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The Effects of CYP3A5 Genetic Polymorphisms on Serum Tacrolimus Dose-Adjusted Concentrations and Long-Term Prognosis in Chinese Heart Transplantation Recipients

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients.

Methods

We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality.

Results

In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A5*3/*3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A5*1/*3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan–Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314).

Conclusions

CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.

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Acknowledgements

Establishment of a Scientific Registration System for Heart Transplantation in China (2011-wy1A).

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Author notes

  1. Bing-yang Liu and Wen-qian Chen contributed equally.

Authors and Affiliations

  1. Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 167 North Lishi Road, Xicheng District, Beijing, 100037, China

    Bing-yang Liu, Wen-qian Chen, Jie Huang, Zhong-kai Liao, Qing Liu, Zhe Zheng, Yun-hu Song, Wei Wang & Sheng-shou Hu

  2. Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China

    Zhi-gao Chen

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  1. Bing-yang Liu
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  2. Wen-qian Chen
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  4. Jie Huang
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  5. Zhong-kai Liao
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Corresponding author

Correspondence to Jie Huang.

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Funding

This study was supported by the ‘Establishment of a Scientific Registration System for Heart Transplantation in China’ program (2011-wy1A).

Conflict of Interest

The authors report no relationships that could be construed as a conflict of interest.

Ethics Approval

All procedures in this study were in accordance with the 1964 Helsinki declaration and its amendments, and have got approval of the Ethics Committee of Fuwai Hospital.

Informed Consent

Written informed consent was obtained from patients, parents or care givers.

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Liu, By., Chen, Wq., Chen, Zg. et al. The Effects of CYP3A5 Genetic Polymorphisms on Serum Tacrolimus Dose-Adjusted Concentrations and Long-Term Prognosis in Chinese Heart Transplantation Recipients. Eur J Drug Metab Pharmacokinet 44, 771–776 (2019). https://doi.org/10.1007/s13318-019-00563-x

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  • DOI: https://doi.org/10.1007/s13318-019-00563-x

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