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

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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 (rs1128503) 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 pharmacokinetics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed, and all relevant primary research articles were critiqued and summarized. Influence of the CYP3A4 −392A>G SNP on the pharmacokinetics of either ciclosporin or tacrolimus appears limited. Variability in CYP3A4 expression due to environmental factors is likely to be more important than patient genotype. Influence of the CYP3A5 6986A>G SNP on the pharmacokinetics of ciclosporin is also uncertain and likely to be small. CYP3A4 may play a more dominant role than CYP3A5 in the metabolism of ciclosporin. The CYP3A5 6986A>G SNP has a well established influence on the pharmacokinetics of tacrolimus. Several studies in kidney, heart and liver transplant recipients have reported an approximate halving of tacrolimus dose-adjusted trough concentrations and doubling of tacrolimus dose requirements in heterozygous or homozygous carriers of a CYP3A5*1 wild-type allele compared with homozygous carriers of a CYP3A5*3 variant allele. Carriers of a CYP3A5*1 allele take a longer time to reach target blood tacrolimus concentrations. Influence of ABCB1 3435C>T, 1236C>T and 2677G>T/A SNPs on the pharmacokinetics of ciclosporin and tacrolimus remains uncertain, with inconsistent results. Genetic linkage between the three variant genotypes suggests that the pharmacokinetic effects are complex and not related to any one ABCB1 SNP. It is likely that these polymorphisms exert a small but combined effect, which is additive to the effects of the CYP3A5 6986A>G SNP. In liver transplant patients, recipient and donor liver genotypes may act together in determining overall drug disposition, hence the importance of assessing both. Studies with low patient numbers may account for many inconsistent results to date. Meta-analyses of the current data should help resolve some discrepancies. 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. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.

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References

  1. Masuda S, Inui K. An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacol Ther 2006; 112(1): 184–98

    Article  PubMed  CAS  Google Scholar 

  2. Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol 2007; 2(2): 374–84

    Article  PubMed  CAS  Google Scholar 

  3. 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 

  4. Evans WE, McLeod HL. Pharmacogenomics: drug disposition, drug targets, and side effects. N Engl J Med 2003; 348(6): 538–49

    Article  PubMed  CAS  Google Scholar 

  5. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmaco-dynamics of calcineurin inhibitors: Part II. Clin Pharmacokinet 2010; 49(4): 207–21

    Article  PubMed  CAS  Google Scholar 

  6. 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 

  7. 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 

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

    CAS  Google Scholar 

  9. 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 

  10. Dai Y, Hebert MF, Isoherranen N, et al. Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab Dispos 2006; 34(5): 836–47

    Article  PubMed  CAS  Google Scholar 

  11. Dai Y, Iwanaga K, Lin YS, et al. In vitro metabolism of cyclosporine A by human kidney CYP3A5. Biochem Pharmacol 2004; 68(9): 1889–902

    Article  PubMed  CAS  Google Scholar 

  12. Sattler M, Guengerich FP, Yun CH, et al. Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos 1992; 20(5): 753–61

    PubMed  CAS  Google Scholar 

  13. Iwasaki K. Metabolism of tacrolimus (FK506) and recent topics in clinical pharmacokinetics. Drug Metab Pharmacokinet 2007; 22(5): 328–35

    Article  PubMed  CAS  Google Scholar 

  14. Lamba JK, Lin YS, Schuetz EG, et al. Genetic contributiontovariable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002; 54(10): 1271–94

    Article  PubMed  CAS  Google Scholar 

  15. Schuetz EG, Schuetz JD, Grogan WM, et al. Expression of cytochrome P450 3A in amphibian, rat, and human kidney. Arch Biochem Biophys 1992; 294(1): 206–14

    Article  PubMed  CAS  Google Scholar 

  16. 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(10): 1108–14

    Article  PubMed  CAS  Google Scholar 

  17. Pauli-Magnus C, Kroetz DL. Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1). Pharm Res 2004; 21(6): 904–13

    Article  PubMed  CAS  Google Scholar 

  18. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004; 43(10): 623–53

    Article  PubMed  CAS  Google Scholar 

  19. Christians U, Strom T, Zhang YL, et al. Active drug transport of immuno-suppressants: new insights for pharmacokinetics and pharmacodynamics. Ther Drug Monit 2006; 28(1): 39–44

    Article  PubMed  CAS  Google Scholar 

  20. Fromm MF. Importance of P-glycoprotein for drug disposition in humans. Eur J Clin Invest 2003; 33 Suppl. 2: 6–9

    Article  PubMed  CAS  Google Scholar 

  21. Cummins CL, Jacobsen W, Benet LZ. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 2002; 300(3): 1036–45

    Article  PubMed  CAS  Google Scholar 

  22. Cummins CL, Salphati L, Reid MJ, et al. In vivo modulation of intestinal CYP3A metabolism by P-glycoprotein: studies using the rat single-pass intestinal perfusion model. J Pharmacol Exp Ther 2003; 305(1): 306–14

    Article  PubMed  CAS  Google Scholar 

  23. Christians U, Sewing KF. Alternative cyclosporine metabolic pathways and toxicity. Clin Biochem 1995; 28(6): 547–59

    Article  PubMed  CAS  Google Scholar 

  24. Benet LZ, Cummins CL. The drug efflux-metabolism alliance: biochemical aspects. Adv Drug Deliv Rev 2001; 50 Suppl. 1: S3–11

    Article  PubMed  CAS  Google Scholar 

  25. Cummins CL, Jacobsen W, Christians U, et al. CYP3A4-transfected Caco-2 cells as a tool for understanding biochemical absorption barriers: studies with sirolimus and midazolam. J Pharmacol Exp Ther 2004; 308(1): 143–55

    Article  PubMed  CAS  Google Scholar 

  26. Christians U, Sewing KF. Cyclosporin metabolism in transplant patients. Pharmacol Ther 1993; 57(2–3): 291–345

    Article  PubMed  CAS  Google Scholar 

  27. Bader A, Hansen T, Kirchner G, et al. Primary porcine enterocyte and hepatocyte cultures to study drug oxidation reactions. Br J Pharmacol 2000; 129(2): 331–42

    Article  PubMed  CAS  Google Scholar 

  28. Balayssac D, Authier N, Cayre A, et al. Does inhibition of P-glycoprotein lead to drug-drug interactions?. Toxicol Lett 2005; 156(3): 319–29

    Article  PubMed  CAS  Google Scholar 

  29. Schinkel AH, Wagenaar E, van Deemter L, et al. Absence of the mdrla P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995; 96(4): 1698–705

    Article  PubMed  CAS  Google Scholar 

  30. 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 

  31. Lemahieu WP, Maes BD, Verbeke K, et al. Alterations of CYP3A4 and P-glycoprotein activity in vivo with time in renal graft recipients. Kidney Int 2004; 66(1): 433–40

    Article  PubMed  CAS  Google Scholar 

  32. Lemahieu WP, Maes BD, Verbeke K, et al. CYP3A4 and P-glycoprotein activity in healthy controls and transplant patients on cyclosporin vs tacrolimus vs sirolimus. Am J Transplant 2004; 4(9): 1514–22

    Article  PubMed  CAS  Google Scholar 

  33. del Mar Fernandez De Gatta M, Santos-Buelga D, Dominguez-Gil A, et al. Immunosuppressive therapy for paediatric transplant patients: pharmaco-kinetic considerations. Clin Pharmacokinet 2002; 41(2): 115–35

    Article  PubMed  Google Scholar 

  34. Lacroix D, Sonnier M, Moncion A, et al. Expression of CYP3A in the human liver: evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem 1997; 247(2): 625–34

    Article  PubMed  CAS  Google Scholar 

  35. Stevens JC, Hines RN, Gu C, et al. Developmental expression of the major human hepatic CYP3A enzymes. J Pharmacol Exp Ther 2003; 307(2): 573–82

    Article  PubMed  CAS  Google Scholar 

  36. Bjorkman S. Prediction of cytochrome p450-mediated hepatic drug clearance in neonates, infants and children: how accurate are available scaling methods?. Clin Pharmacokinet 2006; 45(1): 1–11

    Article  PubMed  Google Scholar 

  37. Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther 2008; 118(2): 250–67

    Article  PubMed  CAS  Google Scholar 

  38. Home page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee [online]. Available from URL: http://www.cypalleles.ki.se/ [Accessed 2009 Feb 19]

  39. Rebbeck TR, Jaffe JM, Walker AH, et al. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1998; 90(16): 1225–9

    Article  PubMed  CAS  Google Scholar 

  40. Westlind A, Lofberg L, Tindberg N, et al. Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5′-upstream regulatory region. Biochem Biophys Res Commun 1999; 259(1): 201–5

    Article  PubMed  CAS  Google Scholar 

  41. Amirimani B, Walker AH, Weber BL, et al. Response: re: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4 [letter]. J Natl Cancer Inst 1999; 91(18): 1588–90

    Article  PubMed  Google Scholar 

  42. Amirimani B, Ning B, Deitz AC, et al. Increased transcriptional activity of the CYP3A4*1B promoter variant. Environ Mol Mutagen 2003; 42(4): 299–305

    Article  PubMed  CAS  Google Scholar 

  43. Ando Y, Tateishi T, Sekido Y, et al. Re: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4 [letter]. J Natl Cancer Inst 1999; 91(18): 1587–90

    Article  PubMed  CAS  Google Scholar 

  44. Lamba JK, Lin YS, Thummel K, et al. Common allelic variants of cyto-chrome P4503A4 and their prevalence in different populations. Pharmaco-genetics 2002; 12(2): 121–32

    CAS  Google Scholar 

  45. Spurdle AB, Goodwin B, Hodgson E, et al. The CYP3A4*1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer. Pharmacogenetics 2002; 12(5): 355–66

    Article  PubMed  CAS  Google Scholar 

  46. Ball SE, Scatina J, Kao J, et al. Population distribution and effects on drug metabolism of a genetic variant in the 5′ promoter region of CYP3A4. Clin Pharmacol Ther 1999; 66(3): 288–94

    Article  PubMed  CAS  Google Scholar 

  47. Garcia-Martin E, Martinez C, Pizarro RM, et al. CYP3A4 variant alleles in White individuals with low CYP3A4 enzyme activity. Clin Pharmacol Ther 2002; 71(3): 196–204

    Article  PubMed  CAS  Google Scholar 

  48. Wandel C, Witte JS, Hall JM, et al. CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B5′-promoter region polymorphism. Clin Pharmacol Ther 2000; 68(1): 82–91

    Article  PubMed  CAS  Google Scholar 

  49. Hustert E, Haberl M, Burk O, et al. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 2001; 11(9): 773–9

    Article  PubMed  CAS  Google Scholar 

  50. 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(4): 383–91

    Article  PubMed  CAS  Google Scholar 

  51. Lin YS, Dowling AL, Quigley SD, et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 2002; 62(1): 162–72

    Article  PubMed  CAS  Google Scholar 

  52. Huang W, Lin YS, McConn II DJ, et al. Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos 2004; 32(12): 1434–45

    Article  PubMed  CAS  Google Scholar 

  53. Paulussen A, Lavrijsen K, Bohets H, et al. Two linked mutations in tran-scriptional regulatory elements of the CYP3A5 gene constitute the major genetic determinant of polymorphic activity in humans. Pharmacogenetics 2000; 10(5): 415–24

    Article  PubMed  CAS  Google Scholar 

  54. US National Center for Biotechnology Information. Single nucleotide polymorphism [online]. Available from: http://www.ncbi.nlm.nih.gov/SNP/GeneGt.cgi?geneID=5243 [Accessed 2009 Feb 23]

  55. Kroetz DL, Pauli-Magnus C, Hodges LM, et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003; 13(8): 481–94

    Article  PubMed  CAS  Google Scholar 

  56. Wang D, Johnson AD, Papp AC, et al. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 2005; 15(10): 693–704

    Article  PubMed  CAS  Google Scholar 

  57. Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 2007; 315(5811): 525–8

    Article  PubMed  CAS  Google Scholar 

  58. 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 U S A 2000; 97(7): 3473–8

    Article  PubMed  CAS  Google Scholar 

  59. Fellay J, Marzolini C, Meaden ER, et al. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 2002; 359(9300): 30–6

    Article  PubMed  CAS  Google Scholar 

  60. 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(4): 293–8

    Article  PubMed  CAS  Google Scholar 

  61. Hitzl M, Schaeffeler E, Hocher B, et al. Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1). Pharmacogenetics 2004; 14(5): 309–18

    Article  PubMed  CAS  Google Scholar 

  62. Tanabe M, Ieiri I, Nagata N, et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 2001; 297(3): 1137–43

    PubMed  CAS  Google Scholar 

  63. Sakaeda T, Nakamura T, Horinouchi M, et al. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res 2001; 18(10): 1400–4

    Article  PubMed  CAS  Google Scholar 

  64. Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001; 70(2): 189–99

    Article  PubMed  CAS  Google Scholar 

  65. Nakamura T, Sakaeda T, Horinouchi M, et al. Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther 2002; 71(4): 297–303

    Article  PubMed  CAS  Google Scholar 

  66. Drescher S, Schaeffeler E, Hitzl M, et al. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 2002; 53(5): 526–34

    Article  PubMed  CAS  Google Scholar 

  67. Siegmund W, Ludwig K, Giessmann T, et al. The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther 2002; 72(5): 572–83

    Article  PubMed  CAS  Google Scholar 

  68. Goto M, Masuda S, Saito H, et al. C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in re-cipientsofliving-donor liver transplantation. Pharmacogenetics 2002; 12(6): 451–7

    Article  PubMed  CAS  Google Scholar 

  69. Wojnowski L, Hustert E, Klein K, et al. Re: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4 [letter]. J Natl Cancer Inst 2002; 94(8): 630–1; author reply 631–2

    Article  PubMed  Google Scholar 

  70. Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmaco-kinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003; 74(3): 245–54

    Article  PubMed  CAS  Google Scholar 

  71. 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 

  72. Op den Buijsch RA, Christiaans MH, Stolk LM, et al. Tacrolimus pharmaco-kinetics and pharmacogenetics: influence of adenosine triphosphate-binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms. Fundam Clin Pharmacol 2007; 21(4): 427–35

    Article  CAS  Google Scholar 

  73. Hesselink DA, van Gelder T, van Schaik RH, et al. Population pharmaco-kinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the MDR-1, CYP3A4, and CYP3A5 genes. Clin Pharmacol Ther 2004; 76(6): 545–56

    Article  PubMed  CAS  Google Scholar 

  74. Yates CR, Zhang W, Song P, et al. The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J Clin Pharmacol 2003; 43(6): 555–64

    PubMed  CAS  Google Scholar 

  75. Loh PT, Lou HX, Zhao Y, et al. Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients. Transplant Proc 2008; 40(5): 1690–5

    Article  PubMed  CAS  Google Scholar 

  76. Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther 2004; 75(5): 422–33

    Article  PubMed  CAS  Google Scholar 

  77. Anglicheau D, Verstuyft C, Laurent-Puig P, et al. Association of the multi-drug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol 2003; 14(7): 1889–96

    Article  PubMed  CAS  Google Scholar 

  78. Salama NN, Yang Z, Bui T, et al. MDR1 haplotypes significantly minimize intracellular uptake and transcellular P-gp substrate transport in recombinant LLC-PK1 cells. J Pharm Sci 2006; 95(10): 2293–308

    Article  PubMed  CAS  Google Scholar 

  79. 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 

  80. Rivory LP, Qin H, Clarke SJ, et al. Frequency of cytochrome P450 3A4 variant genotype in transplant population and lack of association with cyclosporin clearance. Eur J Clin Pharmacol 2000; 56(5): 395–8

    Article  PubMed  CAS  Google Scholar 

  81. Min DI, Ellingrod VL. Association of the CYP3A4*1B 5′-flanking region polymorphism with cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit 2003; 25(3): 305–9

    Article  PubMed  CAS  Google Scholar 

  82. Crettol S, Venetz JP, Fontana M, et al. CYP3A7, CYP3A5, CYP3A4, and ABCB1 genetic polymorphisms, cyclosporine concentration, and dose requirement in transplant recipients. Ther Drug Monit 2008; 30(6): 689–99

    Article  PubMed  CAS  Google Scholar 

  83. Zhao Y, Song M, Guan D, et al. Genetic polymorphisms of CYP3A5 genes and concentrationofthe cyclosporine and tacrolimus. Transplant Proc 2005; 37(1): 178–81

    Article  PubMed  CAS  Google Scholar 

  84. Chu XM, Hao HP, Wang GJ, et al. Influence of CYP3A5 genetic polymorphism on cyclosporine A metabolism and elimination in Chinese renal transplant recipients. Acta Pharmacol Sin 2006; 27(11): 1504–8

    Article  PubMed  CAS  Google Scholar 

  85. Hu YF, Qiu W, Liu ZQ, et al. Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation. Clin Exp Pharmacol Physiol 2006; 33(11): 1093–8

    Article  PubMed  CAS  Google Scholar 

  86. 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(3): 147–54

    Article  PubMed  CAS  Google Scholar 

  87. Min DI, Ellingrod VL, Marsh S, et al. CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit 2004; 26(5): 524–8

    Article  PubMed  CAS  Google Scholar 

  88. 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 2008; 64(11): 1069–84

    Article  PubMed  CAS  Google Scholar 

  89. Chowbay B, Cumaraswamy S, Cheung YB, et al. Genetic polymorphisms in MDR1 and CYP3A4 genes inAsians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics 2003; 13(2): 89–95

    Article  PubMed  CAS  Google Scholar 

  90. Kuzuya T, Kobayashi T, Moriyama N, et al. Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients. Transplantation 2003; 76(5): 865–8

    Article  PubMed  CAS  Google Scholar 

  91. Mai I, Stormer E, Goldammer M, et al. MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients. J Clin Pharmacol 2003; 43(10): 1101–7

    Article  PubMed  CAS  Google Scholar 

  92. Bonhomme-Faivre L, Devocelle A, Saliba F, et al. MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients. Transplantation 2004; 78(1): 21–5

    Article  PubMed  CAS  Google Scholar 

  93. Azarpira N, Aghdaie MH, Behzad-Behbahanie A, et al. Association between cyclosporine concentration and genetic polymorphisms of CYP3A5 and MDR1 during the early stage after renal transplantation. Exp Clin Transplant 2006; 4(1): 416–9

    PubMed  CAS  Google Scholar 

  94. Foote CJ, Greer W, Kiberd BA, et al. MDR1 C3435T polymorphisms correlate with cyclosporine levels in de novo renal recipients. Transplant Proc 2006; 38(9): 2847–9

    Article  PubMed  CAS  Google Scholar 

  95. Fanta S, Niemi M, Jonsson S, et al. Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1 polymorphisms. Pharmacogenet Genomics 2008; 18(2): 77–90

    Article  PubMed  CAS  Google Scholar 

  96. Jiang ZP, Wang YR,XuP, et al. Meta-analysis ofthe effect of MDR1 C3435T polymorphism on cyclosporine pharmacokinetics. Basic Clin Pharmacol Toxicol 2008; 103(5): 433–44

    Article  PubMed  CAS  Google Scholar 

  97. 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(2): 135–40

    Article  PubMed  CAS  Google Scholar 

  98. Herweijer H, Sonneveld P, Baas F, et al. Expression of mdr1 and mdr3 multidrug-resistance genes in human acute and chronic leukemias and association with stimulation of drug accumulation by cyclosporine. J Natl Cancer Inst 1990; 82(13): 1133–40

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  100. 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 

  101. 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 

  102. Tirelli S, Ferraresso M, Ghio L, et al. The effect of CYP3A5 polymorphisms on the pharmacokinetics of tacrolimus in adolescent kidney transplant recipients. Med Sci Monit 2008; 14(5): CR251–4

    PubMed  CAS  Google Scholar 

  103. 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(5): 638–43

    Article  PubMed  Google Scholar 

  104. Macphee IA, 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(4): 499–502

    Article  PubMed  CAS  Google Scholar 

  105. 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 

  106. 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 

  107. Satoh S, Kagaya H, Saito M, et al. Lack of tacrolimus circadian pharmaco-kinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipients. Br J Clin Pharmacol 2008; 65(5): 473–81

    Google Scholar 

  108. Mourad M, Wallemacq P, De Meyer M, et al. The influence of genetic polymorphisms of cytochrome P450 3A5 and ABCB1 on starting dose- and weight-standardized tacrolimus trough concentrations after kidney transplantation in relationtorenal function. Clin Chem Lab Med 2006; 44(10): 1192–8

    Article  PubMed  CAS  Google Scholar 

  109. 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 

  110. Tada H, Tsuchiya N, Satoh S, et al. Impact of CYP3A5 and MDR1(ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplant Proc 2005; 37(4): 1730–2

    Article  PubMed  CAS  Google Scholar 

  111. Mourad M, Mourad G, Wallemacq P, et al. Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids. Transplantation 2005; 80(7): 977–84

    Article  PubMed  CAS  Google Scholar 

  112. Cheung CY, Op den Buijsch RA, Wong KM, et al. Influence of different allelic variants of the CYP3A and ABCB1 genes on the tacrolimus phar-macokinetic profile of Chinese renal transplant recipients. Pharmaco-genomics 2006; 7(4): 563–74

    CAS  Google Scholar 

  113. 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(8): 1182–7

    Article  PubMed  CAS  Google Scholar 

  114. 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(8): 1233–5

    Article  PubMed  CAS  Google Scholar 

  115. Mai I, Perloff ES, Bauer S, et al. MDR1 haplotypes derived from exons 21 and 26 do not affect the steady-state pharmacokinetics of tacrolimus in renal transplant patients. Br J Clin Pharmacol 2004; 58(5): 548–53

    Article  PubMed  CAS  Google Scholar 

  116. Uesugi M, Masuda S, Katsura T, et al. Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients. Pharmacogenet Genomics 2006; 16(2): 119–27

    Article  PubMed  CAS  Google Scholar 

  117. Li D, Lu W, Zhu JY, et al. Population pharmacokinetics of tacrolimus and CYP3A5, MDR1 and IL-10 polymorphisms in adult liver transplant patients. J Clin Pharm Ther 2007; 32(5): 505–15

    Article  PubMed  CAS  Google Scholar 

  118. Fukudo M, Yano I, Masuda S, et al. Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients. Clin Pharmacol Ther 2006; 80(4): 331–45

    Article  PubMed  CAS  Google Scholar 

  119. Li D, Zhu JY, Gao J, et al. Polymorphisms of tumor necrosis factor-alpha, interleukin-10, cytochrome P450 3A5 and ABCB1 in Chinese liver transplant patients treated with immunosuppressant tacrolimus. Clin Chim Acta 2007; 383(1–2): 133–9

    Article  PubMed  CAS  Google Scholar 

  120. 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(7): 471–8

    Article  PubMed  CAS  Google Scholar 

  121. Weilin W, Jing J, Shusen Z, et al. Tacrolimus dose requirement in relation to donor and recipient ABCB1 and CYP3A5 gene polymorphisms in Chinese liver transplant patients. Liver Transpl 2006; 12(5): 775–80

    Article  Google Scholar 

  122. 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 

  123. 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 

  124. Yu S, Wu L, Jin J, et al. Influence of CYP3A5 gene polymorphisms of donor rather than recipient to tacrolimus individual dose requirement in liver transplantation. Transplantation 2006; 81(1): 46–51

    Article  PubMed  CAS  Google Scholar 

  125. Suzuki Y, Homma M, Doki K, et al. Impact of CYP3A5 genetic polymorphism on pharmacokinetics of tacrolimus in healthy Japanese subjects. Br J Clin Pharmacol 2008; 66(1): 154–5

    Article  PubMed  CAS  Google Scholar 

  126. Choi JH, Lee YJ, Jang SB, et al. Influence of the CYP3A5 and MDR1 genetic polymorphisms on the pharmacokinetics of tacrolimus in healthy Korean subjects. Br J Clin Pharmacol 2007; 64(2): 185–91

    Article  PubMed  CAS  Google Scholar 

  127. Haufroid V, Wallemacq P, VanKerckhove V, et al. CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study. Am J Transplant 2006; 6(11): 2706–13

    Article  PubMed  CAS  Google Scholar 

  128. MacPhee IA, Fredericks S, Holt DW. Does pharmacogenetics have the potential to allow the individualisation of immunosuppressive drug dosing in organ transplantation?. Expert Opin Pharmacother 2005; 6(15): 2593–605

    Article  PubMed  CAS  Google Scholar 

  129. 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 

  130. Macphee IA, Fredericks S, Tai T, et al. Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement. Transplantation 2002; 74(11): 1486–9

    Article  PubMed  CAS  Google Scholar 

  131. Anglicheau D, Flamant M, Schlageter MH, et al. Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation. Nephrol Dial Transplant 2003; 18(11): 2409–14

    Article  PubMed  CAS  Google Scholar 

  132. Wang J, Zeevi A, McCurry K, et al. Impact of ABCB1 (MDR1) haplotypes on tacrolimus dosing in adult lung transplant patients who are CYP3A5 *3/*3 non-expressors. Transpl Immunol 2006; 15(3): 235–40

    Article  PubMed  CAS  Google Scholar 

  133. Fukushima-Uesaka H, Saito Y, Watanabe H, et al. Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population. Hum Mutat 2004; 23(1): 100

    Article  PubMed  Google Scholar 

  134. Zeng Y, He YJ, He FY, et al. Effect of bifendate on the pharmacokinetics of cyclosporine in relation to the CYP3A4*18B genotype in healthy subjects. Acta Pharmacol Sin 2009; 30(4): 478–84

    Article  PubMed  CAS  Google Scholar 

  135. Hu YF, Tu JH, Tan ZR, et al. Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects. Xenobiotica 2007; 37(3): 315–27

    Article  PubMed  CAS  Google Scholar 

  136. Daly AK. Significance of the minor cytochrome P450 3A isoforms. Clin Pharmacokinet 2006; 45(1): 13–31

    Article  PubMed  CAS  Google Scholar 

  137. Sim SC, Edwards RJ, Boobis AR, et al. CYP3A7 protein expression is high in a fraction of adult human livers and partially associated with the CYP3A7*1C allele. Pharmacogenet Genomics 2005; 15(9): 625–31

    Article  PubMed  CAS  Google Scholar 

  138. Williams JA, Ring BJ, Cantrell VE, et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos 2002; 30(8): 883–91

    Article  PubMed  CAS  Google Scholar 

  139. Burk O, Tegude H, Koch I, et al. Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine. J Biol Chem 2002; 277(27): 24280–8

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  141. 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 

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Acknowledgements

C. Staatz is currently supported by a Lions Medical Research Fellowship. This research was 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.

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

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

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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 I. Clin Pharmacokinet 49, 141–175 (2010). https://doi.org/10.2165/11317350-000000000-00000

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