Skip to main content

Advertisement

SpringerLink
Log in

Impact of CYP3A5 and CYP3A4 gene polymorphisms on dose requirement of calcineurin inhibitors, cyclosporine and tacrolimus, in renal allograft recipients of North India

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The present study investigated pharmacogenetic associations of common cytochrome P450 3A (CYP3A5 and CYP3A4) polymorphisms with dose requirements of calcineurin inhibitors, cyclosporine (CsA) and tacrolimus (Tac) in renal transplant recipients of North India. Two hundred twenty four patients on CsA and 73 patients on Tac-based immunosuppression regimen were genotyped for CYP3A5*3 (6986A>G) and CYP3A4*1B (-290A>G) and correlated with CsA/Tac dose requirement (mg/kg/day) and dose-adjusted CsA (C2)/Tac (T 0) blood levels (concentration/dose ratio) at 1 month and 3 months posttransplantation. The dose-adjusted levels were significantly lower in CYP3A5 expressers for CsA (p = 0.037; 3 months) and Tac (p < 0.001; 1 month and p < 0.001; 3 months) compared to the non-expressers, suggesting that for a given dose their CsA/Tac blood concentration is lower. The CYP3A5 non-expresser genotype was associated with reduced risk for allograft rejection (HR-0.18, 95% CI 0.03–0.99). No influence of CYP3A4*1B on CsA/Tac pharmacokinetics was observed. CYP3A5 expressers were associated with significantly lower dose-adjusted CsA/Tac concentrations and higher allograft rejection episodes in patients on Tac 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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Ahsan N, Johnson C, Gonwa T et al (2001) Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years. Transplantation 72:245–250

    Article  PubMed  CAS  Google Scholar 

  • Bäckman L, Levy MF, Klintmalm G (1995) Whole-blood and plasma levels of FK 506 after liver transplantation: results from the US Multicenter Trial. FK506 Multicenter Study Group. Transplant Proc 27:1124–1124

    PubMed  Google Scholar 

  • Chou FC, Tzeng SJ, Huang JD (2001) Genetic polymorphism of cytochrome P450 3A5 in Chinese. Drug Metab Dispos 29:1205–1209

    PubMed  CAS  Google Scholar 

  • Dai Y, Hebert MF, Isoherranen N et al (2006) Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab Dispos 34:836–847

    Article  PubMed  CAS  Google Scholar 

  • Dai Y, Iwanaga K, Lin YS et al (2004) In vitro metabolism of cyclosporine A by human kidney CYP3A5. Biochem Pharmacol 68:1889–1902

    Article  PubMed  CAS  Google Scholar 

  • Dunn CJ, Wagstaff AJ, Perry CM, Plosker GL, Goa KL (2001) Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral) 1 in organ transplantation. Drugs 61:1957–2016

    Article  PubMed  CAS  Google Scholar 

  • Eng HS, Mohamed Z, Calne R et al (2006) The influence of CYP3A gene polymorphisms on cyclosporine dose requirement in renal allograft recipients. Kidney Int 69:1858–1864

    Article  PubMed  CAS  Google Scholar 

  • Haufroid V, Mourad M, Van Kerckhove V et al (2004) The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics 14:147–154

    Article  PubMed  CAS  Google Scholar 

  • Haufroid V, Wallemacq P, VanKerckhove V et al (2006) CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study. Am J Transplant 6:2706–2713

    Article  PubMed  CAS  Google Scholar 

  • Hesselink DA, van Schaik RH, van der Heiden IP et al (2003) Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 74:245–254

    Article  PubMed  CAS  Google Scholar 

  • Hu YF, Qiu W, Liu ZQ et al (2006) Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation. Clin Exp Pharmacol Physiol 33:1093–1098

    Article  PubMed  CAS  Google Scholar 

  • Hustert E, Haberl M, Burk O et al (2001) The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 11:773–779

    Article  PubMed  CAS  Google Scholar 

  • Jounaïdi Y, Hyrailles V, Gervot L, Maurel P et al (1996) Detection of CYP3A5 allelic variant: a candidate for the polymorphic expression of the protein? Biochem Biophys Res Commun 221:466–470

    Article  PubMed  Google Scholar 

  • Kahan BD, Welsh M, Schoenberg L et al (1996) Variable oral absorption of cyclosporine. A biopharmaceutical risk factor for chronic renal allograft rejection. Transplantation 62:599–606

    Article  PubMed  CAS  Google Scholar 

  • Kamdem LK, Streit F, Zanger UM et al (2005) Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem 51:1374–1381

    Article  PubMed  CAS  Google Scholar 

  • King BP, Leathart JB, Mutch E, Williams FM, Daly AK (2003) CYP3A5 phenotype-genotype correlations in a British population. Br J Clin Pharmacol 55:625–629

    Article  PubMed  CAS  Google Scholar 

  • Kreutz R, Zürcher H, Kain S, Martus P, Offermann G, Beige J (2004) The effect of variable CYP3A5 expression on cyclosporine dosing, blood pressure and long-term graft survival in renal transplant patients. Pharmacogenetics 14:665–671

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Kuehl P, Zhang J, Lin Y et al (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383–391

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lee SJ, Goldstein JA (2005) Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests. Pharmacogenomics 6:357–371

    Article  PubMed  CAS  Google Scholar 

  • Lee SJ, Lee SS, Jeong HE et al (2007) The CYP3A4*18 allele, the most frequent coding variant in Asian populations, does not significantly affect the midazolam disposition in heterozygous individuals. Drug Metab Dispos 35:2095–2101

    Article  PubMed  CAS  Google Scholar 

  • Lown KS, Bailey DG, Fontana RJ et al (1997) Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 99:2545–2553

    Article  PubMed  CAS  Google Scholar 

  • Macphee IA, Fredericks S, Tai T et al (2002) Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement. Transplantation 74:1486–1489

    Article  PubMed  CAS  Google Scholar 

  • Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215–1215

    Article  PubMed  CAS  Google Scholar 

  • Racusen LC, Solez K, Colvin RB et al (1999) The Banff 97 working classification of renal allograft pathology. Kidney Int 55:713–723

    Article  PubMed  CAS  Google Scholar 

  • Rais N, Chawla YK, Kohli KK (2006) CYP3A phenotypes and genotypes in North Indians. Eur J Clin Pharmacol 62:417–422

    Article  PubMed  CAS  Google Scholar 

  • Renders L, Frisman M, Ufer M, Mosyagin I, Haenisch S, Ott U, Caliebe A, Dechant M, Braun F, Kunzendorf U, Cascorbi I (2007) CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients. Clin Pharmacol Ther 81:228–234

    Article  PubMed  CAS  Google Scholar 

  • Rodríguez-Antona C, Sayi JG, Gustafsson LL, Bertilsson L, Ingelman-Sundberg M (2005) Phenotype–genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles. Biochem Biophys Res Commun 338:299–305

    Article  PubMed  Google Scholar 

  • Sattler M, Guengerich FP, Yun CH, Christians U, Sewing KF (1992) Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos 20:753–761

    PubMed  CAS  Google Scholar 

  • Shih PS, Huang JD (2002) Pharmacokinetics of midazolam and 1′-hydroxymidazolam in Chinese with different CYP3A5 genotypes. Drug Metab Dispos 30:1491–1496

    Article  PubMed  CAS  Google Scholar 

  • van Schaik RH, de Wildt SN, van Iperen NM, Uitterlinden AG, van den Anker JN, Lindemans J (2000) CYP3A4-V polymorphism detection by PCR-restriction fragment length polymorphism analysis and its allelic frequency among 199 Dutch Caucasians. Clin Chem 46:1834–1836

    PubMed  Google Scholar 

  • van Schaik RH, van der Heiden IP, van den Anker JN, Lindemans J (2002) CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem 48:1668–1671

    PubMed  Google Scholar 

  • Venkataramanan R, Swaminathan A, Prasad T et al (1995) Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 29:404–430

    Article  PubMed  CAS  Google Scholar 

  • Xie HG, Wood AJ, Kim RB, Stein CM, Wilkinson GR (2004) Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 5:243–272

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

The authors are obliged to the patients and volunteers for providing the blood samples for the study. The funding provided by the Department of Biotechnology, India is hereby fully acknowledged. The authors are thankful to Dr. Aneesh Srivastava, professor, Department of Urology and Renal Transplantation, for providing clinical details of transplant recipients. RS is thankful to the Council of Scientific and Industrial Research India for Senior Research Fellowship.

Author information

Authors and Affiliations

  1. Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India

    Ranjana Singh, Aneesh Srivastava, Rakesh Kapoor & Rama D. Mittal

  2. Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India

    Raj K. Sharma

Authors
  1. Ranjana Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aneesh Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rakesh Kapoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Raj K. Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rama D. Mittal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rama D. Mittal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Singh, R., Srivastava, A., Kapoor, R. et al. Impact of CYP3A5 and CYP3A4 gene polymorphisms on dose requirement of calcineurin inhibitors, cyclosporine and tacrolimus, in renal allograft recipients of North India. Naunyn-Schmied Arch Pharmacol 380, 169–177 (2009). https://doi.org/10.1007/s00210-009-0415-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-009-0415-y

Keywords

Search

Navigation