-1, 5-Ga, Anam-dong, Seongbuk-Gu, Seoul, 136-705, South Korea

    Kyoung-Ah Kim, In-Bae Park & Ji-Young Park

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Correspondence to Ji-Young Park.

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Kim, KA., Park, IB. & Park, JY. Effects of CYP2D6 and CYP3A5 genetic polymorphisms on steady-state pharmacokinetics and hemodynamic effects of tamsulosin in humans. Eur J Clin Pharmacol 74, 1281–1289 (2018). https://doi.org/10.1007/s00228-018-2501-x

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