Clinical Pharmacokinetics

, Volume 53, Issue 2, pp 123–139

The Role of Pharmacogenetics in the Disposition of and Response to Tacrolimus in Solid Organ Transplantation

  • Dennis A. Hesselink
  • Rachida Bouamar
  • Laure Elens
  • Ron H. N. van Schaik
  • Teun van Gelder
Review Article


The calcineurin inhibitor tacrolimus is the backbone of immunosuppressive drug therapy after solid organ transplantation. Tacrolimus is effective in preventing acute rejection but has considerable toxicity and displays marked inter-individual variability in its pharmacokinetics and pharmacodynamics. The genetic basis of these phenomena is reviewed here. With regard to its pharmacokinetic variability, a single nucleotide polymorphism (SNP) in cytochrome P450 (CYP) 3A5 (6986A>G) has been consistently associated with tacrolimus dose requirement. Patients expressing CYP3A5 (those carrying the A nucleotide, defined as the *1 allele) have a dose requirement that is around 50 % higher than non-expressers (those homozygous for the G nucleotide, defined as the *3 allele). A randomised controlled study in kidney transplant recipients has demonstrated that a CYP3A5 genotype-based approach to tacrolimus dosing leads to more patients reaching the target concentration early after transplantation. However, no improvement of clinical outcomes (rejection incidence, toxicity) was observed, which may have been the result of the design of this particular study. In addition to CYP3A5 genotype, other genetic variants may also contribute to the variability in tacrolimus pharmacokinetics. Among these, the CYP3A4*22 and POR*28 SNPs are the most promising. Individuals carrying the CYP3A4*22 T-variant allele have a lower tacrolimus dose requirement than individuals with the CYP3A4*22 CC genotype and this effect appears to be independent of CYP3A5 genotype status. Individuals carrying the POR*28 T-variant allele have a higher tacrolimus dose requirement than POR*28 CC homozygotes but this association was only found in CYP3A5-expressing individuals. Other, less well-defined SNPs have been inconsistently associated with tacrolimus dose requirement. It is envisaged that in the future, algorithms incorporating clinical, demographic and genetic variables will be developed that will aid clinicians with the determination of the tacrolimus starting dose for an individual transplant recipient. Such an approach may limit early tacrolimus under-exposure and toxicity. With regard to tacrolimus pharmacodynamics, no strong genotype–phenotype relationships have been identified. Certain SNPs associate with rejection risk but these observations await replication. Likewise, the genetic basis of tacrolimus-induced toxicity remains unclarified. SNPs in the genes encoding for the drug transporter ABCB1 and the CYP3A enzymes may relate to chronic nephrotoxicity but findings have been inconsistent. No genetic markers reliably predict new-onset diabetes mellitus after transplantation, hypertension or neurotoxicity. The CYP3A5*1 SNP is currently the most promising biomarker for tailoring tacrolimus treatment. However, before CYP3A5 genotyping is incorporated into the routine clinical care of transplant recipients, prospective clinical trials are needed to determine whether such a strategy improves patient outcomes. The role of pharmacogenetics in tacrolimus pharmacodynamics should be explored further by the study of intra-lymphocyte and tissue tacrolimus concentrations.


  1. 1.
    Kaufman DB, Shapiro R, Lucey MR, et al. Immunosuppression: practice and trends. Am J Transplant. 2004;4(Suppl. 9):38–53.PubMedGoogle Scholar
  2. 2.
    Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2011 annual data report: kidney. Am J Transplant. 2013;13(Suppl. 1):11–46.PubMedGoogle Scholar
  3. 3.
    Wallemacq P, Armstrong VW, Brunet M, et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther Drug Monit. 2009;31:139–52.PubMedGoogle Scholar
  4. 4.
    Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995;29:404–30.PubMedGoogle Scholar
  5. 5.
    Christians U, Jacobsen W, Benet LZ, et al. Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet. 2002;41:813–51.PubMedGoogle Scholar
  6. 6.
    Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43:623–53.PubMedGoogle Scholar
  7. 7.
    van Maarseveen EM, Rogers CC, Trofe-Clark J, et al. Drug-drug interactions between antiretroviral and immunosuppressive agents in HIV-infected patients after solid organ transplantation: a review. AIDS Patient Care STDS. 2012;26:568–81.PubMedGoogle Scholar
  8. 8.
    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;49:141–75.PubMedGoogle Scholar
  9. 9.
    Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part II. Clin Pharmacokinet. 2010;49:207–21.PubMedGoogle Scholar
  10. 10.
    MacPhee IA. Pharmacogenetic biomarkers: cytochrome P450 3A5. Clin Chim Acta. 2012;413:1312–7.PubMedGoogle Scholar
  11. 11.
    Elens L, Hesselink DA, van Schaik RHN, et al. Pharmacogenetics in kidney transplantation: recent updates and potential clinical applications. Mol Diagn Ther. 2012;16:331–45.PubMedGoogle Scholar
  12. 12.
    Zhang Y, Benet LZ. The gut as a barrier to drug absorption. Combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet. 2001;40:159–68.PubMedGoogle Scholar
  13. 13.
    Klimecki WT, Futscher BW, Grogan TM, et al. P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood. 1994;83:2451–8.PubMedGoogle Scholar
  14. 14.
    Kamdem LK, Streit F, Zanger UM, et al. Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem. 2005;51:1374–81.PubMedGoogle Scholar
  15. 15.
    Dai Y, Iwanaga K, Lin YS, et al. In vitro metabolism of cyclosporine A by human kidney CYP3A5. Biochem Pharmacol. 2004;68:1889–902.PubMedGoogle Scholar
  16. 16.
    Dai Y, Hebert MF, Isoherranen N, et al. Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab Dispos. 2006;34:836–47.PubMedGoogle Scholar
  17. 17.
    Möller A, Iwasaki K, Kawamura A, et al. The disposition of 14C-labeled tacrolimus after intravenous and oral administration in healthy human subjects. Drug Metab Dispos. 1999;27:633–6.PubMedGoogle Scholar
  18. 18.
    Thiebaut F, Tsuruo T, Hamada H, et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA. 1987;84:7735–8.PubMedGoogle Scholar
  19. 19.
    Murray GI, McFadyen MCE, Mitchell RT, et al. Cytochrome P450 3A in human renal cell cancer. Br J Cancer. 1999;79:1836–42.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Koch I, Weil R, Wolbold R, et al. Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab Dispos. 2002;30:1108–13.PubMedGoogle Scholar
  21. 21.
    Benkali K, Rostaing L, Premaud A, et al. Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in renal transplant recipients on a new once-daily formulation. Clin Pharmacokinet. 2010;49:683–92.PubMedGoogle Scholar
  22. 22.
    Hougardy J-M, de Jonge H, Kuypers D, et al. The once-daily formulation of tacrolimus: a step forward in kidney transplantation? Transplantation. 2012;93:241–3.PubMedGoogle Scholar
  23. 23.
    Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27:383–91.PubMedGoogle Scholar
  24. 24.
    CYP3A5 allele nomenclature. Accessed 28 Oct 2013.
  25. 25.
    Hustert E, Haberl M, Burk O, et al. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics. 2001;11:773–9.PubMedGoogle Scholar
  26. 26.
    van Schaik RHN, van der Heiden IP, van den Anker JN, et al. CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem. 2002;48:1668–71.PubMedGoogle Scholar
  27. 27.
    Hesselink DA, van Schaik RHN, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and the pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther. 2003;74:245–54.PubMedGoogle Scholar
  28. 28.
    Thervet E, Anglicheau D, King B, et al. Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation. 2003;76:1233–5.PubMedGoogle Scholar
  29. 29.
    Haufroid V, Mourad M, van Kerckhove V, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics. 2004;14:147–54.PubMedGoogle Scholar
  30. 30.
    Tsuchiya N, Satoh S, Tada H, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation. 2004;78:1182–7.PubMedGoogle Scholar
  31. 31.
    MacPhee IAM, Fredericks S, Mohamed M, et al. Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and south Asians. Transplantation. 2005;79:499–502.PubMedGoogle Scholar
  32. 32.
    Zhang X, Liu ZH, Zheng JM, et al. Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin Transplant. 2005;19:638–43.PubMedGoogle Scholar
  33. 33.
    Zhao Y, Song M, Guan D, et al. Genetic polymorphisms of CYP3A5 genes and concentration of the cyclosporine and tacrolimus. Transplant Proc. 2005;37:178–81.PubMedGoogle Scholar
  34. 34.
    Haufroid V, Wallemacq P, van Kerckhove V, et al. CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study. Am J Transplant. 2006;6:2706–13.PubMedGoogle Scholar
  35. 35.
    Roy JN, Barama A, Poirier C, et al. Cyp3A4, Cyp3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients. Pharmacogenet Genom. 2006;16:659–65.Google Scholar
  36. 36.
    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;81:228–34.PubMedGoogle Scholar
  37. 37.
    Rong G, Jing L, Deng-Qing L, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in Chinese renal transplant recipients. Transplant Proc. 2010;42:3455–8.PubMedGoogle Scholar
  38. 38.
    Santoro A, Felipe CR, Tedesco-Silva H, et al. Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients. Pharmacogenomics. 2011;12:1293–303.PubMedGoogle Scholar
  39. 39.
    Glowacki F, Lionet A, Buob D, et al. CYP3A5 and ABCB1 polymorphisms in donor and recipient: impact on tacrolimus dose requirements and clinical outcome after renal transplantation. Nephrol Dial Transplant. 2011;26:3046–50.PubMedGoogle Scholar
  40. 40.
    Gervasini G, Garcia M, Macias RM, et al. Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation. Transplant Int. 2012;25:471–80.Google Scholar
  41. 41.
    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;11:296–300.PubMedGoogle Scholar
  42. 42.
    Zhao W, Elie V, Roussey G, et al. Population pharmacokinetics and pharmacogenetics of tacrolimus in de novo pediatric kidney transplant recipients. Clin Pharmacol Ther. 2009;86:609–18.PubMedGoogle Scholar
  43. 43.
    Elmachad M, Elkabbaj D, Elkerch F, et al. Frequencies of CYP3A5*1/*3 variants in a Moroccan population and effect on tacrolimus daily dose requirements in renal transplant patients. Genet Test Mol Biomarkers. 2012;16:644–7.PubMedGoogle Scholar
  44. 44.
    García-Roca P, Medeiros M, Reyes H, et al. CYP3A5 polymorphism in Mexican renal transplant recipients and its association with tacrolimus dosing. Arch Med Res. 2012;43:283–7.PubMedGoogle Scholar
  45. 45.
    Zheng H, Webber S, Zeevi A, et al. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant. 2003;3:477–83.PubMedGoogle Scholar
  46. 46.
    Zheng H, Zeevi A, Schuetz E, et al. Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. J Clin Pharmacol. 2004;44:135–40.PubMedGoogle Scholar
  47. 47.
    Goto M, Masuda S, Kiuchi T, et al. CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation. Pharmacogenetics. 2004;14:471–8.PubMedGoogle Scholar
  48. 48.
    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 Genom. 2008;18:413–23.Google Scholar
  49. 49.
    Kniepeiss D, Renner W, Trummer O, et al. The role of CYP3A5 genotypes in dose requirements of tacrolimus and everolimus after heart transplantation. Clin Transplant. 2011;25:146–50.PubMedGoogle Scholar
  50. 50.
    Gijsen V, Mital S, van Schaik RH, et al. Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients. J Heart Lung Transplant. 2011;30:1352–9.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Tang HL, Xie HG, Yao Y, et al. Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressers than expressers. Pharmacogenet Genom. 2011;21:713–20.Google Scholar
  52. 52.
    Terrazzino S, Quaglia M, Stratta P, et al. The effect of CYP3A5 6986A>G and ABCB1 3435C>T on tacrolimus dose-adjusted trough levels and acute rejection rates in renal transplant patients: a systematic review and meta-analysis. Pharmacogenet Genom. 2012;22:642–5.Google Scholar
  53. 53.
    Birdwell KA, Grady B, Choi L, et al. The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant patients. Pharmacogenet Genom. 2012;22:32–42.Google Scholar
  54. 54.
    Andrews PA, Sen M, Chang RWS. Racial variation in dosage requirements of tacrolimus. Lancet. 1996;348:1446.PubMedGoogle Scholar
  55. 55.
    Mancinelli LM, Frassetto L, Floren LC, et al. The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups. Clin Pharmacol Ther. 2001;69:24–31.PubMedGoogle Scholar
  56. 56.
    Jacobson PA, Oetting WS, Brearley AM, et al. Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium. Transplantation. 2011;91:300–8.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Passey C, Birnbaum AK, Brundage RC, et al. Dosing equation for tacrolimus using genetic variants and clinical factors. Br J Clin Pharmacol. 2011;72:948–57.PubMedGoogle Scholar
  58. 58.
    Passey C, Birnbaum AK, Brundage RC, et al. Validation of tacrolimus equation to predict troughs using genetic and clinical factors. Pharmacogenomics. 2012;13:1141–7.PubMedCentralPubMedGoogle Scholar
  59. 59.
    PharmGKB. Dutch Pharmacogenetics Working Group guideline for tacrolimus and CYP3A5. Accessed 28 Oct 2013.
  60. 60.
    Lamba J, Hebert JM, Schuetz EG, et al. PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genom. 2012;22:555–8.Google Scholar
  61. 61.
    Wehland M, Bauer S, Brakemeier S, et al. Differential impact of the CYP3A5*1 and CYP3A5*3 alleles on pre-dose concentrations of two tacrolimus formulations. Pharmacogenet Genom. 2011;21:179–84.Google Scholar
  62. 62.
    Glowacki F, Lionet A, Hammelin JP, et al. Influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphism on the pharmacokinetics of the prolonged-release, once-daily formulation of tacrolimus in stable renal transplant recipients. Clin Pharmacokinet. 2011;50:451–9.PubMedGoogle Scholar
  63. 63.
    Niioka T, Satoh S, Kagaya H, et al. Comparison of pharmacokinetics and pharmacogenetics of once- and twice-daily tacrolimus in the early stage after renal transplantation. Transplantation. 2012;94:1013–9.PubMedGoogle Scholar
  64. 64.
    Niioka T, Kagaya H, Miura M, et al. Pharmaceutical and genetic determinants for interindividual differences of tacrolimus bioavailability in renal transplant recipients. Eur J Clin Pharmacol. 2013;69:1659–65.PubMedGoogle Scholar
  65. 65.
    Zhao W, Fakhoury M, Baudouin V, et al. Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients. Eur J Clin Pharmacol. 2013;69:189–95.PubMedGoogle Scholar
  66. 66.
    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;4:914–9.PubMedGoogle Scholar
  67. 67.
    Hesselink DA, van Schaik RHN, van Agteren M, et al. CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients. Pharmacogenet Genom. 2008;18:339–48.Google Scholar
  68. 68.
    Kuypers DRJ, 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;82:711–25.PubMedGoogle Scholar
  69. 69.
    Thervet E, Loriot MA, Barbier S, et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther. 2010;87:721–6.PubMedGoogle Scholar
  70. 70.
    van Gelder T, Hesselink DA. Dosing tacrolimus based on CYP3A5 genotype: will it improve clinical outcome? Clin Pharmacol Ther. 2010;87:640–1.PubMedGoogle Scholar
  71. 71.
    Nederlands Trial Register. Accessed 28 Oct 2013.
  72. 72. Accessed 28 Oct 2013.
  73. 73.
    Kuypers DRJ. Pharmacogenetic vs. concentration-controlled optimization of tacrolimus dosing in renal allograft recipients. Clin Pharmacol Ther. 2010;88:595–6.PubMedGoogle Scholar
  74. 74.
    Bouamar R, Shuker N, Hesselink DA, et al. Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: a pooled analysis from three randomized-controlled clinical trials. Am J Transplant. 2013;13:1253–61.PubMedGoogle Scholar
  75. 75.
    Hoffmeyer S, Burk O, von Richter O, et al. 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 USA. 2000;97:3473–8.PubMedGoogle Scholar
  76. 76.
    Wang D, Johnson AD, Papp AC, et al. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genom. 2005;15:693–704.Google Scholar
  77. 77.
    Kimchi-Sarfaty C, Oh JM, Kim I-W, et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315:525–8.PubMedGoogle Scholar
  78. 78.
    Shuker N, Bouamar R, Weimar W, et al. ATP-binding cassette transporters as pharmacogenetic biomarkers for kidney transplantation. Clin Chim Acta. 2012; 413:1326–37.Google Scholar
  79. 79.
    Wang D, Guo Y, Wrighton SA, et al. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenom J. 2011;11:274–86.Google Scholar
  80. 80.
    Elens L, Becker ML, Haufroid V, et al. Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study. Pharmacogenet Genom. 2011;21:861–6.Google Scholar
  81. 81.
    Elens L, Bouamar R, Hesselink DA, et al. A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients. Clin Chem. 2011;57:1574–83.PubMedGoogle Scholar
  82. 82.
    Elens L, van Schaik RH, Panin N, et al. Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors’ dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics. 2011;12:1383–96.PubMedGoogle Scholar
  83. 83.
    Gijsen VMGJ, van Schaik RHN, Elens L, et al. CYP3A4*22 and CYP3A combined genotypes both correlate with tacrolimus disposition in pediatric heart transplant recipients. Pharmacogenomics. 2013;14:1027–36.PubMedGoogle Scholar
  84. 84.
    Elens L, Hesselink DA, van Schaik RHN, et al. The CYP3A4*22 allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations. Br J Clin Pharmacol. 2013;75:1545–7.PubMedGoogle Scholar
  85. 85.
    Santoro AB, Struchiner CJ, Felipe CR, et al. CYP3A5 genotype but not CYP3A4*1B, CYP3A4*22, or hematocrit, predicts tacrolimus dose requirements in Brazilian renal transplant patients. Clin Pharmacol Ther. 2013;94:201–2.PubMedGoogle Scholar
  86. 86.
    Tavira B, Coto E, Diaz-Corte C, et al. A search for new CYP3A4 variants as determinants of tacrolimus dose requirements in renal-transplanted patients. Pharmacogenet Genom. 2013;23:445–8.Google Scholar
  87. 87.
    Hart SN, Zhong X-B. P450 oxidoreductase: genetic polymorphisms and implications for drug metabolism and toxicity. Expert Opin Drug Metab Toxicol. 2008;4:439–52.PubMedGoogle Scholar
  88. 88.
    Huang N, Agrawal V, Giacomini KM, et al. Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proc Natl Acad Sci USA. 2008;105:1733–8.PubMedGoogle Scholar
  89. 89.
    de Jonge H, Metalidis C, Naesens M, et al. The P450 oxidoreductase*28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients. Pharmacogenomics. 2011;12:1281–91.PubMedGoogle Scholar
  90. 90.
    Elens L, Hesselink DA, Bouamar R, et al. Impact of POR*28 on the pharmacokinetics of tacrolimus and cyclosporine a in renal transplant patients. Ther Drug Monit. Epub 2013 Sep 20. doi:10.1097/FTD.0b013e31829da6dd.
  91. 91.
    Zhang J-J, Zhang H, Ding X-L, et al. Effect of the P450 oxidoreductase *28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers. Eur J Clin Pharmacol. 2013;69:807–12.PubMedGoogle Scholar
  92. 92.
    Miura M, Satoh S, Inoue K, et al. Influence of CYP3A5, ABCB1 and NR1I2 polymorphisms on prednisolone pharmacokinetics in renal transplant recipients. Steroids. 2008;73:1052–9.PubMedGoogle Scholar
  93. 93.
    Benkali K, Prémaud A, Picard N, et al. Tacrolimus population pharmacokinetic–pharmacogenetic analysis and Bayesian estimation in renal transplant recipients. Clin Pharmacokinet. 2009;48:805–16.PubMedGoogle Scholar
  94. 94.
    Press RR, Ploeger BA, den Hartigh J, et al. Explaining variability in tacrolimus pharmacokinetics to optimize early exposure in adult kidney transplant recipients. Ther Drug Monit. 2009;31:187–97.PubMedGoogle Scholar
  95. 95.
    Barraclough KA, Isbel NM, Lee KJ, et al. NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation. Transplantation. 2012;94:1025–32.PubMedGoogle Scholar
  96. 96.
    Shi X-J, Geng F, Jiao Z, et al. Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis. J Clin Pharm Ther. 2011;36:614–24.PubMedGoogle Scholar
  97. 97.
    Zuo X-C, Ng CM, Barrett JS, et al. Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis. Pharmacogenet Genom. 2013;23:251–61.Google Scholar
  98. 98.
    Klein K, Thomas M, Winter S, et al. PPARA: a novel genetic determinant of CYP3A4 in vitro and in vivo. Clin Pharmacol Ther. 2012;91:1044–52.PubMedGoogle Scholar
  99. 99.
    Boughton O, Borgulya G, Cecconi M, et al. A published pharmacogenetic algorithm was poorly predictive of tacrolimus clearance in an independent cohort of renal transplant recipients. Br J Clin Pharmacol. 2013;76:425–31.PubMedGoogle Scholar
  100. 100.
    Halloran PF, Kung L, Noujaim J. Calcineurin and the biological effect of cyclosporine and tacrolimus. Transplant Proc. 1998;30:2167–70.PubMedGoogle Scholar
  101. 101.
    Grinyó J, Vanrenterghem Y, Nashan B, et al. Association of four DNA polymorphisms with acute rejection after kidney transplantation. Transplant Int. 2008;21:879–91.Google Scholar
  102. 102.
    Min S-I, Kim S-Y, Ahn SH, et al. CYP3A5*1 allele: impacts on early acute rejection and graft function in tacrolimus-based renal transplant recipients. Transplantation. 2010;90:1394–400.PubMedGoogle Scholar
  103. 103.
    Israni A, Leduc R, Holmes J, et al. Single-nucleotide polymorphisms, acute rejection, and severity of tubulitis in kidney transplantation, accounting for center-to-center variation. Transplantation. 2010;90:1401–8.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Oetting WS, Schladt DP, Leduc RE, et al. Validation of single nucleotide polymorphisms associated with acute rejection in kidney transplant recipients using a large multi-center cohort. Transplant Int. 2011;24:1231–8.Google Scholar
  105. 105.
    Naesens M, Kuypers DRJ, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;4:481–508.PubMedGoogle Scholar
  106. 106.
    Hesselink DA, Bouamar R, van Gelder T. The pharmacogenetics of calcineurin inhibitor-related nephrotoxicity. Ther Drug Monit. 2010;32:387–93.PubMedGoogle Scholar
  107. 107.
    Jacobson PA, Schladt D, Israni A, et al. Genetic and clinical determinants of early, acute calcineurin inhibitor-related nephrotoxicity: results from a kidney transplant consortium. Transplantation. 2012;93:624–31.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349:931–40.PubMedGoogle Scholar
  109. 109.
    Isnard Bagnis C, Tezenas du Montcel S, Beaufils H, et al. Long-term renal effects of low-dose cyclosporine in uveitis-treated patients: follow-up study. J Am Soc Nephrol. 2002;13:2962–8.Google Scholar
  110. 110.
    van Gelder T, Balk AHMM, Zietse R, et al. Renal insufficiency after heart transplantation: a case-control study. Nephrol Dial Transplant. 1998;13:2322–6.PubMedGoogle Scholar
  111. 111.
    Zheng S, Tasnif Y, Hebert MF, et al. Measurement and compartmental modeling of the effect of CYP3A5 gene variation on systemic and intrarenal tacrolimus disposition. Clin Pharmacol Ther. 2012;92:737–45.PubMedGoogle Scholar
  112. 112.
    Metalidis C, Lerut E, Naesens M, et al. Expression of CYP3A5 and P-glycoprotein in renal allografts with histological signs of calcineurin inhibitor nephrotoxicity. Transplantation. 2011;91:1098–102.PubMedGoogle Scholar
  113. 113.
    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;22:1963–8.PubMedGoogle Scholar
  114. 114.
    Kuypers DRJ, Naesens M, de Jonge H, et al. Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients. Ther Drug Monit. 2010;32:394–404.PubMedGoogle Scholar
  115. 115.
    Quteineh L, Verstuyft C, Furlan V, et al. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. Basic Clin Pharmacol Toxicol. 2008;103:546–52.PubMedGoogle Scholar
  116. 116.
    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;27:741–5.PubMedGoogle Scholar
  117. 117.
    Naesens M, Lerut E, de Jonge H, et al. Donor age and renal P-glycoprotein expression associate with chronic histological damage in renal allografts. J Am Soc Nephrol. 2009;20:2468–80.PubMedGoogle Scholar
  118. 118.
    Joy MS, Nickeleit V, Hogan SL, et al. Calcineurin inhibitor-induced nephrotoxicity and renal expression of P-glycoprotein. Pharmacotherapy. 2005;25:779–89.PubMedGoogle Scholar
  119. 119.
    Moore J, McKnight AJ, Döhler B, et al. Donor ABCB1 variant associates with increased risk for kidney allograft failure. J Am Soc Nephrol. 2012;23:1879–90.Google Scholar
  120. 120.
    Woillard J-B, Rerolle J-P, Picard N, et al. Donor P-gp polymorphisms strongly influence renal function and graft loss in a cohort of renal transplant recipients on cyclosporine therapy in a long-term follow-up. Clin Pharmacol Ther. 2010;88:95–100.PubMedCentralPubMedGoogle Scholar
  121. 121.
    Lemos FBC, Mol WM, Roodnat JI, et al. The beneficial effects of recipient-derived vascular endothelial growth factor on graft survival after kidney transplantation. Transplantation. 2005;79:1221–5.PubMedGoogle Scholar
  122. 122.
    Moore J, McKnight AJ, Simmonds MJ, et al. Association of caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure. JAMA. 2010;303:1282–7.PubMedGoogle Scholar
  123. 123.
    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 Genom. 2008;18:943–53.Google Scholar
  124. 124.
    van de Wetering J, Weimar CHE, Balk AHMM, et al. The impact of transforming growth factor-β1 gene polymorphism on end-stage renal failure after heart transplantation. Transplantation. 2006;82:1744–8.PubMedGoogle Scholar
  125. 125.
    Matas AJ. Chronic progressive calcineurin nephrotoxicity: an overstated concept. Am J Transplant. 2011;11:687–92.PubMedCentralPubMedGoogle Scholar
  126. 126.
    Chapman JR. Chronic calcineurin inhibitor use is nephrotoxic. Clin Pharmacol Ther. 2011;90:207–9.PubMedGoogle Scholar
  127. 127.
    Einecke G, Sis B, Reeve J, et al. Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant. 2009;9:2520–31.PubMedGoogle Scholar
  128. 128.
    McGuire BM, Julian BA, Bynon Jr JS, et al. Glomerulonephritis in patients with hepatitis C undergoing liver transplantation. Ann Intern Med. 2006;144:735–41.Google Scholar
  129. 129.
    van Slambrouck CM, Salem F, Meehan SM, et al. Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction. Kidney Int. 2013;84:192–7.PubMedGoogle Scholar
  130. 130.
    Snanoudj R, Royal V, Elie C, et al. Specificity of histological markers of long-term CNI nephrotoxicity in kidney-transplant recipients under low-dose cyclosporine therapy. Am J Transplant. 2011;11:2635–46.PubMedGoogle Scholar
  131. 131.
    Yates CJ, Fourlanos S, Hjelmesaeth J, et al. New-onset diabetes after kidney transplantation: changes and challenges. Am J Transplant. 2012;12:820–8.PubMedGoogle Scholar
  132. 132.
    Webster AC, Woodroffe RC, Taylor RS, et al. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ. 2005;331:810–20.PubMedGoogle Scholar
  133. 133.
    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;80:1419–24.PubMedGoogle Scholar
  134. 134.
    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;17:2333–40.PubMedGoogle Scholar
  135. 135.
    Kang ES, Kim MS, Kim YS, et al. A variant of the transcription factor 7-like 2 (TCF7L2) gene and the risk of posttransplantation diabetes mellitus in renal allograft recipients. Diabetes Care. 2008;31:63–8.PubMedGoogle Scholar
  136. 136.
    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;57:1043–7.PubMedGoogle Scholar
  137. 137.
    Ghisdal L, Baron C, Le Meur Y, et al. TCF7L2 polymorphism associates with new-onset diabetes after transplantation. J Am Soc Nephrol. 2009;20:2459–67.PubMedGoogle Scholar
  138. 138.
    Yang J, Hutchinson II, Shah T, et al. Genetic and clinical risk factors of new-onset diabetes after transplantation in Hispanic kidney transplant recipients. Transplantation. 2011;91:1114–9.PubMedGoogle Scholar
  139. 139.
    Chen Y, Sampaio MS, Yang JW, et al. Genetic polymorphisms of the transcription factor NFATc4 and development of new-onset diabetes after transplantation in Hispanic kidney transplant recipients. Transplantation. 2012;93:325–30.PubMedGoogle Scholar
  140. 140.
    Elens L, Sombogaard F, Hesselink DA, et al. Single-nucleotide polymorphisms in P450 oxidoreductase and peroxisome proliferator-activated receptor-α are associated with the development of new-onset diabetes after transplantation in kidney transplant recipients treated with tacrolimus. Pharmacogenet Genom. Epub 2013 Oct 9. doi:10.1097/FPC0000000000000001.
  141. 141.
    Tavira B, Coto E, Torres A, et al. Association between a common KCNJ11 polymorphism (rs5219) and new-onset posttransplant diabetes in patients treated with tacrolimus. Mol Genet Metab. 2012;105:525–7.PubMedGoogle Scholar
  142. 142.
    Kang ES, Kim MS, Kim CH, et al. Association of common type 2 diabetes risk gene variants and posttransplantation diabetes mellitus in renal allograft recipients in Korea. Transplantation. 2009;88:693–8.PubMedGoogle Scholar
  143. 143.
    Kang ES, Magkos F, Kim BS, et al. Variants of the adiponectin and adiponectin receptor-1 genes and posttransplantation diabetes mellitus in renal allograft recipients. J Clin Endocrinol Metab. 2012;97:E129–35.PubMedGoogle Scholar
  144. 144.
    Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010;10:535–46.PubMedGoogle Scholar
  145. 145.
    Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transplant Int. 2000;13:313–26.Google Scholar
  146. 146.
    Wijdicks EFM. Neurotoxicity of immunosuppressive drugs. Liver Transplant. 2001;7:937–42.Google Scholar
  147. 147.
    Böttiger Y, Brattström C, Tydén G, et al. Tacrolimus whole blood concentrations correlate closely to side-effects in transplant recipients. Br J Clin Pharmacol. 1999;48:445–8.PubMedGoogle Scholar
  148. 148.
    Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357:2562–75.PubMedGoogle Scholar
  149. 149.
    Vizzini G, Asaro M, Miraglia R, et al. Changing picture of central nervous system complications in liver transplant recipients. Liver Transpl. 2011;17:1279–85.PubMedGoogle Scholar
  150. 150.
    Tan TC, Robinson PJ. Mechanisms of calcineurin inhibitor-induced neurotoxicity. Transplant Rev (Orlando). 2006;20:49–60.Google Scholar
  151. 151.
    Cardon-Cardo C, O’Brien JP, Casals D, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA. 1989;86:695–8.Google Scholar
  152. 152.
    Thiebaut F, Tsuruo T, Hamada H, et al. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J Histochem Cytochem. 1989;37:159–64.PubMedGoogle Scholar
  153. 153.
    Schinkel AH, Wagenaar E, van Deemter L, et al. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995;96:1698–705.PubMedCentralPubMedGoogle Scholar
  154. 154.
    Yokogawa K, Takahashi M, Tamai I, et al. P-glycoprotein-dependent disposition kinetics of tacrolimus: studies in mdr1a knock-out mice. Pharm Res. 1999;16:1213–8.PubMedGoogle Scholar
  155. 155.
    Steiner JP, Dawson TM, Fotuhi M, et al. High brain densities of the immunophilin FKBP colocalized with calcineurin. Nature. 1992;358:584–7.PubMedGoogle Scholar
  156. 156.
    Kaczmarek I, Groetzner J, Meiser B, et al. Impairment of the blood-brain barrier can result in tacrolimus-induced reversible leucoencephalopathy following heart transplantation. Clin Transplant. 2003;17:469–72.PubMedGoogle Scholar
  157. 157.
    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;74:571–8.PubMedGoogle Scholar
  158. 158.
    Yanagimachi M, Naruto T, Tanoshima R, et al. Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation. Clin Transplant. 2010;24:855–61.PubMedGoogle Scholar
  159. 159.
    Arnold R, Pussell BA, Pianta TJ, et al. Association between calcineurin inhibitor treatment and peripheral nerve dysfunction in renal transplant recipients. Am J Transplant. 2013;13:2426–32.PubMedGoogle Scholar
  160. 160.
    Hoorn EJ, Walsh SB, McCormick JA, et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nat Med. 2011;17:1304–9.PubMedCentralPubMedGoogle Scholar
  161. 161.
    Bochud M, Bovet P, Burnier M, et al. CYP3A5 and ABCB1 genes and hypertension. Pharmacogenomics. 2009;10:477–87.PubMedGoogle Scholar
  162. 162.
    Ferraresso M, Turolo S, Ghio L, et al. Association between CYP3A5 polymorphisms and blood pressure in kidney transplant recipients receiving calcineurin inhibitors. Clin Exp Hypertens. 2011;33:359–65.PubMedGoogle Scholar
  163. 163.
    Kreutz R, Zürcher H, Kain S, et al. The effect of variable CYP3A5 expression on cyclosporine dosing, blood pressure and long-term graft survival in renal transplant patients. Pharmacogenetics. 2004;14:665–71.PubMedGoogle Scholar
  164. 164.
    Torio A, Auyanet I, Montes-Ares O, et al. Effect of CYP3A5*1/*3 polymorphism on blood pressure in renal transplant recipients. Transplant Proc. 2012;44:2596–8.PubMedGoogle Scholar
  165. 165.
    Li J-L, Wang X-D, Chen S-Y, et al. Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective. Pharmacogenomics J. 2011;11:300–6.PubMedGoogle Scholar
  166. 166.
    Chen S-Y, Li J-L, Meng F-H, et al. Individualization of tacrolimus dosage basing on cytochrome P450 3A5 polymorphism—a prospective, randomized, controlled study. Clin Transplant. 2013;27:E272–81.PubMedGoogle Scholar
  167. 167.
    Hooper DK, Fukuda T, Gardiner R, et al. Risk of tacrolimus toxicity in CYP3A5 nonexpressers treated with intravenous nicardipine after kidney transplantation. Transplantation. 2012;93:806–12.PubMedGoogle Scholar
  168. 168.
    Moreton M, Fredericks S, McKeown DA, et al. CYP3A5 genotype does not influence the blood concentration of tacrolimus measured with the Abbott immunoassay. Clin Chem. 2005;51:2214–5.PubMedGoogle Scholar
  169. 169.
    Yoon S-H, Cho J-H, Kwon O, et al. CYP3A and ABCB1 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of tacrolimus and its metabolites (M-I and M-III). Transplantation. 2013;95:828–34.PubMedGoogle Scholar
  170. 170.
    Capron A, Musuamba F, Latinne D, et al. Validation of a liquid chromatography-mass spectrometric assay for tacrolimus in peripheral blood mononuclear cells. Ther Drug Monit. 2009;31:178–86.PubMedGoogle Scholar
  171. 171.
    Capron A, Lerut J, Latinne D, et al. Correlation of tacrolimus levels in peripheral blood mononuclear cells with histological staging of rejection after liver transplantation: preliminary results of a prospective study. Transplant Int. 2012;25:41–7.Google Scholar
  172. 172.
    Hitzl M, Drescher S, van der Kuip H, et al. The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells. Pharmacogenetics. 2001;11:293–8.PubMedGoogle Scholar
  173. 173.
    Crettol S, Venetz J-P, Fontana M, et al. Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients. Pharmacogenet Genom. 2008;18:307–15.Google Scholar
  174. 174.
    Capron A, Mourad M, de Meyer M, et al. CYP3A5 and ABCB1 polymorphisms influence tacrolimus concentrations in peripheral blood mononuclear cells after renal transplantation. Pharmacogenomics. 2010;11:703–14.PubMedGoogle Scholar
  175. 175.
    Llaudo I, Colom H, Giménez-Bonafe P, et al. Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study. Transplant Int. 2013;26:177–86.Google Scholar
  176. 176.
    Vafadari R, Bouamar R, Hesselink DA, et al. Genetic polymorphisms in ABCB1 influence the pharmacodynamics of tacrolimus. Ther Drug Monit. 2013;35:459–65.PubMedGoogle Scholar
  177. 177.
    Capron A, Lerut J, Verbaandert C, et al. Validation of a liquid chromatography-mass spectrometric assay for tacrolimus in liver biopsies after hepatic transplantation: correlation with histopathologic staging of rejection. Ther Drug Monit. 2007;29:340–8.PubMedGoogle Scholar
  178. 178.
    Noll BD, Coller JK, Somogyi AA, et al. Validation of an LC-MS/MS method to measure tacrolimus in rat kidney and liver tissue and its application to human kidney biopsies. Ther Drug Monit. 2013;35:617–23.PubMedGoogle Scholar
  179. 179.
    Elens L, Capron A, van Kerckhove V, et al. 1199G>A and 2677G>T/A polymorphisms of ABCB1 independently affect tacrolimus concentration in hepatic tissue after liver transplantation. Pharmacogenet Genom. 2007;17:873–83.Google Scholar
  180. 180.
    Zahir H, McCaughan G, Gleeson M, et al. Changes in tacrolimus distribution in blood and plasma protein binding following liver transplantation. Ther Drug Monit. 2004;26:506–15.PubMedGoogle Scholar
  181. 181.
    Weinshillboum R. Inheritance and drug response. N Engl J Med. 2003;348:529–37.Google Scholar
  182. 182.
    Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358:568–79.PubMedGoogle Scholar
  183. 183.
    Chen P, Lin J-J, Lu C-S, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med. 2011;364:1126–33.PubMedGoogle Scholar
  184. 184.
    McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364:1134–43.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Dennis A. Hesselink
    • 1
  • Rachida Bouamar
    • 2
  • Laure Elens
    • 3
  • Ron H. N. van Schaik
    • 4
  • Teun van Gelder
    • 1
    • 2
  1. 1.Division of Nephrology and Renal Transplantation, Department of Internal Medicine, Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands
  2. 2.Clinical Pharmacology Unit, Department of Hospital Pharmacy, Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands
  3. 3.Louvain Centre for Toxicology and Applied PharmacologyUniversité Catholique de LouvainBrusselsBelgium
  4. 4.Department of Clinical Chemistry, Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands

Personalised recommendations