Abstract
The impact of CYP3A5*3, a CYP3A5 nonexpresser genotype, on inhibitory effects of diltiazem on tacrolimus metabolism has not been assessed. In retrospective study, when coadministered with diltiazem, mean increments in dose-adjusted C0D7, Cmax and AUC0–12 h for tacrolimus were larger in CYP3A5 expressers than in CYP3A5 nonexpressers (48.7 vs 3.7%, 31.7 vs 17.2% and 38.2 vs 18.5%, respectively). Subsequently, a prospective study was carried out, patients were randomized to algorithm-predicted dosing or standard dosing. For CYP3A5 expressers, an algorithm guided by CYP3A5 and diltiazem significantly reduced tacrolimus maintenance dosage (P=0.009) and improved the accuracy of tacrolimus initial dose, resulting in reduction in out-of-range C0 after initial dose (P=0.002) and dose adjustments (P=0.004). However, for CYP3A5 nonexpressers, primary end points were not achieved, and tacrolimus-sparing effect of diltiazem was not remarkable. Our study results show that CYP3A5 genotype-guided tacrolimus–diltiazem combination is a promising therapy in renal transplant recipients in the early postoperative stage.
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Acknowledgements
We acknowledge the financial support provided by the National Major Projects for science and technology development from Science and Technology Ministry of China (no. 2009ZX09304-003), National Natural Science Foundations of China (nos. 30873124 and 30873125) and Science and Technology Planning Project of Guangdong Province (no 2007B031511001). The authors would like to thank Dr Qibiao Su (Department of Pharmacokinetics & Pharmacodynamics, The South China Center for Innovative Pharmaceuticals) for the language editing of the paper.
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Li, JL., Wang, XD., Chen, SY. et al. Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective. Pharmacogenomics J 11, 300–306 (2011). https://doi.org/10.1038/tpj.2010.42
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DOI: https://doi.org/10.1038/tpj.2010.42
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