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Genetic and clinical determinants of mizoribine pharmacokinetics in renal transplant recipients

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Aim

Mizoribine (MZR) is an immunosuppressant for the prevention of allograft rejection in Asian countries, but the great variability in pharmacokinetics (PK) limits its clinical use. This study was to explore genetic and clinical factors that affect the MZR PK process.

Methods

Blood samples and clinical data were collected from 60 Chinese renal transplant recipients. MZR plasma concentration was measured at pre-dose (0 h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 h post-dose by high performance liquid chromatography with an ultraviolet detector. PK parameters were calculated by non-compartmental analysis. High-throughput sequenced single nucleotide polymorphism was applied screening possible genetic factors.

Results

Extensive inter-individual MZR PK differences were reflected in the process of elimination (ke, CL/F, MRT and t1/2) and intestinal absorption (Cmax and Tmax), as well as in the dose-normalized exposure (AUC0–12h/D). From 146 SNPs within 39 genes screened, AUC0–12h/D was found higher in recipients with CREB1 rs11904814 TT than with G allele carriers (3.135 ± 0.928 versus 2.084 ± 0.379 μg h ml−1 mg−1, p = 0.007). Recipients with SLC28A3 rs10868138 TT had lower t1/2 as compared to C allele carriers (0.728 ± 0.189 versus 0.951 ± 0.196 h, p = 0.001). Serum creatinine (SCr) explained 35.5% of C0/D variability (p < 0.001). Pure effects of genotypes CREB1 and SLC28A3 were 13.7% (p = 0.004) and 17.5% (p = 0.001) for AUC0–12h/D and t1/2, respectively. When additionally taking SCr into models, CREB1 and SLC28A3 genotypes explained 20.0% (p = 0.038) and 46.5% (p < 0.001) of AUC0–12h/D and t1/2 variability, respectively.

Conclusion

CREB1 and SLC28A3 genotypes, as well as SCr, are identified as determinants in predicting inter-individual MZR PK differences in renal transplant recipients.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This study was financially supported by Guangdong Basic and Applied Basic Research Foundation (No. 2020A1515010138), Young Teacher Foundation of Sun Yat-sen University (19ykpy79, 19ykpy04), and National Key R&D Program of China (2017YFC0909900).

Author information

Author notes

  1. Rui Dai and Jingjie Li contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, Guangzhou, People’s Republic of China

    Rui Dai, Jingjing Wu, Jiajia Yan, Xiao Chen & Pan Chen

  2. Institute of Clinical Pharmacology, Sun Yat-sen University, Guangzhou, China

    Rui Dai & Changxi Wang

  3. Center of Reproductive Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Jingjie Li

  4. Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Qian Fu & Guoping Zhong

Authors
  1. Rui Dai
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  2. Jingjie Li
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  3. Jingjing Wu
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  4. Qian Fu
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  5. Jiajia Yan
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  7. Changxi Wang
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  8. Xiao Chen
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  9. Pan Chen
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Contributions

Conception and design: Pan Chen, Xiao Chen.

Acquisition of data: Qian Fu, Changxi Wang.

Analysis and interpretation of the data: Rui Dai, Jingjie Li, Jingjing Wu, Guoping Zhong.

Drafting of the article: Rui Dai, Pan Chen, Jingjie Li.

Critical review: All authors.

Corresponding authors

Correspondence to Xiao Chen or Pan Chen.

Ethics declarations

This study was approved by the ethics committee of the First Affiliated Hospital of Sun Yat-sen University (approved no: 2015118), and informed consent was obtained from each enrolled patient.

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The authors declare that they have no conflict of interest.

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Dai, R., Li, J., Wu, J. et al. Genetic and clinical determinants of mizoribine pharmacokinetics in renal transplant recipients. Eur J Clin Pharmacol 77, 45–53 (2021). https://doi.org/10.1007/s00228-020-02936-7

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