Du Wenwen, Wang Xiaoxing, Zhang Dan, Chen Wenqian, Zhang Xianglin, Li Pengmei
Department of Pharmacy, China-Japan Friendship Hospital, Chaoyang District, Beijing, China.
Int J Clin Pharm. 2022 Apr;44(2):418-427. doi: 10.1007/s11096-021-01359-3. Epub 2021 Dec 3.
Background Tacrolimus (Tac) is the cornerstone of immunosuppressant therapy after lung transplantation (LTx). It shows great inter-individual variability in pharmacokinetics, which could partly be explained by pharmacogenetic factors. Aim We aim to investigate the influence of cytochrome P450 3A5 (CYP3A5) genotypes on early post-LTx Tac metabolism and whether it is affected by concomitant use of azole antifungals. Also, we explored the association between CYP3A5 genotype and clinical outcomes. Method 90 recipients who underwent LTx from 2017 to 2019 were enrolled in the study. The effect of CYP3A5 genotype on Tac metabolism and interaction with azole antifungals were assessed during week 1-4 after transplantation. Associations between CYP3A5 genotype and the incidence of acute kidney injury (AKI), length of hospital stay and mortality were analyzed. ResultsCYP3A51 carriers had lower dose adjusted concentration (C/D) than CYP3A53/3 group at all time points (p < 0.05). The dose ratio of CYP3A51 carriers to CYP3A5*3/*3 was between 1.3 and 2.4 when comparable concentrations were reached. Use of azole antifungals did not blunt the effect of CYP3A5 genotypes on Tac metabolism. Logistic regression showed Tac concentration ≥ 7.5 ng/mL at week 1 was associated with higher incidence of AKI. No statistically significant difference was found between CYP3A5 genotypes and the length of hospital stay. Kaplan-Meier analysis showed no statistically significant difference between 30-day or 1-year mortality and CYP3A5 genotype. Conclusion CYP3A5 genotype could affect Tac metabolism early after LTx. However, it had no influence on the incidence of AKI, length of hospital stay and mortality.
背景 他克莫司（Tac）是肺移植（LTx）后免疫抑制治疗的基石。其药代动力学存在很大的个体间差异，这部分可由药物遗传学因素解释。目的 我们旨在研究细胞色素P450 3A5（CYP3A5）基因型对LTx术后早期他克莫司代谢的影响，以及其是否受唑类抗真菌药联合使用的影响。此外，我们还探讨了CYP3A5基因型与临床结局之间的关联。方法 本研究纳入了2017年至2019年接受LTx的90例受者。在移植后第1 - 4周评估CYP3A5基因型对他克莫司代谢的影响以及与唑类抗真菌药的相互作用。分析CYP3A5基因型与急性肾损伤（AKI）发生率、住院时间和死亡率之间的关联。结果 在所有时间点，CYP3A51携带者的剂量调整浓度（C/D）均低于CYP3A53/3组（p < 0.05）。当达到可比浓度时，CYP3A51携带者与CYP3A5*3/*3的剂量比在1.3至2.4之间。唑类抗真菌药的使用并未减弱CYP3A5基因型对他克莫司代谢的影响。逻辑回归显示，第1周时他克莫司浓度≥7.5 ng/mL与AKI发生率较高相关。CYP3A5基因型与住院时间之间未发现统计学显著差异。Kaplan - Meier分析显示，30天或1年死亡率与CYP3A5基因型之间无统计学显著差异。结论 CYP3A5基因型可在LTx术后早期影响他克莫司代谢。然而，它对AKI发生率、住院时间和死亡率无影响。
