Skip to main content
SpringerLink
Log in

Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients

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

Abstract

Objective

The objective of this study was to retrospectively evaluate the effects of MDR1, CYP3A4*18B, and CYP3A5*3 genetic polymorphisms on cyclosporine A (CsA) pharmacokinetics in Chinese renal transplant patients during the first month after transplantation.

Methods

A total of 103 renal transplant recipients receiving CsA were genotyped for MDR1 (C1236T, G2677T/A, and C3435T), CYP3A4*18B, and CYP3A5*3. The predose and 2-h postdose concentrations of CsA (C0 and C2, respectively) were determined by fluorescence polarization immunoassay, and their relationships with corresponding genotypes and haplotypes were investigated.

Results

Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted concentration compared with those with CYP3A4*18B/*18B, as follows: for C2, 19.3% (P = 0.008) during days 8-15, 35.2% (P = 0.008) during days 16–30, and for C0, 39.7% (P = 0.012) during days 16–30. The dose-adjusted C0 was higher in patients with MDR1 1236CC compared with those with 1236TT in the first month postoperation. The dose-adjusted C0 in patients with the CYP3A5*3/*3 genotype was 25.5% and 30.7% higher than those with the wild-type genotype during days 8–15 (P = 0.011) and days 16–30 (P = 0.015), respectively. Haplotype analysis revealed that the dose-adjusted C0 was higher in the first month following surgery in carriers of haplotype MDR1 CAC than in noncarriers. Polymorphisms of MDR1 and CYP3A5*3 did not affect dose-adjusted C2.

Conclusion

The data suggests that the CYP3A4*18B genotype affects CsA pharmacokinetics during the first month following surgery in Chinese renal transplant recipients. Patients with CYP3A4*18B alleles may require higher doses of CsA to reach the target levels. Large prospective studies may be needed to further explore the impact of MDR1 and CYP3A5*3 polymorphisms on CsA pharmacokinetics in renal transplant recipients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hesselink DA, Smak Gregoor PJ, Weimar W (2004) The use of cyclosporine in renal transplantation. Transplant Proc 36(2 Suppl):99S–106S

    Article  PubMed  CAS  Google Scholar 

  2. Hebert MF (1997) Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev 27(2–3):201–214

    Article  PubMed  CAS  Google Scholar 

  3. Kronbach T, Fischer V, Meyer UA (1988) Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther 43(6):630–635

    PubMed  CAS  Google Scholar 

  4. Zhang Y, Benet LZ (2001) The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 40(3):159–168

    Article  PubMed  CAS  Google Scholar 

  5. Rendic S, Di Carlo FJ (1997) Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 29(1–2):413–580

    Article  PubMed  CAS  Google Scholar 

  6. Cholerton S, Daly AK, Idle JR (1992) The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol Sci 13(12):434–439

    Article  PubMed  CAS  Google Scholar 

  7. 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

    Article  PubMed  CAS  Google Scholar 

  8. Fukushima-Uesaka H, Saito Y, Watanabe H, Shiseki K, Saeki M, Nakamura T, Kurose K, Sai K, Komamura K, Ueno K, Kamakura S, Kitakaze M, Hanai S, Nakajima T, Matsumoto K, Saito H, Goto Y, Kimura H, Katoh M, Sugai K, Minami N, Shirao K, Tamura T, Yamamoto N, Minami H, Ohtsu A, Yoshida T, Saijo N, Kitamura Y, Kamatani N, Ozawa S, Sawada J (2004) Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population. Hum Mutat 23(1):100

    Article  PubMed  Google Scholar 

  9. Hu YF, Tu JH, Tan ZR, Liu ZQ, Zhou G, He J, Wang D, Zhou HH (2007) Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects. Xenobiotica 37(3):315–327

    Article  PubMed  CAS  Google Scholar 

  10. Hall SD, Thummel KE, Watkins PB, Lown KS, Benet LZ, Paine MF, Mayo RR, Turgeon DK, Bailey DG, Fontana RJ, Wrighton SA (1999) Molecular and physical mechanisms of first-pass extraction. Drug Metab Dispos 27(2):161–166

    PubMed  CAS  Google Scholar 

  11. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97(7):3473–3478

    Article  PubMed  CAS  Google Scholar 

  12. Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, Schaeffeler E, Eichelbaum M, Brinkmann U, Roots I (2001) Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 69(3):169–174

    Article  PubMed  CAS  Google Scholar 

  13. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70(2):189–199

    Article  PubMed  CAS  Google Scholar 

  14. Yates CR, Zhang W, Song P, Li S, Gaber AO, Kotb M, Honaker MR, Alloway RR, Meibohm B (2003) The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J Clin Pharmacol 43(6):555–564

    PubMed  CAS  Google Scholar 

  15. von Ahsen N, Richter M, Grupp C, Ringe B, Oellerich M, Armstrong VW (2001) No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V allele) on dose-adjusted cyclosporin A trough concentrations or rejection incidence in stable renal transplant recipients. Clin Chem 47(6):1048–1052

    Google Scholar 

  16. Mai I, Stormer E, Goldammer M, Johne A, Kruger H, Budde K, Roots I (2003) MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients. J Clin Pharmacol 43(10):1101–1107

    Article  PubMed  CAS  Google Scholar 

  17. Chowbay B, Cumaraswamy S, Cheung YB, Zhou Q, Lee EJ (2003) Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics 13(2):89–95

    Article  PubMed  CAS  Google Scholar 

  18. Hesselink 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(3):245–254

    Article  PubMed  CAS  Google Scholar 

  19. Hu YF, Qiu W, Liu ZQ, Zhu LJ, Liu ZQ, Tu JH, Wang D, Li Z, He J, Zhong GP, Zhou G, Zhou HH (2006) Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation. Clin Exp Pharmacol Physiol 33(11):1093–1098

    Article  PubMed  CAS  Google Scholar 

  20. Anglicheau D, Thervet E, Etienne I, Hurault De Ligny B, Le Meur Y, Touchard G, Buchler M, Laurent-Puig P, Tregouet D, Beaune P, Daly A, Legendre C, Marquet P (2004) CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther 75(5):422–433

    Article  PubMed  CAS  Google Scholar 

  21. Wang W, Zhang XD, Guan DL, Lu YP, Ma LL, Hu XP, Zhang P, Wang Y, Chen X (2005) Relationship between MDR1 polymorphism and blood concentration of cyclosporine A. Chin Med J (Engl) 118(24):2097–2100

    CAS  Google Scholar 

  22. Foote CJ, Greer W, Kiberd BA, Fraser A, Lawen J, Nashan B, Belitsky P (2006) MDR1 C3435T polymorphisms correlate with cyclosporine levels in de novo renal recipients. Transplant Proc 38(9):2847–2849

    Article  PubMed  CAS  Google Scholar 

  23. 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 patients. Pharmacogenetics 14(3):147–154

    Article  PubMed  CAS  Google Scholar 

  24. Jiao Z, Liang HQ, Ding JJ, Li ZD, Shi XJ, Zhong MK (2004) Effect of MDR1 polymorphic expression on oral disposition of cyclosporine A. Yao Xue Xue Bao 39(12):971–974

    PubMed  CAS  Google Scholar 

  25. Johne A, Kopke K, Gerloff T, Mai I, Rietbrock S, Meisel C, Hoffmeyer S, Kerb R, Fromm MF, Brinkmann U, Eichelbaum M, Brockmoller J, Cascorbi I, Roots I (2002) Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 72(5):584–594

    Article  PubMed  CAS  Google Scholar 

  26. Anglicheau D, Verstuyft C, Laurent-Puig P, Becquemont L, Schlageter MH, Cassinat B, Beaune P, Legendre C, Thervet E (2003) Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol 14(7):1889–1896

    Article  PubMed  CAS  Google Scholar 

  27. 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

    Google Scholar 

  28. Tang K, Ngoi SM, Gwee PC, Chua JM, Lee EJ, Chong SS, Lee CG (2002) Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics 12(6):437–450

    Article  PubMed  CAS  Google Scholar 

  29. Chu XM, Hao HP, Wang GJ, Guo LQ, Min PQ (2006) Influence of CYP3A5 genetic polymorphism on cyclosporine A metabolism and elimination in Chinese renal transplant recipients. Acta Pharmacol Sin 27(11):1504–1508

    Article  PubMed  CAS  Google Scholar 

  30. Zhao Y, Song M, Guan D, Bi S, Meng J, Li Q, Wang W (2005) Genetic polymorphisms of CYP3A5 genes and concentration of the cyclosporine and tacrolimus. Transplant Proc 37(1):178–181

    Article  PubMed  CAS  Google Scholar 

  31. Levy G, Thervet E, Lake J, Uchida K (2002) Patient management by Neoral C(2) monitoring: an international consensus statement. Transplantation 73(9 Suppl):S12–18

    Article  PubMed  Google Scholar 

  32. Li D, Zhang GL, Lou YQ, Li Q, Wang X, Bu XY (2007) Genetic polymorphisms in MDR1 and CYP3A5 and MDR1 haplotype in mainland Chinese Han, Uygur and Kazakh ethnic groups. J Clin Pharm Ther 32(1):89–95

    Article  PubMed  Google Scholar 

  33. Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE, DeYoung J, Taylor T, Carlson EJ, Herskowitz I, Giacomini KM, Clark AG (2003) Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 13(8):481–494

    Article  PubMed  CAS  Google Scholar 

  34. Aarnoudse AL, van Schaik RH, Dieleman J, Molokhia M, van Riemsdijk MM, Ligthelm RJ, Overbosch D, van der Heiden IP, Stricker BH (2006) MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine. Clin Pharmacol Ther 80(4):367–374

    Article  PubMed  CAS  Google Scholar 

  35. Tanabe M, Ieiri I, Nagata N, Inoue K, Ito S, Kanamori Y, Takahashi M, Kurata Y, Kigawa J, Higuchi S, Terakawa N, Otsubo K (2001) Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 297(3):1137–1143

    PubMed  CAS  Google Scholar 

  36. Fredericks S, Jorga A, MacPhee IA, Reboux S, Shiferaw E, Moreton M, Carter ND, Holt DW, Johnston A (2007) Multi-drug resistance gene-1 (MDR-1) haplotypes and the CYP3A5*1 genotype have no influence on ciclosporin dose requirements as assessed by C0 or C2 measurements. Clin Transplant 21(2):252–257

    Article  PubMed  Google Scholar 

  37. Sakaeda T, Nakamura T, Okumura K (2004) Pharmacogenetics of drug transporters and its impact on the pharmacotherapy. Curr Top Med Chem 4(13):1385–1398

    Article  PubMed  CAS  Google Scholar 

  38. Knight SR, Morris PJ (2007) The clinical benefits of cyclosporine C2-level monitoring: a systematic review. Transplantation 83(12):1525–1535

    Article  PubMed  CAS  Google Scholar 

  39. Pape L, Lehnhardt A, Latta K, Ehrich JH, Offner G (2003) Cyclosporin A monitoring by 2-h levels: preliminary target levels in stable pediatric kidney transplant recipients. Clin Transplant 17(6):546–548

    Article  PubMed  CAS  Google Scholar 

  40. Teisseyre J, Markiewicz M, Drewniak T, Kalicinski P, Kaminski A, Ismail H, Szymczak M, Teisseyre M, Nachulewicz P (2003) Switching cyclosporine blood concentration monitoring from C0 to C2 in children late after liver transplantation. Transplant Proc 35(6):2287–2288

    Article  PubMed  CAS  Google Scholar 

  41. Marcen R, Pascual J, Tato A, Villafruela JJ, Teruel JL, Rivera ME, Tenorio M, Fernandez M, Burgos FJ, Ortuno J (2003) Comparison of C0 and C2 cyclosporine monitoring in long-term renal transplant recipients. Transplant Proc 35(5):1780–1782

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Mingxin Li, Dr. Jianyong Zhong, and the staff of the renal transplantation center for their assistance; Mr. Yinqing Ying for his contribution in data input; Ms. Kitty Law for her critical reading of the manuscript; and Mr. Jianping Chen for statistical analysis support. This work was partly supported by the 100 Elites Program Grant of Shanghai Health Bureau (No 98BR009).

Author information

Authors and Affiliations

  1. Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M. Rd, Shanghai, 200040, People’s Republic of China

    Xiao-yan Qiu, Zheng Jiao, Long-jin Zhong, Hui-qi Liang, Chun-lai Ma, Liang Zhang & Ming-kang Zhong

  2. School of Pharmacy, Fudan University, Shanghai, People’s Republic of China

    Zheng Jiao

  3. Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China

    Ming Zhang

Authors
  1. Xiao-yan Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zheng Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Long-jin Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hui-qi Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chun-lai Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ming-kang Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zheng Jiao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qiu, Xy., Jiao, Z., Zhang, M. et al. Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients. Eur J Clin Pharmacol 64, 1069–1084 (2008). https://doi.org/10.1007/s00228-008-0520-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-008-0520-8

Keywords

Search

Navigation