Abstract
Aim:
To examine how the endogenous CYP3A4 phenotype and CYP3A5*3 genotype of Chinese renal transplant recipients influenced the dose-corrected trough concentration (C0/D) and weight-corrected daily dose (D/W) of tacrolimus.
Methods:
A total of 101 medically stable kidney transplant recipients were enrolled, and their blood and urine samples were gathered. The endogenous CYP3A4 phenotype was assessed by the ratio of 6β-hydroxycortisol and 6β-hydroxycortisone to cortisol and cortisone in urine. CYP3A5*3 genotype was determined using PCR-RELP.
Results:
In overall renal transplant recipients, a multiple regression analysis including the endogenous CYP3A4 phenotype, CYP3A5*3 genotype and post-operative period accounted for 60.1% of the variability in C0/D ratio; a regression equation consisting of the endogenous CYP3A4 phenotype, post-operative period, body mass index, CYP3A5*3 genotype, gender, total bilirubin and age explained 61.0% of the variability in D/W ratio. In CYP3A5*3/*3 subjects, a combination of the endogenous CYP3A4 phenotype, post-operative period and age was responsible for 65.3% of the variability in C0/D ratio; a predictive equation including the endogenous CYP3A4 phenotype, post-operative period, body mass index, gender and age explained 61.2% of the variability in the D/W ratio. Base on desired target range of tacrolimus trough concentrations, individual daily dosage regimen was calculated, and all the observed daily doses were within the predicted range.
Conclusion:
This study provides the equations to predict tacrolimus metabolism and dosage requirements based on the endogenous CYP3A4 phenotype, CYP3A5*3 genotype and other non-genetic variables.
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Acknowledgements
The research was funded by the National Natural Science Foundation of China (No 81072700/H3110). The project was funded by the China Postdoctoral Science Foundation (No 2014M562140), Research Fund for Young Scholars of Fujian Province Health and Family Planning Commission (No 2014-1-79) and Scientific Research Foundation for Postdoctoral of Central South University (No 31000-160320068). We gratefully thank Wen-zhao XIE and Ya GONG for gathering the biological samples. We also thank Qing LIU for her kind help with the data analysis.
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Supplementary Table S1 is available at the Acta Pharmacologica Sinica's website.
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Supplementary Information Table S1
The C0/D and D/W ratios of Tac across the three CYP3A5*3 genotypes in Chinese renal transplant recipients. (DOC 30 kb)
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Luo, X., Zhu, Lj., Cai, Nf. et al. Prediction of tacrolimus metabolism and dosage requirements based on CYP3A4 phenotype and CYP3A5*3 genotype in Chinese renal transplant recipients. Acta Pharmacol Sin 37, 555–560 (2016). https://doi.org/10.1038/aps.2015.163
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DOI: https://doi.org/10.1038/aps.2015.163
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