TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Lina Zhong,Longjie Li,Qingfeng He,Xiao Zhu,Ping Xiang,Xiaoqiang Xiang,Hui Yan
U-47700, a synthetic μ-opioid receptor agonist and emerging new psychoactive substance, poses critical public health risks due to its high abuse liability and fatal overdose potential. Ethical barriers prohibit clinical pharmacokinetic studies of such controlled substances, necessitating alternative approaches. Here, we developed the first physiologically based pharmacokinetic (PBPK) model for U-47700 by integrating in vitro experiments—including Caco-2 permeability, tissue-plasma partitioning, plasma protein binding, and human liver microsomal clearance. The rat PBPK model accurately predicted plasma concentration-time profiles across doses, and the metabolite's PBPK model was further established and validated to describe the kinetics of N -desmethyl-U-47700 and N , N -didesmethyl-U-47700. Human extrapolation via IVIVE ( in vitro-in vivo extrapolation) and allometric scaling revealed rapid systemic clearance (0.944–1.371 L/h/kg). For illicit drugs like U-47700, where clinical trials are unfeasible, this PBPK framework bridges computational modeling, preclinical insights, and real-world evidence, offering a critical tool to decode pharmacokinetic curves, estimate administration timelines from postmortem samples, and assess polydrug interaction risks. By enabling mechanistic insights into synthetic opioid toxicity, this work informs overdose prevention strategies and mitigates the societal impact of high-risk designer drugs.
研究领域:
毒理学
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药理学
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计算生物学
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DOI
PubMed
高影响因子
Pharmaceutics
·
2024
·Vol. 16
·期 12
·1596
·
IF 4.9
Xiaoqiang Zhu,Weimin Kong,Zehua Wang,Xiaodong Liu,Li Liu
Background/Objectives:SPT-07A, a D-borneol, is currently being developed in China for the treatment of ischemic stroke. We aimed to create a whole-body physiologically-based pharmacokinetic (PBPK) model to predict the pharmacokinetics of SPT-07A in rats, dogs, and humans.Methods:The in vitro metabolism of SPT-07A was studied using hepatic, renal, and intestinal microsomes. The pharmacokinetics of SPT-07A in rats were simulated using the developed PBPK model and in vitro data. Following validation using pharmacokinetic data in rats, the developed PBPK model was scaled up to dogs and humans.Results:Data from hepatic microsomes revealed that SPT-07A was primarily metabolized by UDP-glucuronosyltransferase (UGTs). Glucuronidation of SPT-07A also occurred in the kidney and intestine. The in vitro to in vivo extrapolation analysis showed that hepatic clearance of SPT-07A in rats, dogs, and humans accounted for 62.2%, 87.3%, and 76.5% of the total clearance, respectively. The renal clearance of SPT-07A in rats, dogs, and humans accounted for 32.6%, 12.7%, and 23.1% of the total clearance, respectively. Almost all of the observed concentrations of SPT-07A following single or multi-dose to rats, dogs, and humans were within the 5th–95th percentiles of simulations from 100 virtual subjects. Sensitivity analysis showed that hepatic metabolic velocity, renal metabolic velocity, and hepatic blood flow remarkably affected the exposure to SPT-07A in humans. Dedrick plots were also used to predict the pharmacokinetics of SPT-07A in humans. Prediction accuracy using the PBPK model is superior to that of Dedrick plots.Conclusions:We elucidate UGT-mediated SPT-07A metabolism in the liver, kidney, and intestine of rats, dogs, and humans. The pharmacokinetics of SPT-07A were successfully simulated using the developed PBPK model.
研究领域:
药理学
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生物医学工程
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药物代谢研究
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DOI
PubMed
高影响因子
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2022
·Vol. 130
·期 5
·592-605
·
IF 3.688
Zhiping Jin,Qingfeng He,Xiao Zhu,Mingshe Zhu,Yike Wang,Xin-an Wu,Qianzhou Lv,Xiaoqiang Xiang
Anlotinib is a small molecule of novel tyrosine kinase inhibitor initially approved to treat non-small cell lung cancer in China. Drug–drug interaction (DDI) is an extrinsic factor important for the appropriate use of anlotinib in clinical practice. In vitro experiments demonstrated that anlotinib is a substrate of cytochrome P450 (CYP) enzymes and moderate inhibitor of several common ones; however, no clinical DDI studies have been performed to investigate inhibitory effects of anlotinib on these CYP enzymes. Thus, its drug label recommends avoiding co-administration with substrates of these enzymes, which have narrow therapeutic windows. In this study, we performed a CYP450 inhibition study, followed by gathering in vitro and clinical pharmacokinetic data to build the first physiologically based pharmacokinetic (PBPK) model of anlotinib. The verified model was subsequently used to predict the DDI mediated by anlotinib. As a result, the marginal plasma exposure changes of typical CYP3A and CYP2C9 substrates were less than the bioequivalence threshold, indicating that anlotinib has a very low potential of causing clinically meaningful DDI through the inhibition of several major CYP enzymes. According to the FDA's latest guideline on DDI, the established model with the simulation results may support the revision of anlotinib labelling without further clinical studies, lifting unnecessary restrictions on anlotinib regimens.
研究领域:
药理学
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临床药学
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DOI
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2023
·Vol. 51
·期 11
·1515-1526
·
IF 3.9
Xiaowen Wang,Yiqun Yu,Hongrui Liu,Fengjiao Bu,Chunying Shen,Qingfeng He,Xiao Zhu,Pin Jiang,Bing Han,Xiaoqiang Xiang
Ensartinib (X-396) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of ALK-positive patients with locally advanced or metastatic non–small cell lung cancer. Although in vitro experiments and molecular docking suggested its potential as a cytochrome P450 inhibitor, no further investigation or clinical trials have been conducted to assess its drug–drug interaction (DDI) risk. In this study, we conducted a series of in vitro experiments to elucidate the inhibition mechanism of ensartinib. Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed based on in vitro, in silico, and in vivo parameters, verified using clinical data, and applied to predict the clinical DDI mediated by ensartinib. The in vitro incubation experiments suggested that ensartinib exhibited strong time-dependent inhibition. Simulation results from the PBPK model indicated a significant increase in the exposure of CYP3A substrates in the presence of ensartinib, with the maximal plasma concentration and area under the plasma concentration-time curve increasing up to 12-fold and 29-fold for sensitive substrates. Based on these findings, it is evident that co-administration of ensartinib and CYP3A substrates requires careful regulatory consideration.
研究领域:
药理学
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临床药学
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生物医学工程
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DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2024
·
IF 8.5
Yan Qi,Chuwen Mao,Yanru Zhou,Zuohua Xie,Chao Wu,Songyi Lin
This paper employed a physiologically based pharmacokinetic model (PBPK) to investigate the transformations of folic acid and its metabolites in vivo. Additionally, an ultra-performance liquid chromatography (UPLC) method was developed to accurately measure the body's retention rate and conversion rate of folic acid, tetrahydrofolate, and 5-methyltetrahydrofolate. Furthermore, the bioavailability of folic acid in the body was assessed by combining this method with an evaluation technique for animal models. The study found that the gastric metabolism time was 2 h, while the small intestinal metabolism duration was 4 h. The maximum conversion rate was observed in plasma and liver after 6 h, and in the brain after 8 h. This serves as a framework for creating a model to assess the bioavailability of folic acid in living organisms, to enhance the safety and efficacy of folic acid intake.
研究领域:
药理学
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分析化学
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生物医学工程
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DOI
PubMed
高影响因子
Pharmaceutics
·
2026
·Vol. 18
·期 8
·1031
·
IF 6.9
Yuchen Qu,Zhuan Yang,Wen Ma,Peng Xiao,Yani Gu,Jie Pan,Xinyun Zhang,Chen Zhao,Yunli Yu
Background: In patients with atrial fibrillation receiving long-term anticoagulation therapy with dabigatran etexilate (DABE), moxifloxacin (MFLX) is frequently coadministered to treat concurrent infections; however, the potential drug–drug interaction (DDI) between these agents remains unclear. Herein, we examined the underlying mechanism by which MFLX attenuates DABE pharmacokinetics in rats; subsequently, we elucidated the DDI in humans by establishing a physiologically based pharmacokinetic (PBPK) model based on these animal data.Methods: The 3- and 14-day effects of 40 mg/kg MFLX once daily and secondary bile acid (SBA)-containing dietary intervention on the pharmacokinetic profile of DABE and its active form, dabigatran (DAB), were examined in a rat model. Ileum tissues were harvested to measure the expression of P-glycoprotein (P-gp), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor alpha (PPARα). In addition, we examined the effects of secondary bile acids (SBAs) on P-gp expression and quantified P-gp-mediated DABE efflux transport activity in Caco-2 cells. A PBPK model was used to predict the risk of DAB exposure under this DDI scenario and under combined high-risk conditions, including renal impairment and advanced age.Results:Treatment with MFLX for 3 and 14 days inhibited SBA-producing gut microbiota, thereby suppressing the conversion of primary bile acids to SBAs. Concurrently, a marked reduction in intestinal P-gp expression was observed, along with a significant enhancement of the oral bioavailability of DABE. These effects were reversed by SBA-containing diets. In vitro experiments using Caco-2 cells revealed that physiologically relevant concentrations of SBA significantly upregulated P-gp expression and function, whereas MFLX incubation alone showed no direct modulatory effect on these transporters or regulators. PBPK simulation results showed that in vivo exposure of DAB would increase by 41.7%, 104%, 251%, and 115% when coadministered with MFLX alone, with coexisting mild renal impairment, moderate renal impairment, and aging, respectively.Conclusions: MFLX increases DAB exposure by reducing SBA-regulated intestinal P-gp function. PBPK simulations suggest a low risk of DDI from MFLX coadministration alone; however, caution is warranted in patients with aging or renal impairment.
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高影响因子
Expert Opinion on Drug Metabolism & Toxicology
·
2023
·
IF 4.3
Pin Jiang,Tao Chen,Lin-Feng Chu,Ren-Peng Xu,Jin-Ting Gao,Li Wang,Qiang Liu,Lily Tang,Hong Wan,Ming Li,Hong-Can Ren
Background Enhancing the precision of drug–drug interaction (DDI) prediction is essential for improving drug safety and efficacy. The aim is to identify the most effective fraction metabolized by CY3A4 (fm) for improving DDI prediction using physiologically based pharmacokinetic (PBPK) models.Research Design and Methods The fm values were determined for 33 approved drugs using a human liver microsome for in vitro measurements and the ADMET Predictor software for in silico predictions. Subsequently, these fm values were integrated into PBPK models using the GastroPlus platform. The PBPK models, combined with a ketoconazole model, were utilized to predict AUCR (AUCcombo with ketoconazole/AUCdosing alone), and the accuracy of these predictions was evaluated by comparison with observed AUCR.Results The integration of in vitro fm method demonstrates superior performance compared to the in silico fm method and fm of 100% method. Under the Guest-limits criteria, the integration of in vitro fm achieves an accuracy of 76%, while the in silico fm and fm of 100% methods achieve accuracies of 67% and 58%, respectively.Conclusions Our study highlights the importance of in vitro fm data to improve the accuracy of predicting DDIs and demonstrates the promising potential of in silico fm in predicting DDIs.
研究领域:
药理学
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药物代谢
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药学
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生物医学工程
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2018
·Vol. 39
·期 9
·1522-1532
·
IF 3.562
Xue Cai-fu,Zhang Zhe,Jin Yan,Zhu Bin,Xing Jun-fen,Ma Guo,Xiang Xiao-qiang,Cai Wei-min
Liver metabolism is commonly considered the major determinant in drug discovery and development. Many in vitro drug metabolic studies have been developed and applied to understand biotransformation. However, these methods have disadvantages, resulting in inconsistencies between in vivo and in vitro experiments. A major factor is that they are static systems that do not consider the transport process in the liver. Here we developed an in vitro dynamic metabolic system (Bio-PK metabolic system) to mimic the human pharmacokinetics of tolbutamide. Human liver microsomes (HLMs) encapsulated in a F127'-Acr-Bis hydrogel (FAB hydrogel) were placed in the incubation system. A microdialysis sampling technique was used to monitor the metabolic behavior of tolbutamide in hydrogels. The measured results in the system were used to fit the in vitro intrinsic clearance of tolbutamide with a mathematical model. Then, a PBPK model that integrated the corresponding in vitro intrinsic clearance was developed to verify the system. Compared to the traditional incubation method, reasonable PK profiles and the in vivo clearance of tolbutamide could be predicted by integrating the intrinsic clearance of tolbutamide obtained from the Bio-PK metabolic system into the PBPK model. The predicted maximum concentration ( C
max ), area under the concentration-time curve (AUC), time to reach the maximum plasma concentration ( T
max ) and in vivo clearance were consistent with the clinically observed data. This novel in vitro dynamic metabolic system can compensate for some limitations of traditional incubation methods; it may provide a new method for screening compounds and predicting pharmacokinetics in the early stages, supporting the development of compounds.
研究领域:
药理学
·
药物代谢
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
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