A New Donors' and Recipients' Cluster Predicting Tacrolimus Disposition, and New-onset Hypertension in Chinese Liver Transplant Patients

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Oct 21

PMID 29050276

Authors

Yuan Liu

Tao Zhang

Xiaoqing Zhang

Ling Ye

Haitao Gu

Lin Zhong

Hongcheng Sun

Chenlong Song

Zhihai Peng

Junwei Fan

Affiliations

Soon will be listed here.

Abstract

Aim: The purpose of the current study was to investigate individualized therapy of tacrolimus (Tac), as well as complications after liver transplantation (LT) with the known genetic determinants and clinical factors.

Methods: In this retrospective study, two cohorts (n=170) from the China Liver Transplant Registry (CLTR) database from July 2007 to March 2015 were included.

Results: Both donors' *3 and recipients' *1G had a correlation with Tac pharmacokinetics at four weeks (all <0.05), except recipients' *1G nearly had an association at week 2 (=0.055). The model of donors' *3, recipients' , and total bilirubin (TBL), for the prediction of Tac disposition, was better than donors' *3 only at week 1, 2, and 3 (=0.010, =0.007, and =0.010, respectively), but not apparent at week 4 (=0.297). Besides, when the value was greater than or equal to 0.6685 after considering the false-positive rate R=10%, the patients were considered to have a faster metabolism, according to the mentioned model. Interestingly, we found that if more than or equal to two alleles A were present in the combination of donors' *3 and recipients' *1G genotype, there was a lower Tac C/D ration at week 1, 2, and 3 (<0.001, =0.001, and <0.001), except at week 4 (=0.082), and the probability of new-onset hypertension was lesser (<0.001).

Conclusions: These data provided a potential basis for a comprehensive approach to predicting the Tac dose requirement in individual patients and provided a strategy for the effective prevention, early diagnosis of new-onset hypertension in Chinese LT recipients.

References

Hustert E, Haberl M, Burk O, Wolbold R, He Y, Klein K . The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics. 2001; 11(9):773-9. DOI: 10.1097/00008571-200112000-00005. View

McCarty M . Serum bilirubin may serve as a marker for increased heme oxygenase activity and inducibility in tissues--a rationale for the versatile health protection associated with elevated plasma bilirubin. Med Hypotheses. 2013; 81(4):607-10. DOI: 10.1016/j.mehy.2013.07.013. View

Paine M, Hart H, Ludington S, Haining R, Rettie A, Zeldin D . The human intestinal cytochrome P450 "pie". Drug Metab Dispos. 2006; 34(5):880-6. PMC: 2222892. DOI: 10.1124/dmd.105.008672. View

Almeida-Paulo G, Dapia Garcia I, Lubomirov R, Borobia A, Alonso-Sanchez N, Espinosa L . Weight of ABCB1 and POR genes on oral tacrolimus exposure in CYP3A5 nonexpressor pediatric patients with stable kidney transplant. Pharmacogenomics J. 2017; 18(1):180-186. DOI: 10.1038/tpj.2016.93. View

Andreu F, Colom H, Elens L, van Gelder T, van Schaik R, Hesselink D . A New CYP3A5*3 and CYP3A4*22 Cluster Influencing Tacrolimus Target Concentrations: A Population Approach. Clin Pharmacokinet. 2017; 56(8):963-975. DOI: 10.1007/s40262-016-0491-3. View

Starzl T, Fung J . Themes of liver transplantation. Hepatology. 2010; 51(6):1869-84. PMC: 4507423. DOI: 10.1002/hep.23595. View

Hesselink D, Bouamar R, Elens L, van Schaik R, van Gelder T . The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2013; 53(2):123-39. DOI: 10.1007/s40262-013-0120-3. View

Staatz C, Tett S . Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004; 43(10):623-53. DOI: 10.2165/00003088-200443100-00001. View

Gijsen V, Mital S, van Schaik R, Soldin O, Soldin S, van der Heiden I . Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients. J Heart Lung Transplant. 2011; 30(12):1352-9. PMC: 3640375. DOI: 10.1016/j.healun.2011.08.001. View

10.

Fan J, Zhang X, Ren L, Chen D, Wu S, Guo F . Donor IL-18 rs5744247 polymorphism as a new biomarker of tacrolimus elimination in Chinese liver transplant patients during the early post-transplantation period: results from two cohort studies. Pharmacogenomics. 2015; 16(3):239-50. DOI: 10.2217/pgs.14.166. View

11.

Du J, Yu L, Wang L, Zhang A, Shu A, Xu L . Differences in CYP3A41G genotype distribution and haplotypes of CYP3A4, CYP3A5 and CYP3A7 in 3 Chinese populations. Clin Chim Acta. 2007; 383(1-2):172-4. DOI: 10.1016/j.cca.2007.04.027. View

12.

Debette-Gratien M, Woillard J, Picard N, Sebagh M, Loustaud-Ratti V, Sautereau D . Influence of Donor and Recipient CYP3A4, CYP3A5, and ABCB1 Genotypes on Clinical Outcomes and Nephrotoxicity in Liver Transplant Recipients. Transplantation. 2016; 100(10):2129-2137. DOI: 10.1097/TP.0000000000001394. View

13.

Du J, Xing Q, Xu L, Xu M, Shu A, Shi Y . Systematic screening for polymorphisms in the CYP3A4 gene in the Chinese population. Pharmacogenomics. 2006; 7(6):831-41. DOI: 10.2217/14622416.7.6.831. View

14.

Zhang X, Wang Z, Fan J, Liu G, Peng Z . Impact of interleukin-10 gene polymorphisms on tacrolimus dosing requirements in Chinese liver transplant patients during the early posttransplantation period. Eur J Clin Pharmacol. 2011; 67(8):803-13. DOI: 10.1007/s00228-011-0993-8. View

15.

Fukushima-Uesaka H, Saito Y, Watanabe H, Shiseki K, Saeki M, Nakamura T . Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population. Hum Mutat. 2003; 23(1):100. DOI: 10.1002/humu.9210. View

16.

Thervet E, Loriot M, Barbier S, Buchler M, Ficheux M, Choukroun G . Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther. 2010; 87(6):721-6. DOI: 10.1038/clpt.2010.17. View

17.

Staatz C, Goodman L, Tett S . Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin Pharmacokinet. 2010; 49(3):141-75. DOI: 10.2165/11317350-000000000-00000. View

18.

Kuypers D, de Jonge H, Naesens M, Lerut E, Verbeke K, Vanrenterghem Y . CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin Pharmacol Ther. 2007; 82(6):711-25. DOI: 10.1038/sj.clpt.6100216. View

19.

Meng X, Guo C, Feng G, Zhao Y, Zhou B, Han J . Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China. Acta Pharmacol Sin. 2012; 33(12):1563-70. PMC: 4001839. DOI: 10.1038/aps.2012.136. View

20.

Muraoka K, Fujimoto K, Sun X, Yoshioka K, Shimizu K, Yagi M . Immunosuppressant FK506 induces interleukin-6 production through the activation of transcription factor nuclear factor (NF)-kappa(B). Implications for FK506 nephropathy. J Clin Invest. 1996; 97(11):2433-9. PMC: 507328. DOI: 10.1172/JCI118690. View