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Rosuvastatin pharmacokinetics and pharmacogenetics in Caucasian and Asian subjects residing in the United States

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Systemic exposure to rosuvastatin in Asian subjects living in Japan or Singapore is approximately twice that observed in Caucasian subjects in Western countries or in Singapore. This study was conducted to determine whether pharmacokinetic differences exist among the most populous Asian subgroups and Caucasian subjects in the USA.

Method

Rosuvastatin pharmacokinetics was studied in Chinese, Filipino, Asian-Indian, Korean, Vietnamese, Japanese and Caucasian subjects residing in California. Plasma concentrations of rosuvastatin and metabolites after a single 20-mg dose were determined by mass spectrometric detection. The influence of polymorphisms in SLCO1B1 (T521>C [Val174Ala] and A388>G [Asn130Asp]) and in ABCG2 (C421>A [Gln141Lys]) on exposure to rosuvastatin was also assessed.

Results

The average rosuvastatin area under the curve from time zero to time of last quantifiable concentration was between 64 and 84 % higher, and maximum drug concentration was between 70 and 98 % higher in East Asian subgroups compared with Caucasians. Data for Asian-Indians was intermediate to these two ethnic groups at 26 and 29 %, respectively. Similar increases in exposure to N-desmethyl rosuvastatin and rosuvastatin lactone were observed. Rosuvastatin exposure was higher in subjects carrying the SLCO1B1 521C allele compared with that in non-carriers of this allele. Similarly, exposure was higher in subjects carrying the ABCG2 421A allele compared with that in non-carriers.

Conclusion

Plasma exposure to rosuvastatin and its metabolites was significantly higher in Asian populations residing in the USA compared with Caucasian subjects living in the same environment. This study suggests that polymorphisms in the SLCO1B1 and ABCG2 genes contribute to the variability in rosuvastatin exposure.

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References

  1. Warwick MJ, Dane AL, Raza A, Schneck DW (2000) Single- and multiple-dose pharmacokinetics and safety of the new HMG-CoA reductase inhibitor ZD4522. Atherosclerosis 151:39

    Article  Google Scholar 

  2. Martin PD, Mitchell PD, Schneck DW (2002) Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers. Br J Clin Pharmacol 54:472–477

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Sekino H, Onishi T (2005) Phase I study of ZD4522 (rosuvastatin), a new HMG-CoA reductase inhibitor—evaluation of tolerance and pharmacokinetics in healthy adult male volunteers after single and repeated oral administration. J Clin Ther Med 21:187–203

    Google Scholar 

  4. Tzeng T-B, Schneck DW, Birmingham B, Mitchell PD, Zhang H, Martin PD, Kung L-P (2008) Population pharmacokinetics of rosuvastatin: implications of renal impairment, race and dyslipidaemia. Curr Med Res Opin 24:2575–2585

    Article  CAS  PubMed  Google Scholar 

  5. Lee E, Ryan S, Birmingham B, Zalikowski J, March R, Ambrose H, Moore R, Lee C, Chen Y, Schneck D (2005) Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther 78:330–341

    Article  CAS  PubMed  Google Scholar 

  6. Martin PD, Warwick MJ, Dane AL, Cantarini MV (2003) A double-blind, randomized, incomplete crossover trial to assess the dose proportionality of rosuvastatin in healthy volunteers. Clin Ther 25:2215–2224

    Article  CAS  PubMed  Google Scholar 

  7. Martin PD, Warwick MJ, Dane AL, Brindley C, Short T (2003) Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers. Clin Ther 25:2553–2563

    Article  CAS  PubMed  Google Scholar 

  8. Elsby R, Hilgendorf C, Fenner K (2012) Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1. Clin Pharmacol Ther 92:584–598

    Article  CAS  PubMed  Google Scholar 

  9. McCormick AD, McKillop D, Butters CJ, Miles GS, Baba T, Touchi A, Yamaguchi Y (2000) ZD4522—an HMG-CoA reductase inhibitor free of metabolically mediated drug interactions: metabolic studies in human in vitro systems. J Clin Pharmacol 40:1055

    Google Scholar 

  10. 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 25:2822–2835

    Article  CAS  PubMed  Google Scholar 

  11. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV (2002) The effect of fluconazole on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol 58:527–531

    Article  CAS  PubMed  Google Scholar 

  12. Tirona RG (2005) Ethic differences in statin disposition. Clin Pharmacol Ther 78:311–316

    Article  CAS  PubMed  Google Scholar 

  13. Choi JH, Lee MG, Cho JY, Lee JE, Kim KH, Park K (2008) Influence of OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans. Clin Pharmacol Ther 83:251–257

    Article  CAS  PubMed  Google Scholar 

  14. Lee HK, Hu M, Lui SS, Ho CS, Wong CK, Tomlinson B (2013) Effects of polymorphisms in ABCG2, SLCO1B1, SLC10A1 and CYP2C9/19 on plasma concentrations of rosuvastatin and lipid response in Chinese patients. Pharmacogenomics 14:1283–1294

    Article  CAS  PubMed  Google Scholar 

  15. Zhang W, Yu BN, He YJ, Fan L, Li Q, Liu ZQ, Wang A, Liu YL, Tan ZR, Fen-Jiang, Huang YF, Zhou HH (2006) Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta 373:99–103

  16. Yamazaki M, Akiyama S, Nishigaki R, Sugiyama Y (1996) Uptake is the rate-limiting step in the overall hepatic elimination of pravastatin at steady-state in rats. Pharm Res 13:1559–1564

    Article  CAS  PubMed  Google Scholar 

  17. 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 130:1793–1806

    Article  CAS  PubMed  Google Scholar 

  18. Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T, Takane H, Irie S, Kusuhara H, Urasaki Y, Urae A, Higuchi S, Otsubo K, Sugiyama Y (2003) Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 73:554–565

    Article  CAS  PubMed  Google Scholar 

  19. Mwinyi J, Johne A, Bauer S, Roots I, Gerloff T (2004) Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther 75:415–421

    Article  CAS  PubMed  Google Scholar 

  20. Niemi M, Schaeffeler E, Lang T, Fromm MF, Neuvonen M, Kyrklund C, Backman JT, Kerb R, Schwab M, Neuvonen PJ, Eichelbaum M, Kivistö KJ (2004) High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 14:429–440

    Article  CAS  PubMed  Google Scholar 

  21. Chung JY, Cho JY, Yu KS, Kim JR, Oh DS, Jung HR, Lim KS, Moon KH, Shin SG, Jang IJ (2005) Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 78:342–350

    Article  CAS  PubMed  Google Scholar 

  22. Keskitalo JE, Zolk O, Fromm MF, Kurkinen KJ, Neuvonen PJ, Niemi M (2009) ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 86:197–203

    Article  CAS  PubMed  Google Scholar 

  23. Martin PD, Dane AL, Nwose OM, Schneck DW, Warwick MJ (2002) No effect of age and gender on the pharmacokinetics of rosuvastatin: a new HMG-CoA reductase inhibitor. J Clin Pharmacol 42:1116–1121

    Article  CAS  PubMed  Google Scholar 

  24. Yang CS, Pan E (2012) The effects of green tea polyphenols on drug metabolism. Expert Opin Drug Metab Toxicol 8:677–689

    Article  CAS  PubMed  Google Scholar 

  25. Gradhand U, Kim RB (2008) Pharmacogenomics of MRP transporters (ABCC1-5) and BCRP (ABCG2). Drug Metab Rev 40:317–354

    Article  CAS  PubMed  Google Scholar 

  26. Huang L, Wang Y, Grimm S (2006) ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein. Drug Metab Dispos 34:738–742

    Article  CAS  PubMed  Google Scholar 

  27. Zamber CP, Lamba JK, Yasuda K, Farnum J, Thummel K, Schuetz JD, Schuetz EG (2003) Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. Pharmacogenetics 13:19–28

    Article  CAS  PubMed  Google Scholar 

  28. Lee SS, Jeong HE, Yi JM, Jung HJ, Jang JE, Kim EY, Lee SJ, Shin JG (2007) Identification and functional assessment of BCRP polymorphisms in a Korean population. Drug Metab Dispos 35:623–632

    Article  CAS  PubMed  Google Scholar 

  29. Birmingham BK, Bujac SR, Elsby R, Azumaya CT, Wei C, Chen Y, Mosqueda-Garcia R, Ambrose HJ (2015) Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect?. Eur J Clin Pharmacol doi:10.1007/s00228-014-1801-z

  30. Niemi M (2010) Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Ther 87:130–133

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Debra Ennis, an employee of AstraZeneca, performed the study analyses. Editorial support was provided by Kerry Knight and Valerie Moss of Prime Medica Ltd and Maren White of White Quill Ltd, supported by AstraZeneca.

Conflict of interest

B. Birmingham, S.R. Bujac, R. Elsby, C. Azumaya and H.J. Ambrose are employees of AstraZeneca. Y. Chen and J. Zalikowski are former employees of AstraZeneca. S.R. Bujac, R. Elsby, C. Azumaya, Y. Chen, J. Zalikowski and H.J. Ambrose all hold stock in AstraZeneca.

Responsibility for opinions, conclusions and interpretation of data lies with the authors.

Author information

Author notes

  1. Julie Zalikowski

    Present address: Accium BioSciences, Seattle, WA, USA

  2. Yusong Chen

    Present address: PAREXEL International, Waltham, MA, USA

Authors and Affiliations

  1. AstraZeneca, Wilmington, DE, USA

    Bruce K. Birmingham, Connie T. Azumaya, Julie Zalikowski & Yusong Chen

  2. AstraZeneca, Macclesfield, Cheshire, UK

    Sarah R. Bujac, Robert Elsby & Helen J. Ambrose

  3. WCCT Global, 3545 Howard Way, Costa mesa, CA, 92626, USA

    Kenneth Kim

  4. West Chester, Chester, PA, USA

    Bruce K. Birmingham

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  1. Bruce K. Birmingham
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Correspondence to Bruce K. Birmingham.

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Birmingham, B.K., Bujac, S.R., Elsby, R. et al. Rosuvastatin pharmacokinetics and pharmacogenetics in Caucasian and Asian subjects residing in the United States. Eur J Clin Pharmacol 71, 329–340 (2015). https://doi.org/10.1007/s00228-014-1800-0

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  • DOI: https://doi.org/10.1007/s00228-014-1800-0

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