Skip to main content
SpringerLink
Log in

Effect of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Calcineurin Inhibitors: Part II

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes — in particular, CYP3A4 and CYP3A5 — and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 —392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1 128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacodynamics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed and all relevant primary research articles were critiqued and summarized. There is no evidence that the CYP3A4 —392A>G SNP has an effect on the pharmacodynamics of either ciclosporin or tacrolimus; however, studies have been limited.

For patients prescribed ciclosporin, the CYP3A5 6986A>G SNP may influence long-term survival, possibly because of a different metabolite pattern over time. This SNP has no clear association with acute rejection during ciclosporin therapy. Despite a strong association between the CYP3A5 6986A>G SNP and tacrolimus pharmacokinetics, there is no consistent evidence of organ rejection as a result of genotype-related under-immunosuppression. This is likely to be explained by the practice of performing tacrolimus dose adjustments in the early phase after transplantation. The effect of the CYP3A5 6986A>G SNP on ciclosporin-and tacrolimus-related nephrotoxicity and development of hypertension is unclear. Similarly, the ABCB1 SNPs exert no clear influence on either ciclosporin or tacrolimus pharmacodynamics, with studies showing conflicting results in regard to the main parameters of acute rejection and nephrotoxicity. In kidney transplant patients, consideration of the donor kidney genotype rather than the recipient genotype may be more important when assessing development of nephrotoxicity. Studies with low patient numbers may account for many inconsistent results to date. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful, particularly ones that consider both donor and recipient genotype. The effects of polymorphisms associated with the pregnane X receptor, organic anion transporting polypeptides, calcineurin inhibitor target sites and immune response pathways need to be further investigated. A large standardized clinical trial is now required to evaluate the relationship between the pharmacokinetics and pharmacodynamics of CYP3A5-mediated tacrolimus metabolism, particularly in regard to the outcomes of acute rejection and nephrotoxicity. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.

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

Table I
Table II

Similar content being viewed by others

References

  1. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin Pharmacokinet 2010; 49(3): 141–75

    Article  PubMed  CAS  Google Scholar 

  2. Thervet E, Anglicheau D, Legendre C, et al. Role of pharmacogenetics of immunosuppressive drugs in organ transplantation. Ther Drug Monit 2008; 30(2): 143–50

    Article  PubMed  CAS  Google Scholar 

  3. de Jonge H, Kuypers DR. Pharmacogenetics in solid organ transplantation: current status and future directions. Transplant Rev 2008; 22(1): 6–20

    Article  Google Scholar 

  4. Cattaneo D, Baldelli S, Perico N. Pharmacogenetics of immunosuppressants: progress, pitfalls and promises. Am J Transplant 2008; 8(7): 1374–83

    Article  PubMed  CAS  Google Scholar 

  5. Ekbal NJ, Holt DW, Macphee IA. Pharmacogenetics of immunosuppressive drugs: prospect of individual therapy for transplant patients. Pharmacogenomics 2008; 9(5): 585–96

    Article  PubMed  CAS  Google Scholar 

  6. Anglicheau D, Legendre C, Beaune P, et al. Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. Pharmacogenomics 2007; 8(7): 835–49

    Article  PubMed  CAS  Google Scholar 

  7. Thervet E, Pfeffer P, Scolari MP, et al. Clinical outcomes during the first three months posttransplant in renal allograft recipients managed by C2 monitoring of cyclosporine microemulsion. Transplantation 2003; 76(6): 903–8

    Article  PubMed  CAS  Google Scholar 

  8. Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation 1996; 62(7): 920–6

    Article  PubMed  CAS  Google Scholar 

  9. Staatz C, Taylor P, Tett S. Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation. Nephrol Dial Transplant 2001; 16(9): 1905–9

    Article  PubMed  CAS  Google Scholar 

  10. Kock K, Grube M, Jedlitschky G, et al. Expression of adenosine triphosphatebinding cassette (ABC) drug transporters in peripheral blood cells: relevance for physiology and pharmacotherapy. Clin Pharmacokinet 2007; 46(6): 449–70

    Article  PubMed  Google Scholar 

  11. Farrell RJ, Menconi MJ, Keates AC, et al. P-glycoprotein-170 inhibition significantly reduces cortisol and ciclosporin efflux from human intestinal epithelial cells and T lymphocytes. Aliment Pharmacol Ther 2002; 16(5): 1021–31

    Article  PubMed  CAS  Google Scholar 

  12. Singh D, Alexander J, Owen A, et al. Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression. Transplantation 2004; 77(4): 557–61

    Article  PubMed  CAS  Google Scholar 

  13. Crettol S, Venetz JP, Fontana M, et al. Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients. Pharmacogenet Genomics 2008; 18(4): 307–15

    Article  PubMed  CAS  Google Scholar 

  14. Christians U, Kohlhaw K, Budniak J, et al. Ciclosporin metabolite pattern in blood and urine of liver graft recipients: I. Association of ciclosporin metabolites with nephrotoxicity. Eur J Clin Pharmacol 1991; 41(4): 285–90

    Article  PubMed  CAS  Google Scholar 

  15. Kempkes-Koch M, Fobker M, Erren M, et al. Cyclosporine A metabolite AM19 as a potential biomarker in urine for CSA nephropathy. Transplant Proc 2001; 33(3): 2167–9

    Article  PubMed  CAS  Google Scholar 

  16. Lemoine A, Azoulay D, Gries JM, et al. Relationship between graft cytochrome P-450 3A content and early morbidity after liver transplantation. Transplantation 1993; 56(6): 1410–4

    Article  PubMed  CAS  Google Scholar 

  17. Schmidt LE, Rasmussen A, Kirkegaard P, et al. Relationship between postoperative erythromycin breath test and early morbidity in liver transplant recipients. Transplantation 2003; 76(2): 358–63

    Article  PubMed  Google Scholar 

  18. Joy MS, Hogan SL, Thompson BD, et al. Cytochrome P450 3A5 expression in the kidneys of patients with calcineurin inhibitor nephrotoxicity. Nephrol Dial Transplant 2007; 22(7): 1963–8

    Article  PubMed  CAS  Google Scholar 

  19. Ernest S, Bello-Reuss E. P-glycoprotein functions and substrates: possible roles of MDR1 gene in the kidney. Kidney Int Suppl 1998; 65: S11–7

    PubMed  CAS  Google Scholar 

  20. Joy MS, Nickeleit V, Hogan SL, et al. Calcineurin inhibitor-induced nephrotoxicity and renal expression of P-glycoprotein. Pharmacotherapy 2005; 25(6): 779–89

    Article  PubMed  CAS  Google Scholar 

  21. Tsuruoka S, Sugimoto KI, Fujimura A, et al. P-glycoprotein-mediated drug secretion in mouse proximal tubule perfused in vitro. J Am Soc Nephrol 2001; 12(1): 177–81

    PubMed  CAS  Google Scholar 

  22. Kochi S, Takanaga H, Matsuo H, et al. Effect of cyclosporin A or tacrolimus on the function of blood-brain barrier cells. Eur J Pharmacol 1999; 372(3): 287–95

    Article  PubMed  CAS  Google Scholar 

  23. Yokogawa K, Takahashi M, Tamai I, et al. P-glycoprotein-dependent disposition kinetics of tacrolimus: studies in mdr1a knockout mice. Pharm Res 1999; 16(8): 1213–8

    Article  PubMed  CAS  Google Scholar 

  24. Ho H, Pinto A, Hall SD, et al. Association between the CYP3A5 genotype and blood pressure. Hypertension 2005; 45(2): 294–8

    Article  PubMed  CAS  Google Scholar 

  25. Fromm MF, Schmidt BM, Pahl A, et al. CYP3A5 genotype is associated with elevated blood pressure. Pharmacogenet Genomics 2005; 15(10): 737–41

    Article  PubMed  CAS  Google Scholar 

  26. Bochud M, Eap CB, Elston RC, et al. Association of CYP3A5 genotypes with blood pressure and renal function in African families. J Hypertens 2006; 24(5): 923–9

    Article  PubMed  CAS  Google Scholar 

  27. Kivisto KT, Niemi M, Schaeffeler E, et al. CYP3A5 genotype is associated with diagnosis of hypertension in elderly patients: data from the DEBATE study. Am J Pharmacogenomics 2005; 5(3): 191–5

    Article  PubMed  Google Scholar 

  28. Kamdem LK, Hamilton L, Cheng C, et al. Genetic predictors of glucocorticoid-induced hypertension in children with acute lymphoblastic leukemia. Pharmacogenet Genomics 2008; 18(6): 507–14

    Article  PubMed  CAS  Google Scholar 

  29. Givens RC, Lin YS, Dowling AL, et al. CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. J Appl Physiol 2003; 95(3): 1297–300

    PubMed  CAS  Google Scholar 

  30. Uhr M, Holsboer F, Muller MB. Penetration of endogenous steroid hormones corticosterone, cortisol, aldosterone and progesterone into the brain is enhanced in mice deficient for both mdr1a and mdr1b P-glycoproteins. J Neuroendocrinol 2002; 14(9): 753–9

    Article  PubMed  CAS  Google Scholar 

  31. Ueda K, Okamura N, Hirai M, et al. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J Biol Chem 1992; 267(34): 24248–52

    PubMed  CAS  Google Scholar 

  32. Eap CB, Bochud M, Elston RC, et al. CYP3A5 and ABCB1 genes influence blood pressure and response to treatment, and their effect is modified by salt. Hypertension 2007; 49(5): 1007–14

    Article  PubMed  CAS  Google Scholar 

  33. von Ahsen N, Richter M, Grupp C, et al. 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 2001; 47(6): 1048–52

    Google Scholar 

  34. Grinyo J, Vanrenterghem Y, Nashan B, et al. Association of four DNA polymorphisms with acute rejection after kidney transplantation. Transpl Int 2008; 21(9): 879–91

    Article  PubMed  CAS  Google Scholar 

  35. Eng HS, Mohamed Z, Calne R, et al. The influence of CYP3A gene polymorphisms on cyclosporine dose requirement in renal allograft recipients. Kidney Int 2006; 69(10): 1858–64

    Article  PubMed  CAS  Google Scholar 

  36. Klauke B, Wirth A, Zittermann A, et al. No association between single nucleotide polymorphisms and the development of nephrotoxicity after orthotopic heart transplantation. J Heart Lung Transplant 2008; 27(7): 741–5

    Article  PubMed  Google Scholar 

  37. Hauser IA, Schaeffeler E, Gauer S, et al. ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation. J Am Soc Nephrol 2005; 16(5): 1501–11

    Article  PubMed  CAS  Google Scholar 

  38. Kreutz R, Bolbrinker J, van der Sman-de Beer F, et al. CYP3A5 genotype is associated with longer patient survival after kidney transplantation and long-term treatment with cyclosporine. Pharmacogenomics J 2008; 8(6): 416–22

    Article  PubMed  CAS  Google Scholar 

  39. Hebert MF, Dowling AL, Gierwatowski C, et al. Association between ABCB1 (multidrug resistance transporter) genotype and post-liver transplantation renal dysfunction in patients receiving calcineurin inhibitors. Pharmacogenetics 2003; 13(11): 661–74

    Article  PubMed  CAS  Google Scholar 

  40. Bandur S, Petrasek J, Hribova P, et al. Haplotypic structure of ABCB1/MDR1 gene modifies the risk of the acute allograft rejection in renal transplant recipients. Transplantation 2008; 86(9): 1206–13

    Article  PubMed  CAS  Google Scholar 

  41. Hesselink DA, van Schaik RH, van Agteren M, et al. CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients. Pharmacogenet Genomics 2008; 18(4): 339–48

    Article  PubMed  CAS  Google Scholar 

  42. Roy JN, Barama A, Poirier C, et al. Cyp3A4, Cyp3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients. Pharmacogenet Genomics 2006; 16(9): 659–65

    Article  PubMed  CAS  Google Scholar 

  43. Zheng HX, Zeevi A, McCurry K, et al. The impact of pharmacogenomic factors on acute persistent rejection in adult lung transplant patients. Transpl Immunol 2005; 14(1): 37–42

    Article  PubMed  Google Scholar 

  44. Ferraresso M, Tirelli A, Ghio L, et al. Influence of the CYP3A5 genotype on tacrolimus pharmacokinetics and pharmacodynamics in young kidney transplant recipients. Pediatr Transplant 2007; 11(3): 296–300

    Article  PubMed  CAS  Google Scholar 

  45. Renders L, Frisman M, Ufer M, et al. CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients. Clin Pharmacol Ther 2007; 81(2): 228–34

    Article  PubMed  CAS  Google Scholar 

  46. Fukudo M, Yano I, Yoshimura A, et al. Impact of MDR1 and CYP3A5 on the oral clearance of tacrolimus and tacrolimus-related renal dysfunction in adult living-donor liver transplant patients. Pharmacogenet Genomics 2008; 18(5): 413–23

    Article  PubMed  CAS  Google Scholar 

  47. Elens L, Capron A, Kerckhove VV, et al. 1199G>A and 2677G>T/A polymorphisms of ABCB1 independently affect tacrolimus concentration in hepatic tissue after liver transplantation. Pharmacogenet Genomics 2007; 17(10): 873–83

    Article  PubMed  CAS  Google Scholar 

  48. Numakura K, Satoh S, Tsuchiya N, et al. Clinical and genetic risk factors for posttransplant diabetes mellitus in adult renal transplant recipients treated with tacrolimus. Transplantation 2005; 80(10): 1419–24

    Article  PubMed  CAS  Google Scholar 

  49. Kuypers DR, de Jonge H, Naesens M, et al. CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin Pharmacol Ther 2007; 82(6): 711–25

    Article  PubMed  CAS  Google Scholar 

  50. Yamauchi A, Ieiri I, Kataoka Y, et al. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002; 74(4): 571–2

    Article  PubMed  CAS  Google Scholar 

  51. Fredericks S, Moreton M, Reboux S, et al. Multidrug resistance gene-1 (MDR-1) haplotypes have a minor influence on tacrolimus dose requirements. Transplantation 2006; 82(5): 705–8

    Article  PubMed  CAS  Google Scholar 

  52. MacPhee IA, Fredericks S, Tai T, et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant 2004; 4(6): 914–9

    Article  PubMed  CAS  Google Scholar 

  53. Smith HE, Jones III JP, Kalhorn TF, et al. Role of cytochrome P450 2C8 and 2J2 genotypes in calcineurin inhibitor-induced chronic kidney disease. Pharmacogenet Genomics 2008; 18(11): 943–53

    Article  PubMed  CAS  Google Scholar 

  54. Rosenfeld JM, Vargas Jr R, Xie W, et al. Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor. Mol Endocrinol 2003; 17(7): 1268–82

    Article  PubMed  CAS  Google Scholar 

  55. Zhang J, Kuehl P, Green ED, et al. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics 2001; 11(7): 555–72

    Article  PubMed  CAS  Google Scholar 

  56. Lamba J, Lamba V, Schuetz E. Genetic variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Curr Drug Metab 2005; 6(4): 369–83

    Article  PubMed  CAS  Google Scholar 

  57. Hagenbuch B, Meier PJ. The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 2003; 1609(1): 1–18

    Article  PubMed  CAS  Google Scholar 

  58. Niemi M, Schaeffeler E, Lang T, et al. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 2004; 14(7): 429–40

    Article  PubMed  CAS  Google Scholar 

  59. Gerber DJ, Hall D, Miyakawa T, et al. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc Natl Acad Sci USA 2003; 100(15): 8993–8

    Article  PubMed  CAS  Google Scholar 

  60. Tang W, Arnett DK, Devereux RB, et al. Identification of a novel 5-base pair deletion in calcineurin B (PPP3R1) promoter region and its association with left ventricular hypertrophy. Am Heart J 2005; 150(4): 845–51

    Article  PubMed  CAS  Google Scholar 

  61. Goldfarb-Rumyantzev AS, Naiman N. Genetic prediction of renal transplant outcome. Curr Opin Nephrol Hypertens 2008; 17(6): 573–9

    Article  PubMed  CAS  Google Scholar 

  62. Hoffmann TW, Halimi JM, Buchler M, et al. Association between a polymorphism in the IL-12p40 gene and cytomegalovirus reactivation after kidney transplantation. Transplantation 2008; 85(10): 1406–11

    Article  PubMed  CAS  Google Scholar 

  63. Leite JL, Manfrinatto JA, Mazzali M, et al. Polymorphisms at exon 4 of p53 and the susceptibility to herpesvirus types 6 and 1 infection in renal transplant recipients. Transpl Int 2006; 19(9): 732–7

    Article  PubMed  CAS  Google Scholar 

  64. Bamoulid J, Courivaud C, Deschamps M, et al. IL-6 promoter polymorphism - 174 is associated with new-onset diabetes after transplantation. J Am Soc Nephrol 2006; 17(8): 2333–40

    Article  PubMed  CAS  Google Scholar 

  65. Kang ES, Kim MS, Kim YS, et al. A polymorphism in the zinc transporter gene SLC30A8 confers resistance against posttransplantation diabetes mellitus in renal allograft recipients. Diabetes 2008; 57(4): 1043–7

    Article  PubMed  CAS  Google Scholar 

  66. Numakura K, Satoh S, Tsuchiya N, et al. Incidence and risk factors of clinical characteristics, tacrolimus pharmacokinetics, and related genomic polymorphisms for posttransplant diabetes mellitus in the early stage of renal transplant recipients. Transplant Proc 2005; 37(4): 1865–7

    Article  PubMed  CAS  Google Scholar 

  67. Laing ME, Dicker P, Moloney FJ, et al. Association of methylenetetrahy-drofolate reductase polymorphism and the risk of squamous cell carcinoma in renal transplant patients. Transplantation 2007; 84(1): 113–6

    Article  PubMed  CAS  Google Scholar 

  68. Gallon L, Akalin E, Lynch P, et al. ACE gene D/D genotype as a risk factor for chronic nephrotoxicity from calcineurin inhibitors in liver transplant recipients. Transplantation 2006; 81(3): 463–8

    Article  PubMed  CAS  Google Scholar 

  69. Azarpira N, Bagheri M, Raisjalali GA, et al. Angiotensinogen, angiotensine converting enzyme and plasminogen activator inhibitor-1 gene polymorphism in chronic allograft dysfunction. Mol Biol Rep 2008; 36(5): 909–15

    Article  PubMed  Google Scholar 

  70. Ayed K, Ayed-Jendoubi S, Ben Abdallah T, et al. Polymorphism of the renin-angiotensin-aldosterone system in patients with chronic allograft dysfunction. Transpl Immunol 2006; 15(4): 303–9

    Article  PubMed  CAS  Google Scholar 

  71. Satoh S, Saito M, Inoue K, et al. Association of cytokine polymorphisms with subclinical progressive chronic allograft nephropathy in Japanese renal transplant recipients: preliminary study. Int J Urol 2007; 14(11): 990–4

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

C. Staatz is currently supported by a Lions Medical Research Fellowship. This research is supported by a National Health and Medical Research Council Project Grant (no. 511109). C. Staatz, L. Goodman and S. Tett do not have any pharmaceutical industry affiliation and have no pecuniary interests (personal or professional), grants or other potential conflicts of interest with any pharmaceutical company.

Author information

Authors and Affiliations

  1. School of Pharmacy, University of Queensland, Brisbane, Queensland, 4072, Australia

    Christine E. Staatz, Lucy K. Goodman & Susan E. Tett

Authors
  1. Christine E. Staatz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucy K. Goodman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susan E. Tett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christine E. Staatz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Staatz, C.E., Goodman, L.K. & Tett, S.E. Effect of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Calcineurin Inhibitors: Part II. Clin Pharmacokinet 49, 207–221 (2010). https://doi.org/10.2165/11317550-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11317550-000000000-00000

Keywords

Search

Navigation