Department of Pharmacy, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.
Institute of Hospital Pharmacy, Central South University, Changsha, 410008, China.
Eur J Clin Pharmacol. 2020 Jun;76(6):833-842. doi: 10.1007/s00228-020-02841-z. Epub 2020 Mar 10.
To evaluate the influence of three proton pump inhibitors (PPIs) on plasma voriconazole (VOR) concentrations and characterize potential drug-drug interactions (DDIs) between VOR and three PPIs (omeprazole, lansoprazole, and pantoprazole) in Chinese patients with malignant hematological diseases.
A simple and reliable 2D-HPLC with internal quality control method was used to ensure accurate concentration measurements. A total of 194 patients in this retrospective study were divided into control (N = 59), omeprazole (OME, N = 57), lansoprazole (LAN, N = 26), and pantoprazole (PAN, N = 52) groups for comparison of plasma VOR trough concentrations. To further validate our retrospective analysis of clinical data, we used molecular docking simulation to analyze the binding affinity of PPIs to the cytochrome P450 2C19 (CYP2C19) and cytochrome P450 3A4 (CYP3A4) enzymes that are integral to the metabolism of PPIs and VOR.
Our findings indicated that VOR trough concentrations were significantly higher in patient on PPIs compared with those who were not (P = 0.012). Patients on LAN (P < 0.01) or OME (P < 0.05) had significantly elevated VOR concentrations compared with the control group, whereas those on PAN did not. Although VOR trough concentrations were not significantly elevated with PAN, more patients in the PAN group reached therapeutic VOR concentrations than in any other group.
In conclusion, our retrospective data analysis and molecular docking simulations results indicate that LAN and OME interact with VOR via CYP2C19 and CYP3A4 to increase VOR plasma concentrations. This study helps with selection of PPIs in Chinese patients with malignant hematological cancer administered VOR.
评估三种质子泵抑制剂（PPIs）对伏立康唑（VOR）血浆浓度的影响，并分析中国恶性血液病患者伏立康唑与三种 PPIs（奥美拉唑、兰索拉唑和泮托拉唑）之间潜在的药物-药物相互作用（DDI）。
采用简单可靠的二维高效液相色谱法（2D-HPLC）结合内部质量控制方法，以确保准确的浓度测量。本回顾性研究共纳入 194 例患者，分为对照组（N=59）、奥美拉唑组（OME，N=57）、兰索拉唑组（LAN，N=26）和泮托拉唑组（PAN，N=52），比较各组患者伏立康唑谷浓度。为了进一步验证我们对临床数据的回顾性分析，我们使用分子对接模拟分析了 PPIs 与细胞色素 P450 2C19（CYP2C19）和细胞色素 P450 3A4（CYP3A4）酶的结合亲和力，这些酶与 PPIs 和 VOR 的代谢密切相关。
我们的研究结果表明，与未服用 PPI 的患者相比，服用 PPI 的患者伏立康唑谷浓度显著升高（P=0.012）。与对照组相比，服用 LAN（P<0.01）或 OME（P<0.05）的患者伏立康唑浓度显著升高，而服用 PAN 的患者则没有。尽管服用 PAN 的患者伏立康唑谷浓度没有显著升高，但 PAN 组达到治疗性伏立康唑浓度的患者比例高于其他任何组。
综上所述，我们的回顾性数据分析和分子对接模拟结果表明，LAN 和 OME 通过 CYP2C19 和 CYP3A4 与 VOR 相互作用，增加 VOR 血浆浓度。本研究有助于指导中国恶性血液病患者在使用 VOR 时选择合适的 PPI。
