Abstract
Background: Cytochrome P450 3A5 (CYP3A5) and ABCB1 polymorphisms have been shown to influence tacrolimus (Tc) blood concentrations in the stable phase after organ transplantation. We hypothesized that Tc pharmacokinetics may be affected by genetic mutations subsequent to starting doses.
Methods: We retrospectively analyzed data from a cohort of 59 kidney transplant recipients, in whom CYP3A5 (intron 3) and ABCB1 (exons 12, 21 and 26) genotypes were correlated to dose- and weight-standardized Tc trough concentrations obtained after initial Tc doses. Renal function, expressed as glomerular filtration rate (GFR) (MDRD equation), on days 7 and 14 after transplantation was evaluated and its relationship with Tc concentrations was analyzed.
Results: Dose- and weight-standardized Tc trough concentrations were lower in patients carrying the CYP3A5 *1 allele (p<0.01). There was no statistically significant association with ABCB1 polymorphisms. In a multivariate analysis, both the presence of at least one CYP3A5 *1 allele (p=0.006) and age at the time of transplantation (p=0.010) were significant independent variables affecting Tc trough blood concentrations standardized to the first dosages (model r2=0.23). GFR was not affected by Tc concentrations.
Conclusions: Prospective trials are needed to prove that a genetic approach to Tc pharmacokinetics and its related side effects during the early period after grafting may improve patient outcome.
Clin Chem Lab Med 2006;44:1192–8.
References
1. Venkataramanan R, Swaminathan A, Prasad T, Jain A, Zuckerman S, Warty V, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 1995; 29:404–30.10.2165/00003088-199529060-00003Search in Google Scholar
2. Sattler M, Guengerich FP, Yun CH, Christians U, Sewing KF. Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos 1992; 20:753–61.Search in Google Scholar
3. Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T. P-glycoprotein transports cyclosporin A and FK506. J Biol Chem 1993; 268:6077–80.10.1016/S0021-9258(18)53221-XSearch in Google Scholar
4. Haufroid V, Mourad M, Van Kerckhove V, Wawrzyniak J, De Meyer M, Chaib Eddour D, 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; 14:147–54.10.1097/00008571-200403000-00002Search in Google Scholar
5. MacPhee IA, Fredericks S, Tai T, Syrris P, Carter ND, Johnston A, et al. Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome P450A5 and P-glycoprotein correlate with dose requirement. Transplantation 2002; 74:1486–9.10.1097/00007890-200212150-00002Search in Google Scholar
6. Zheng HX, Webber S, Zeevi A, Schuetz E, Zhang J, Bowman P, et al. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant 2003; 3:477–83.10.1034/j.1600-6143.2003.00077.xSearch in Google Scholar
7. Thervet E, Anglicheau D, King B, Schlageter MH, Cassinat B, Beaune P, et al. Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 2003; 76:1233–5.10.1097/01.TP.0000090753.99170.89Search in Google Scholar
8. Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003; 74:245–54.10.1016/S0009-9236(03)00168-1Search in Google Scholar
9. MacPhee IA, Fredericks S, Tai T, Syrris P, Carter ND, Johnston A, et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant 2004; 4:914–9.10.1111/j.1600-6143.2004.00435.xSearch in Google Scholar PubMed
10. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130:461–70.10.7326/0003-4819-130-6-199903160-00002Search in Google Scholar PubMed
11. Wallemacq PE, Leal T, Besse T, Squifflet JP, Reding R, Otte JB, et al. IMx tacrolimus II vs. IMx tacrolimus microparticle enzyme immunoassay evaluated in renal and hepatic transplant patients. Clin Chem 1997; 43:1989–91.10.1093/clinchem/43.10.1989Search in Google Scholar
12. Goto M, Masuda S, Kiuchi T, Ogura Y, Oike F, Okuda M, et al. CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation. Pharmacogenetics 2004; 14:471–8.10.1097/01.fpc.0000114747.08559.49Search in Google Scholar PubMed
13. Goto M, Masuda S, Saito H, Uemoto S, Kiuchi T, Tanaka K, et al. C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. Pharmacogenetics 2002; 12:451–7.10.1097/00008571-200208000-00005Search in Google Scholar PubMed
14. Anglicheau D, Vertuyft C, Laurent-Puig P, Becquemont L, Schlageter MH, Cassinat B, et al. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol 2003; 14:1889–96.10.1097/01.ASN.0000073901.94759.36Search in Google Scholar PubMed
15. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, 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; 97:3473–8.10.1073/pnas.97.7.3473Search in Google Scholar PubMed PubMed Central
16. Tanabe M, Ieiri I, Nagata N, Inoue K, Ito S, Kanamori Y, 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; 297:1137–43.Search in Google Scholar
17. Yamauchi A, Ieiri I, Kataoka Y, Tanabe M, Nishizaki T, Oishi R, et al. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002; 74:571–3.10.1097/00007890-200208270-00024Search in Google Scholar PubMed
18. MacPhee IA, Fredericks S, Mohamed M, Moreton M, Carter ND, Johnston A, et al. Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in Whites and south Asians. Transplantation 2005; 79:499–502.10.1097/01.TP.0000151766.73249.12Search in Google Scholar PubMed
19. Moutabarrik A, Ishibashi M, Fukunaga M, Kameoka H, Kawaguchi N, Takano Y, et al. FK506-induced kidney tubular cell injury. Transplantation 2002; 54:1041–7.10.1097/00007890-199212000-00018Search in Google Scholar PubMed
20. Hebert MF, Dowling AL, Gierwatowski C, Lin YS, Edwards KL, Davis CL, et al. Association between ABCB1 (multidrug resistance transporter) genotype and post-liver transplantation renal dysfunction in patients receiving calcineurin inhibitors. Pharmacogenetics 2003; 13:661–74.10.1097/00008571-200311000-00002Search in Google Scholar PubMed
21. Anglicheau D, Le Corre D, Lechaton S, Laurent-Puig P, Kreis H, Beaune P, et al. Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy. Am J Transplant 2005; 5:595–603.10.1111/j.1600-6143.2005.00745.xSearch in Google Scholar PubMed
©2006 by Walter de Gruyter Berlin New York
