Skip to main content

CYP3A5 *1 allele associated with tacrolimus trough concentrations but not subclinical acute rejection or chronic allograft nephropathy in Japanese renal transplant recipients

European Journal of Clinical Pharmacology volume 65, Article number: 473 (2009) Cite this article

Abstract

Purpose

We assessed reported associations of CYP3A5 *1 allele with a delay in achieving target tacrolimus concentrations, and occurrence of biopsy-confirmed subclinical acute rejection (SAR) and chronic allograft nephropathy (CAN) in Japanese subjects.

Methods

Forty-one renal allograft recipients were studied. The targeted tacrolimus trough concentrations were 20–25 ng/mL up to 2 weeks post-transplantation, 10–15 ng/mL up to 6 weeks, and 5–10 ng/mL thereafter. At 1 month and 1 year post-transplantation, allograft biopsies were performed.

Results

The CYP3A5 *1/*1 + *1/*3 (expresser) and *3/*3 (nonexpresser) alleles were detected in 19 and 22 patients, respectively. Although the mean trough concentrations were lower in CYP3A5 expressers than nonexpressers for the first 3 weeks, no difference in frequency of SAR among CYP3A5 genotypes was found. The mean trough concentrations were lower from 8 to 12 months post-transplantation, and the frequency of CAN was lower in CYP3A5 expressers.

Conclusions

In contrast to the previous reports, the CYP3A5 *1 allele was not associated with the frequency of SAR or CAN, suggesting that further studies of different immunosuppressive strategies using tacrolimus are needed to confirm the adequate dosing and concentration of tacrolimus for each CYP3A5 genotype.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Venkataramanan R, Swaminathan A, Prasad T, Jain A, Zuckerman S, Warty V, McMichael J, Lever J, Burckart G, Starzl T (1995) Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 29:404–430

    PubMed  Article  CAS  Google Scholar 

  2. Haufroid V, Wallenmacq P, VanKerckhove V, Elens L, De Meyer M, Eddour DC, Malaise J, Lison D, Mourad M (2006) CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study. Am J Transplant 6:2706–2713

    PubMed  Article  CAS  Google Scholar 

  3. Hessenlink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, Weimar W, van Gelder T (2003) Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 74:245–254

    Article  CAS  Google Scholar 

  4. Haufroid V, Mourad M, Van Kerckhove V, Wawrzyniak J, De Meyer M, Eddour DC, Malaise J, Lison D, Squifflet JP, Wallemacq P (2004) The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant recipients. Pharmacogenetics 14:147–154

    PubMed  Article  CAS  Google Scholar 

  5. Tsuchiya N, Satoh S, Tada H, Li Z, Ohyama C, Sato K, Suzuki T, Habuchi T, Kato T (2004) Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation 78:1182–1187

    PubMed  Article  CAS  Google Scholar 

  6. Tada H, Tsuchiya N, Satoh S, Kagaya H, Li Z, Sato K, Miura M, Suzuki T, Kato T, Habuchi T (2005) Impact of CYP3A5 and MDR1 (ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplant Proc 37:1730–1732

    PubMed  Article  CAS  Google Scholar 

  7. Roy JN, Barama A, Poirier C, Vinet B, Roger M (2006) Cyp3A4, Cyp3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients. Pharmacogenet Genomics 16:659–665

    PubMed  Article  CAS  Google Scholar 

  8. MacPhee IA, Fredericks S, Tai T, Syrris P, Carter ND, Johnston A, Goldberg L, Holt DW (2004) The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant 4:914–919

    PubMed  Article  CAS  Google Scholar 

  9. Kuypers DR, de Jonge H, Naesens M, Lerut E, Verbeke K, Vanrenterghem Y (2007) CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin Pharmacol Ther 82:711–725

    PubMed  Article  CAS  Google Scholar 

  10. Undre NA, van Hooff J, Christiaans M, Vanrenterghem Y, Donck J, Heeman U, Kohnle M, Zanker B, Land W, Morales JM, Andres A, Schafer A, Stevenson P (1999) Low systemic exposure to tacrolimus correlates with acute rejection. Transplant Proc 31:296–298

    PubMed  Article  CAS  Google Scholar 

  11. Staatz C, Taylor P, Tett S (2001) Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation. Nephrol Dial Transplant 16:1905–1909

    PubMed  Article  CAS  Google Scholar 

  12. Tada H, Satoh S, Iinuma M, Shimoda N, Murakami M, Hayase Y, Kato T, Suzuki T (2003) Chronopharmacokinetics of tacrolimus in kidney transplant recipients: occurrence of acute rejection. J Clin Pharmacol 43:859–865

    PubMed  Article  CAS  Google Scholar 

  13. Inoue K, Miura M, Satoh S, Kagara H, Saito M, Habuchi T, Suzuki T (2007) Influence of UGT1A7 and UGT1A9 intronic I1399 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Ther Drug Monit 29:299–304

    PubMed  Article  CAS  Google Scholar 

  14. Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T et al (1999) The Banff 97 working classification of renal allograft pathology. Kidney Int 55:713–723

    PubMed  Article  CAS  Google Scholar 

  15. Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE et al (2007) Banff ’05 meeting report; differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (CAN). Am J Transplant 7:518–526

    PubMed  Article  CAS  Google Scholar 

  16. Numakura K, Satoh S, Tsuchiya N, Horikawa Y, Inoue T, Kakinuma H, Matsuura S, Saito M, Tada H, Suzuki T, Habuchi T (2005) Clinical and genetic risk factors for posttransplant diabetes mellitus in adult renal transplant recipients treated with tacrolimus. Transplantation 80:1419–1424

    PubMed  Article  CAS  Google Scholar 

  17. Vincenti F, Laskow DA, Neylan JF, Mendez R, Matas AJ (1996) One-year follow up of an open-label trial of FK506 for primary kidney transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group. Transplantation 61:1576–1581

    PubMed  Article  CAS  Google Scholar 

  18. Japanese FK506 Study Group (1992) Japanese study of kidney transplantation. 1. Results of early phase II study. Transplant Int 5(Suppl 1):S524–S528

    Google Scholar 

  19. Spencer CM, Goa KL, Gillis JC (1997) Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs 54:925–975

    PubMed  Article  CAS  Google Scholar 

  20. Gruber SA, Hewitt JM, Sorenson AL, Barber DL, Bowers L, Rynders G, Arrazola L, Matas AJ, Rosenberg ME, Canafax DM (1994) Pharmacokinetics of FK506 after intravenous and oral administration in patients awaiting renal transplantation. J Clin Pharmacol 34:859–864

    PubMed  CAS  Google Scholar 

  21. Jain AB, Abu-Elmagd K, Abdallah H, Warty V, Fung J, Todo S, Starzl TE, Venkataramanan R (1993) Pharmacokinetics of FK506 in liver transplant recipients after continuous intravenous infusion. J Clin Pharmacol 33:606–611

    PubMed  CAS  Google Scholar 

  22. Satoh S, Tada H, Tachiki Y, Tcuchiya N, Shimoda N, Akao T, Sato K, Habuchi T, Suzuki T, Kato T (2001) Chrono and clinical pharmacokinetic study of tacrolimus in continuous intravenous administration. Int J Urol 8:353–358

    PubMed  Article  CAS  Google Scholar 

  23. Miller J, Mendez R, Pirsch JD, Jensik SC (2000) Safety and efficacy of tacrolimus in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF dose-ranging kidney transplant study group. Transplantation 69:875–880

    PubMed  Article  CAS  Google Scholar 

  24. Ortiz F, Paavonen T, Tornroth T, Koskinen P, Finne P, Salmela K, Kyllonen L, Gronhagen-Riska C, Honkanen E (2005) Predictors of renal allograft histologic damage progression. J Am Soc Nephrol 16:817–824

    PubMed  Article  Google Scholar 

  25. Bakker RC, Hollander AA, Mallat MJ, Bruijin JA, Paul LC, de Fijter JW (2003) Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy. Kidney Int 64:1027–1034

    PubMed  Article  CAS  Google Scholar 

  26. Lamba JK, Lin YS, Schuetz EG, Thummel KE (2002) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Delivery Rev 54:1271–1294

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was partially supported by a grant (No. 20591894) from the Japanese Society for the Promotion of Science, and published at the 2008 American Transplant Congress in Toronto.

Author information

Affiliations

  1. Division of Renal Replacement Therapeutic Science, Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    Shigeru Satoh

  2. Department of Urology, Akita University School of Medicine, Akita, Japan

    Mitsuru Saito, Takamitsu Inoue, Norihiko Tsuchiya & Tomonori Habuchi

  3. Department of Pharmacy, Akita University Hospital, Akita, Japan

    Hideaki Kagaya, Masatomo Miura, Kazuyuki Inoue & Toshio Suzuki

  4. Department of Nephrology and Rheumatology, Akita University School of Medicine, Akita, Japan

    Atsushi Komatsuda

Authors
  1. Shigeru Satoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitsuru Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takamitsu Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hideaki Kagaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masatomo Miura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuyuki Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Atsushi Komatsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Norihiko Tsuchiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Toshio Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tomonori Habuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shigeru Satoh.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Satoh, S., Saito, M., Inoue, T. et al. CYP3A5 *1 allele associated with tacrolimus trough concentrations but not subclinical acute rejection or chronic allograft nephropathy in Japanese renal transplant recipients. Eur J Clin Pharmacol 65, 473 (2009). https://doi.org/10.1007/s00228-008-0606-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00228-008-0606-3

Keywords

  • Tacrolimus
  • Pharmacogenetics
  • CYP3A5 A6986G polymorphism
  • CYP3A5 expresser
  • Subclinical acute rejection
  • Chronic allograft nephropathy