CYP3A5 genotypes affect tacrolimus pharmacokinetics and infectious complications in Chinese pediatric liver transplant patients
Feng Xue
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
These authors contributed equally to this paper.Search for more papers by this authorLongzhi Han
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
These authors contributed equally to this paper.Search for more papers by this authorYikuan Chen
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Search for more papers by this authorZhifeng Xi
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Search for more papers by this authorQigen Li
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Search for more papers by this authorNing Xu
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Search for more papers by this authorYun Xia
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Search for more papers by this authorKatie Streicher
Translational Science Department, MedImmune, Gaithersburg, MD, USA
Search for more papers by this authorCorresponding Author
Jianjun Zhang
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Jianjun Zhang and Qiang Xia, Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, 1630 Dong-fang Road, Shanghai 200127, China
Tel.: +86-21-6838-3775
Fax: +86-21-5873-7232
E-mails: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Qiang Xia
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Jianjun Zhang and Qiang Xia, Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, 1630 Dong-fang Road, Shanghai 200127, China
Tel.: +86-21-6838-3775
Fax: +86-21-5873-7232
E-mails: [email protected]; [email protected]
Search for more papers by this authorFeng Xue
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
These authors contributed equally to this paper.Search for more papers by this authorLongzhi Han
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
These authors contributed equally to this paper.Search for more papers by this authorYikuan Chen
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Search for more papers by this authorZhifeng Xi
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Search for more papers by this authorQigen Li
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Search for more papers by this authorNing Xu
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Search for more papers by this authorYun Xia
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Search for more papers by this authorKatie Streicher
Translational Science Department, MedImmune, Gaithersburg, MD, USA
Search for more papers by this authorCorresponding Author
Jianjun Zhang
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Jianjun Zhang and Qiang Xia, Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, 1630 Dong-fang Road, Shanghai 200127, China
Tel.: +86-21-6838-3775
Fax: +86-21-5873-7232
E-mails: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Qiang Xia
Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
Jianjun Zhang and Qiang Xia, Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, 1630 Dong-fang Road, Shanghai 200127, China
Tel.: +86-21-6838-3775
Fax: +86-21-5873-7232
E-mails: [email protected]; [email protected]
Search for more papers by this authorAbstract
Little information is available regarding the impact of cytochrome P450 (CYP) 3A5 on the metabolism of TAC in infant LTx. Therefore, the CYP3A5 genotype of Chinese pediatric recipients (intestine) as well as donors (graft liver) was performed for the purpose of establishing an optimal dosage regimen in children. Sixty-four patients were divided according to CYP3A5 genotype (expression of *1 allele: EX and NEX) for each recipient (R) and donor (D), EX-R/EX-D (n = 21), EX-R/NEX-D (n = 8), NEX-R/EX-D (n = 8) and NEX-R/NEX-D (n = 27). Results indicated that initial TAC daily dose requirement was higher among EX-R/EX-D children compared with those who did not express CYP3A5 (0.28 ± 0.10 vs. 0.19 ± 0.08 mg/kg/day, p < 0.01). CYP3A5 expression contributed an overall of 38.35% to its C/D ratios, and graft liver was a key determinant. Additionally, the EX-R/EX-D group showed significantly higher incidence of infectious complications, lower immune response and was an independent risk factor for the development of infections (odds ratio 3.86, p = 0.025). Donor CYP3A5 expression partially explains TAC dose requirement, the effect of CYP3A5 variation may influence clinical outcomes; therefore, monitoring immune response may be important for preventing risks associated with under- and over-immunosuppression.
References
- 1Penninga L, Møller CH, Gustafsson F, Steinbrüchel DA, Gluud C. Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: Systematic review with meta-analyses and trial sequential analyses of randomised trials. Eur J Clin Pharmacol 2010: 66: 1177–1187. Review.
- 2Kim JS, Aviles DH, Silverstein DM, Leblanc PL, Matti Vehaskari V. Effect of age, ethnicity, and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients. Pediatr Transplant 2005: 9: 162–169.
- 3Kausman JY, Patel B, Marks SD. Standard dosing of tacrolimus leads to overexposure in pediatric renal transplantation recipients. Pediatr Transplant 2008: 12: 329–335.
- 4Ferraris JR, Argibay PF, Costa L, et al. Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: Age dependency and pharmacological interaction with steroids. Pediatr Transplant 2011: 15: 525–532.
- 5Gijsen 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: 1352–1359.
- 6Iwasaki K. Metabolism of tacrolimus (FK506) and recent topics in clinical pharmacokinetics. Drug Metab Pharmacokinet 2007: 22: 328–335. Review.
- 7Kuehl 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: 383–391.
- 8MacPhee 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: 499–502.
- 9MacPhee 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: 914–919.
- 10Min SI, Kim SY, Ahn SH, et al. CYP3A5 *1 allele: Impacts on early acute rejection and graft function in tacrolimus-based renal transplant recipients. Transplantation 2010: 90: 1394–1400.
- 11Cho JH, Yoon YD, Park JY, et al. Impact of cytochrome P450 3A and ATP-binding cassette subfamily B member 1 polymorphisms on tacrolimus dose-adjusted trough concentrations among Korean renal transplant recipients. Transplant Proc 2012: 44: 109–114.
- 12Gijsen VM, Madadi P, Dube MP, Hesselink DA, Koren G, de Wildt SN. Tacrolimus-induced nephrotoxicity and genetic variability: A review. Ann Transplant 2012: 17: 111–121. Review.
- 13Fukudo 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: 413–423.
- 14Muraki Y, Usui M, Isaji S, et al. Impact of CYP3A5 genotype of recipients as well as donors on the tacrolimus pharmacokinetics and infectious complications after living-donor liver transplantation for Japanese adult recipients. Ann Transplant 2011: 16: 55–62.
- 15Wei-lin W, Jing J, Shu-sen 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: 775–780.
- 16Li L, Li CJ, Zheng L, et al. Tacrolimus dosing in Chinese renal transplant recipients: A population-based pharmacogenetics study. Eur J Clin Pharmacol 2011: 67: 787–795.
- 17Xue F, Zhang J, Han L, et al. Immune cell functional assay in monitoring of adult liver transplantation recipients with infection. Transplantation 2010: 89: 620–626.
- 18Kowalski RJ, Post DR, Mannon RB, et al. Assessing relative risks of infection and rejection: A meta-analysis using an immune function assay. Transplantation 2006: 82: 663–668.
- 19Uesugi M, Masuda S, Katsura T, Oike F, Takada Y, Inui K. Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients. Pharmacogenet Genomics 2006: 16: 119–127.
- 20Tang XY, Xia Q, Zhang JJ, et al. Metabolic characteristics and usage of tacrolimus in patients subject to living-donor partial liver transplantation. Chin J Organ Transplant 2010: 31: 749–752.
- 21Fukudo 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: 331–345.
- 22Blake MJ, Castro L, Leeder JS, Kearns GL. Ontogeny of drug metabolizing enzymes in the neonate. Semin Fetal Neonatal Med 2005: 10: 123–138. Review.
- 23Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med 2003: 349: 1157–1167. Review.
- 24Zuo XC, 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 Genomics 2013: 23: 251–261.
- 25Hesselink 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: 339–348.
- 26Satoh S, Saito M, Inoue T, et al. CYP3A5 *1 allele associated with tacrolimus trough concentrations but not subclinical acute rejection or chronic allograft nephropathy in Japanese renal transplant recipients. Eur J Clin Pharmacol 2009: 65: 473–481.
- 27Alak AM, Moy S. Biological activity of tacrolimus (FK506) and its metabolites from whole blood of kidney transplant patients. Transplant Proc 1997: 29: 2487–2490.
- 28Kuypers DR, Naesens M, de Jonge H, Lerut E, Verbeke K, Vanrenterghem Y. 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.
- 29Mizuno S, Hamada T, Nakatani K, et al. Monitoring peripheral blood CD4+ adenosine triphosphate activity after living donor liver transplantation: Impact of combination assays of immune function and CYP3A5 genotype. J Hepatobiliary Pancreat Sci 2011: 18: 226–232; discussion 232-4.
Citing Literature
