Background: Tacrolimus pharmacokinetics has large inter-individual variability. Objectives: This study aimed to investigate the impact of donor and recipient gene polymorphisms on tacrolimus dosing and pharmacokinetics in Asian liver transplant patients.Methods:Steady-statetacrolimus concentrations at 0, 1, 2, 4 and 6 h were measured. Pharma- cokinetic parameters were estimated with a one-compartment linear model using WinNonlin 6.1 program. DNA from donor liver and recipient blood samples were genotyped for CYP3Aand ABCB1 polymorphisms. Results:A total of 13 donors and 17 recipients were included. Donor genotypes influenced tacrolimus trough concentration-to-dose (C0/D) ratio only at Week 1. Patients with liver grafts from CYP3A5 expressors (*1*1 and *1*3) achieved lower mean C0/D ratio than those with grafts from non-expressors (*3*3) (64.48 versus 129.21(mcg/L)/(mg/kg/day), P=0.040). Hence, the dose required to achieve target concentration in patients with donor genotype CYP3A5 expressors was higher than non-expressors (0.12 versus 0.08 mg/kg, P=0.045). Recipient with ABCB1-C3435T genotype TT demonstrated higher apparent oral clearance of tacrolimus as compared to genotype CC (17.7 versus7.9 L/h, P=0.033).Conclusions:Donor liverCYP3Apolymorphism could potentially affect tacrolimus C0/D ratio as early as the first week post liver transplant. Genotyping of liver donors may be useful to achieve the optimal drug concentration during this critical period.
References
[1]
The US Multicenter FK506 Liver Study Group, “A Comparison of Tacrolimus (FK 506) and Cyclosporine for Immunosuppression in Liver Transplantation,” The New England Journal of Medicine, Vol. 331, No. 17, 1994, pp. 1110-1115.
[2]
European FK506 Multicenter Liver Study Group, “Randomised Trial Comparing Tacrolimus (FK506) and Cycloporin in Prevention of Liver Allograft Rejection,” Lancet, Vol. 344, No. 8920, 1994, pp. 423-428.
doi:10.1016/S0140-6736(94)91766-3
[3]
J. J. Fung, M. Eliasziw, S. Todo et al., “The Pittsburgh Randomized Trial of Tacrolimus Compared to Cyclosporine for Hepatic Transplantation,” Journal of the American College of Surgeons, Vol. 183, No. 2, 1996, pp. 117-125.
[4]
D. Li, W. Lu, J.-Y. Zhu, et al., “Population Pharmacokinetic of Tacrolimus and CYP3A5, MDR1 and IL-10 Polymorphisms in Adult Liver Transplant Patients,” Journal of Clinical Pharmacy and Therapeutics, Vol. 32, No. 5, 2007, pp. 505-515.
doi:10.1111/j.1365-2710.2007.00850.x
[5]
M. Goto, S. Masuda, T. Kiuchi, et al., “CYP3A5*1-Carrying Graft Liver Reduces the Concentration/Oral Dose Ratio of Tacrolimus in Recipients of Living-Donor Liver Transplantation,” Pharmacogenetics, Vol. 14, No. 7, 2004, pp. 471-478. doi:10.1097/01.fpc.0000114747.08559.49
[6]
S. F. Yu, L. H. Wu, J. Jin, et al., “Influence of CYP3A5 Gene Polymorphisms of Donor Rather Than Recipient to Tacrolimus Individual Dose Requirement in Liver Transplantation,” Transplantation, Vol. 81, No. 1, 2006, pp. 46-51. doi:10.1097/01.tp.0000188118.34633.bf
[7]
E. Laure, C. Arnaud, V. K. Valerie, et al., “1199G > A and 2677G > T/A Polymorphisms of ABCB1 Independently Affect Tacrolimus Concentration in Hepatic Tissue after Liver Transplantation,” Pharmacogenetics and Genomics, Vol. 17, No. 10, 2007, pp. 873-883.
[8]
P. T. Loh, H. X. Lou, Y. Zhao, et al., “Significant Impact of Gene Polymorphisms on Tacrolimus But Not Cyclosporine Dosing in Asian Renal Transplant Recipients,” Transplantation Proceedings, Vol. 40, No. 5, 2008, pp. 1690-1695. doi:10.1016/j.transproceed.2008.04.010
[9]
K. R. Jun, W. C. Lee, M. S. Jang, et al., “Tacrolimus Concentrations in Relation to CYP3A and ABCB1 Polymorphisms among Solid Organ Transplant Recipient in Korea,” Transplantation, Vol. 87, No. 8, 2009, pp. 1225-1231. doi:10.1097/TP.0b013e31819f117e
[10]
T. Eric, A. Dany, K. Barry, et al., “Impact of Cytochrome P450 3A5 Genetic Polymorpisms on Tacrolimus Doses and Concentration-to-Dose Ratio in Renal Transplant Recipients,” Transplantation, Vol. 76, No. 8, 2003, pp. 1233-1235.
[11]
H. Zahir, A. J. McLachlan, A. Nelson, et al., “Population Pharmacokinetic Estimation of Tacrolimus Apparent Clearance in Adult Liver Transplant Recipients,” Therapeutic Drug Monitoring, Vol. 27, No. 4, 2005, pp. 422-430. doi:10.1097/01.ftd.0000170029.36573.a0
[12]
V. Mardigyan, J. Tchervenkov, P. Metrakos, et al., “Best Single Time Points as Surrogates to the Tacrolimus and Mycophenolic Acid Area under the Curve in Adult Liver Transplant Patients Beyond 12 Months of Transplantation,” Clinical Therapeutics, Vol. 27, No. 4, 2005, pp. 463-468. doi:10.1016/j.clinthera.2005.04.004
[13]
M. Cantarovich, J. Fridell, J. Barkun, et al., “Optimal Time Points for the Prediction of the Area-Under-The-Curve in Liver Transplant Patients Receiving Tacrolimus,” Transplantation Proceedings, Vol. 30, No. 4, 1998, pp. 1460-1461. doi:10.1016/S0041-1345(98)00315-7
[14]
A. Jain, R. Venkataramanan, R. Sharma, et al., “Pharmacokinetics of Tacrolimus in Living Donor Liver Transplant and Deceased Donor Liver Transplant Recipients,” Transplantation, Vol. 85, No. 4, 2008, pp. 554-560.
doi:10.1097/TP.0b013e3181642c95
[15]
IMx “Tacrolimus II Package Insert,” Abbott Laboratories, Diagnostic Division, Revised September 2007.
[16]
D. I. Min, H. Y. Chen, A. Fabrega, et al., “Circadian Variation of Tacrolimus Disposition in Liver Allograft Recipients,” Transplantation, Vol. 62, No. 8, 1996, pp. 1190-1192. doi:10.1097/00007890-199610270-00031
[17]
R. Venkataramanan, A. Swaminathan, T. Prasad, et al., “Clinical Pharmacokinetics of Tacrolimus,” Clinical Pharmacokinetics, Vol. 29, No. 6, 1995, pp. 404-30.
doi:10.2165/00003088-199529060-00003
[18]
G. Plosker and R. Foster, “Tacrolimus—A Further Update of its Pharmacology and Therapeutic Use in the Management of Organ Transplantation,” Drugs, Vol. 59, No. 2, 2000, pp. 323-389.
doi:10.2165/00003495-200059020-00021
[19]
W. J. Sam, L. S. Tham, M. J. Holmes, et al., “Population Pharmacokinetics of Tacrolimus in Whole Blood and Plasma in Asian Liver Transplant Patients,” Clinical Pharmacokinetics, Vol. 45, No. 1, 2006, pp. 59-75.
doi:10.2165/00003088-200645010-00004
[20]
J. Y. Lee, H. J. Hahn, I. J. Son, et al., “Factors Affecting the Apparent Clearance of Tacrolimus in Korean Adult Liver Transplant Recipients,” Pharmacotherapy, Vol. 26, No. 8, 2006, pp. 1067-1077.
[21]
H. Zahir, G. McCaughan, M. Gleeson, et al., “Factors Affecting Variability in Distribution of Tacrolimus in Liver Transplant Recipients,” British Journal of Clinical Pharmacology, Vol. 57, No. 3, 2004, pp. 298-309.
[22]
R. Domiati-Saad, G. B. Klintmalm, G. Netto, et al., “Acute Graft versus Host Disease after Liver Transplantation: Patterns of Lymphocyte Chimerism,” American Journal of Transplantation, Vol. 5, No. 12, 2005, pp. 2968-2973.
doi:10.1111/j.1600-6143.2005.01110.x
[23]
T. E. Starzl, “Chimerism and Tolerance in Transplantation,” Proceedings of the National Academy of Sciences, Vol. 101, Suppl. 2, 5 October 2004, pp. 14607-14614.
