BIOMEDICAL CHROMATOGRAPHY
·
2023
·Vol. 37
·期 12
·e5751
·
IF 1.8
Feng Chen,Xiaoxia Yang,Huanhuan Li,Xiaodan Zeng,Ziwei Deng,Hongqiang Wang,Yuanxiang Jin,Chengfeng Qiu,Zhihua Shi
In order to facilitate therapeutic drug monitoring of tacrolimus and cyclosporine A in clinical practice, a simple, rapid, robust, sensitive and specific LC–MS/MS assay was developed and validated for the simultaneous determination of tacrolimus and cyclosporine A in human whole blood. Erythrocytes were destroyed using internal standard solution with 10% (w/v) zinc sulfate in water. The analytes were extracted from 100 μl of whole blood by protein precipitation with acetonitrile. Chromatographic separation was conducted on a Kinetex PFP column (60°C) by a gradient elution with a flow rate of 0.450 ml/min in 2.5 min. Quantitative analysis was performed using electrospray ionization and multiple reaction monitoring in positive ionization mode. The method was fully validated as per current guidelines on bioanalytical methodologies of the US Food and Drug Administration and European Medicines Agency. The method developed was applied successfully in analyzing clinical samples from patients administered tacrolimus or cyclosporine A. The sample treatment procedure was rationalized and improved to fulfill the complete target extraction. The chromatography conditions were optimized to achieve rapid and accurate quantification of both analytes. This method may be beneficial as a constructive input for the therapeutic drug monitoring of tacrolimus and cyclosporine A in obtaining individualized therapy.
研究领域:
临床药理学
·
分析化学
·
医学检验
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产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2021
·Vol. 14
·期 3
·198
·
IF 5.863
Qingfeng He,Fengjiao Bu,Hongyan Zhang,Qizhen Wang,Zhijia Tang,Jing Yuan,Hai-Shu Lin,Xiaoqiang Xiang
Wuzhi capsule (WZC) is commonly prescribed with tacrolimus in China to ease drug-induced hepatotoxicity. Two abundant active ingredients, schisantherin A (STA) and schisandrin A (SIA) are known to inhibit CYP3A enzymes and increase tacrolimus’s exposure. Our previous study has quantitatively demonstrated the contribution of STA and SIA to tacrolimus pharmacokinetics based on physiologically-based pharmacokinetic (PBPK) modeling. In the current work, we performed reversible inhibition (RI) and time-dependent inhibition (TDI) assays withCYP3A5genotyped human liver microsomes (HLMs), and further integrated the acquired parameters into the PBPK model to predict the drug–drug interaction (DDI) in patients with differentCYP3A5alleles. The results indicated STA was a time-dependent and reversible inhibitor of CYP3A4 while only a reversible inhibitor of CYP3A5; SIA inhibited CYP3A4 and 3A5 in a time-dependent manner but also reversibly inhibited CYP3A5. The predicted fold-increases of tacrolimus exposure were 2.70 and 2.41, respectively, after the multidose simulations of STA. SIA also increased tacrolimus’s exposure but to a smaller extent compared to STA. An optimized physiologically-based pharmacokinetic (PBPK) model integrated withCYP3A5polymorphism was successfully established, providing more insights regarding the long-term DDI between tacrolimus and Wuzhi capsules in patients with differentCYP3A5genotypes.
研究领域:
药理学
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临床医学
·
遗传学
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DOI
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 9
·4485
·
IF 6.208
Qingfeng He,Fengjiao Bu,Qizhen Wang,Min Li,Jiaying Lin,Zhijia Tang,Wen Yao Mak,Xiaomei Zhuang,Xiao Zhu,Hai-Shu Lin,Xiaoqiang Xiang
Schizandrol A (SZA) and schizandrol B (SZB) are two active ingredients of Wuzhi capsule (WZC), a Chinese proprietary medicine commonly prescribed to alleviate tacrolimus (FK-506)-induced hepatoxicity in China. Due to their inhibitory effects on cytochrome P450 (CYP) 3A enzymes, SZA/SZB may display drug–drug interaction (DDI) with tacrolimus. To identify the extent of this DDI, the enzymes’ inhibitory profiles, including a 50% inhibitory concentration (IC50) shift, reversible inhibition (RI) and time-dependent inhibition (TDI) were examined with pooled human-liver microsomes (HLMs) and CYP3A5-genotyped HLMs. Subsequently, the acquired parameters were integrated into a physiologically based pharmacokinetic (PBPK) model to quantify the interactions between the SZA/SZB and the tacrolimus. The metabolic studies indicated that the SZB displayed both RI and TDI on CYP3A4 and CYP3A5, while the SZA only exhibited TDI on CYP3A4 to a limited extent. Moreover, our PBPK model predicted that multiple doses of SZB would increase tacrolimus exposure by 26% and 57% in CYP3A5 expressers and non-expressers, respectively. Clearly, PBPK modeling has emerged as a powerful approach to examine herb-involved DDI, and special attention should be paid to the combined use of WZC and tacrolimus in clinical practice.Keywords:physiologically based pharmacokinetic (PBPK);Wuzhi capsule (WZC);tacrolimus (FK-506);CYP3A5 polymorphism;drug–drug interaction (DDI);schizandrol A (SZA);schizandrol B (SZB)
研究领域:
药理学
·
临床医学
·
中药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CLINICA CHIMICA ACTA
·
2026
·
IF 4.1
Xin-Yu Wu,Xiao-Kang Fu,Ao Li,Wei Zhang,Han-Peng Jiang,Na An,Quan-Fei Zhu,Shao-Ting Wang,Yu-Qi Feng
Background Therapeutic drug monitoring (TDM) of tacrolimus requires accurate, high-throughput methods, but conventional liquid chromatography–tandem mass spectrometry (LC-MS/MS) is limited by lengthy run times and complex sample preparation. Methods We developed a chromatography-free assay for quantification of tacrolimus in whole blood by integrating cold-induced phase separation with acoustic ejection mass spectrometry (AEMS). This workflow only requires less than 10 μL of whole blood, eliminates centrifugation, and enables direct nanoliter-scale injection into the mass spectrometer. The AEMS assay performance was validated in accordance with CLSI C62-A and ICH M10 guidelines using 62 patient samples and matrix-matched calibrators, demonstrating its suitability for high-throughput therapeutic drug monitoring. Results The AEMS assay exhibited excellent linearity (0.5–50 μg/L; R 2 = 0.9987), with a lower limit of quantification of 0.5 μg/L, which was well below clinically relevant trough concentrations. Accuracy (93.3%–100.1%) and precision (intra-day RSD: 3.7%–11.3%; inter-day RSD: 2.3%–12.4%) met regulatory acceptance criteria. Results showed strong concordance with routine LC-MS/MS (Spearman ρ = 0.972; Passing–Bablok slope = 1.100 [95% CI: 1.026–1.177]). The total analysis cycle time was less than 3 s per sample, enabling a throughput exceeding 1000 samples per hour theoretically. Conclusion This study establishes the first chromatography-free mass spectrometry platform validated for clinical TDM of TAC. By integrating ultra-high throughput capability, minimal sample consumption, and robust analytical performance, the AEMS workflow offers a transformative analytical solution for high-demand clinical environments, including transplant centers and pediatric monitoring settings.
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产品关联
DOI
PubMed
高影响因子
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