Pharmacogenomics and personalized medicine of tacrolimus

Abstract

Abstract: Tacrolimus (FK506), a widely used immunosuppressant, exerts a key effect in patients with organ transplantation. The drug requires therapeutic monitoring due to its narrow therapeutic index and great inter-individual variability. FK506 is known to be a substrate of CYP3A and P-glycoprotein (P-gp) . FK506 is metabolized by CYP3A and transported by P-gp. The difference in expression level and the bioactivity of these proteins may explain individual variations of FK506 pharmacokinetics.The differences in bioactivities of CYP3A and P-gp are believed to be due to CYP3A and MDR1 geneticmutation. Therefore, genetic variations of CYP3A and MDR1 may play an important role in the inter-individual variability of FK506. In this article, we reviewed the effect of CYP3A and MDR1 gene polymorphisms on pharmacokinetics of FK506 in patients with organ transplantation. This article presents an overview of the current research progress of pharmacogenomics of tacrolimus.

Key words: Tacrolimus, Gene polymorphism, CYP3A4, CYP3A5, MDR1

CLC Number:

ZHU Lin, HUA Zhi-hui, SONG Hong-tao. Pharmacogenomics and personalized medicine of tacrolimus[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2011, 16(6): 710-715.

References

[1] Wallemacq PE, Verbeeck PK. Comparative clinical pharmacokimetics of tacrolimus in paediatric and adult patients[J]. Clin Pharmacokinet, 2001, 40(4): 283-295.
[2] Kahan BD, Keown P, Levy GA, et al. Therapeutic drug monitoring of immunosuppressant drug in clinical practice[J]. Clin Atherapeutics, 2002,24(3): 330-350.
[3] 陈业辉,郑克立,陈立中,等. 口服他克莫司血药浓度-时间曲线下面积[J].中华泌尿外科杂志,2004,25(11):750-752.
[4] Kalra BS. Cytochrome P450 enzyme isoforms and their therapeutic implications:an update[J]. Indian J Med Sci, 2007, 61(2): 102-116.
[5] Lamba JK, Lin YS, Schuetz EG, et al. Genetic contribution to variable human CYP3A-mediated metabolism[J]. Adv Drug Deliv Rev, 2002, 54(10): 1271-1294.
[6] Min DI,Ellingrod VL.Association of the CYP3A4^*1B 5'-flanking region polymorphism with cyclosporine pharmacokinetics in healthy subjects[J]. Ther Drug Monit, 2003, 25(3): 305-309.
[7] 周宏灏. 细胞色素P450药物代谢酶的遗传药理学进展[J]. 药理学进展,2000,19(2):87-90.
[8] Hesselink DA, Schaik RH, Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus[J]. Clin Pharmacol Ther, 2003, 74(3): 245-254.
[9] Roy JN, Barama A, Poirier C, et al. CYP3A4, CYP3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients[J]. Pharmacogenet Genomics, 2006, 16(9): 659-665.
[10] 侯明明,侯颖,宋洪涛,等. 肾移植患者CYP3A4基因多态性对他克莫司疗效和不良反应的影响[J]. 中国药房,2010,21(26):2427-2429.
[11] Lin YS, Dowling AL, Quigley SD, et al. Coregulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism[J].Mol Pharmacol, 2002, 62(1): 162-172.
[12] 侯明明,宋洪涛,王庆华,等. 肾移植患者CYP3A5^*3基因多态性对他克莫司血药浓度/剂量比和疗效的影响[J]. 中国医院药学杂志,2010,30(4):313-316.
[13] 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[J]. Transplant Proc, 2010,42(9):3455-3458.
[14] Jun KR, Lee W, Jang M S, et al. Tacrolimus concentrations in relation to CYP3A and ABCB1 polymorphisms among solid organ transplant recipients in Korea[J].Transplantation, 2009, 87(8): 1225-1231.
[15] Macphee IA, Fredericks S, Tai T, et al. Tacrolimusphar-macogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement [J].Transplantation, 2002, 74(11): 1486-1489.
[16] Zhu B, Chen GL, Chen XP, et al. Genotype of CYP3AP1 associated with CYP3A activity in ChineseHan population[J]. Acta Pharmacol Sin, 2002, 23(6): 567-572.
[17] 侯明明,宋洪涛,王庆华,等. 肾移植患者MDR1 C3435T基因多态性对他克莫司血药浓度/剂量比及疗效的影响[J]. 药学实践杂志,2010,28(1):29-31.
[18] Bonhomme FL, Picard V, Saliba F, et al. Effect of the ABCB1 3435C>T polymorphism on tacrolimus concentrations and dosage requirements in liver transplant recipients[J]. Am J Health Syst Pharm, 2009, 66(18): 1645-1651.
[19] Capron A, Mourad M, De MM, et al. CYP3A5 and ABCB1 polymorphisms influence tacrolimus concentrations in peripheral blood mononuclear cells after renal transplantation[J]. Pharmacogenomics, 2010, 11(5): 703-714.
[20] Li D, Zhu JY, Gao J, et al. Polymorphisms of tumor necrosis factor-α, interleukin-10, cytochrome P4503A5 and ABCB1 in Chinese liver transplant patients treated with immunosuppressant tacrolimus[J]. Clinica Chimica Acta, 2007, 383 (1/2) 133-139.
[21] Yamauchi A, Leiri I, Kataoka Y, et a1. Neurotoxicity indiced by tacrolimus after 1iver transplantation: relation to genetic polymorphisms of the ABCB1(MDR1) gene[J]. Transplantation, 2002, 74(4): 571-578.
[22] Wang J, Adriana Z, Kenneth M, et al. Impact of ABCB1 (MDR1) haplotypes on tacrolimus dosing in adult lung transplant patients who are CYP3A5^*3/^*3 nonexpressors[J]. Transplant Immunology, 2006, 15(3): 235-240.
[23] Anglicheau D, Verstuyft C, Laurent PP, et al. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients [J]. J Am Soc Nephrol, 2003, 14(7): 1889-1896.
[24] Haufroid V, Mourad M, Van KV, 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[J]. Pharmacogenetics, 2004, 14(3): 147-154.
[25] 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[J]. Br J Clin Pharmacol, 2004, 58(5): 548-553.
[26] Turner DM, Williams DM, Sankaran D, et al. An investigation of polymorphism in the interleukin-10 gene promoter[J]. Eur J Immunogenet, 1997, 24(1): 1-8.
[27] Warle MC, Metsetselaar HJ, Hop WC, et al. Cytokine gene polymorphisms and acute liver graft rejection: a meta-analysis[J]. Liver Transpl, 2005, 11(1):19-26.
[28] Benkali K, Premaud A, Picard N, et al. Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients[J]. Clin Pharmacokinet, 2009, 48(12): 805-816.
[29] Press RR, Ploeger BA, Den HJ, et al. Explaining variability in tacrolimus pharmacokinetics to optimize early exposure in adult kidney transplant recipients[J].Ther Drug Monit, 2009, 31(2):187-197.
[30] Mendes J, Martinho A, Simoes O, et al. Genetic polymorphisms in CYP3A5 and MDR1 genes and their correlations with plasma levels of tacrolimus and cyclosporine in renal transplant recipients[J]. Transplant Proc, 2009, 41(3): 840-842.
[31] 付绍杰,王彦斌,于立新,等. 肾移植受者他克莫司剂量/浓度个体差异影响因素及其变化规律[J]. 南方医科大学学报,2008,28(12):2161-2164.