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| 1 | High degree of pharmacokinetic compatibility exists between the five-herb medicine XueBiJing and antibiotics comedicated in sepsis care显示文摘Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding Xue Bi Jing, a five-herb medicine, to antibioticbased sepsis care. Although adding Xue Bi Jing further reduced 28-day mortality via modulating the host response, pharmacokinetic herbedrug interaction is a widely recognized issue that needs to be studied.Building on our earlier systematic chemical and human pharmacokinetic investigations of Xue Bi Jing, we evaluated the degree of pharmacokinetic compatibility for Xue Bi Jing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both Xue Bi Jing-antibiotic and antibiotic-Xue Bi Jing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study Xue Bi Jing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no Xue Bi Jing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could,due to their inhibition of uridine 50-diphosphoglucuronosyltransferase 2 B15, organic anion transporters1/2 and/or organic anion-transporting polypeptide 1 B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions(resulting in increased exposure) are likely desirable due to these Xue Bi Jing compounds’ low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from Xue Bi Jing.Collectively, Xue Bi Jing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations. | Jian Li Olajide E.Olaleye Xuan Yu Weiwei Jia Junling Yang Chuang Lu Songqiao Liu Jingjing Yu Xiaona Duan Yaya Wanga Kai Dong Rongrong He Chen Cheng Chuan Li | 2019 | Acta Pharmaceutica Sinica B2019，9，5： | 10 |
| 2 | Human pharmacokinetics of ginkgo terpene lactones and impact of carboxylation in blood on their platelet-activating factor antagonistic activity显示文摘Terpene lactones are a class of bioactive constituents of standardized preparations of Ginkgo biloba leaf extract, extensively used as add-on therapies in patients with ischemic cardiovascular and cerebrovascular diseases. This investigation evaluated human pharmacokinetics of ginkgo terpene lactones and impact of their carboxylation in blood. Human subjects received oral YinXing- TongZhi tablet or intravenous ShuXueNing, two standardized ginkgo preparations. Their plasma protein-binding and plateletactivating factor antagonistic activity were assessed in vitro. Their carboxylation was assessed in phosphate-buffered saline (pH 7.4) and in human plasma. After dosing YinXing-TongZhi tablet, ginkgolides A and B and bilobalide exhibited significantly higher systemic exposure levels than ginkgolides C and J; after dosing ShuXueNing, ginkgolides A, B, C, and J exhibited high exposure levels. The compounds’ unbound fractions in plasma were 45–92%. Apparent oral bioavailability of ginkgolides A and B was mostly >100%, while that of ginkgolides C and J was 6–15%. Bilobalide’s bioavailability was probably high but lower than that of ginkgolides A/B. Terminal half-lives of ginkgolides A, B, and C (4–7 h) after dosing ShuXueNing were shorter than their respective values (6–13 h) after dosing YinXing-TongZhi tablet. Half-life of bilobalide after dosing the tablet was around 5 h. Terpene lactones were roughly evenly distributed in various body fluids and tissues; glomerular-filtration-based renal excretion was the predominant elimination route for the ginkgolides and a major route for bilobalide. Terpene lactones circulated as trilactones and monocarboxylates. Carboxylation reduced platelet-activating factor antagonistic activity of ginkgolides A, B, and C. Ginkgolide J, bilobalide, and ginkgo flavonoids exhibited no such bioactivity. Collectively, differences in terpene lactones’ exposure between the two preparations and influence of their carboxylation in blood should be considered in investigating the relative contributions of terpene lactones to ginkgo preparations’ therapeutic effects. The results here will inform rational clinical use of ginkgo preparations. | Xin-wei Liu Jun-ling Yang Wei Niu Wei-wei Jia Olajide E.Olaleye Qi Wen Xiao-na Duan Yu-hong Huang Feng-qing Wang Fei-fei Du Chen-chun Zhong Yan-fen Li Fang Xu Qi Gao Li Li Chuan Li | 2018 | Acta Pharmacologica Sinica2018，39，12： | 8 |
| 3 | 中药多成分药代动力学:发现与中药安全性和有效性关联的物质并揭示其药代特征显示文摘中医药对中华民族健康和国家稳定发挥了重要作用,揭示决定中药有效性和安全性的物质是推进中药现代化的一项重要工作。对于化学组成复杂的中药,可通过开展多成分药代研究,根据给药后中药成分能否以某种形式被机体利用产生显著的体内暴露(以成分原形和/或代谢物形式),选拔出用于考察药效活性的中药物质,研究物质产生疗效的体内过程和药代特征,由此为揭示决定中药药效作用的物质创造条件。此外,这类多成分药代研究还可用于揭示与中药不良反应或联合用药风险关联的中药物质。经过十多年的努力,中药多成分药代研究在理论、方法、技术、应用上已取得突破,成为药代动力学的一个新分支。本文系统阐述了中药多成分药代动力学的研究方法、技术要求和分析技术,并用一类活性中药成分(三七的皂苷类成分)的研究和围绕一种已上市中药制剂(连花清瘟胶囊)的研究介绍了两类多成分药代研究实例,最后讨论了中药多成分药代研究的进一步发展。 | 李川 程晨 贾伟伟 杨军令 余玄 Olajide E.OLALEYE | 2021 | 药学学报2021，56，9： | 7 |
| 4 | 白藜芦醇潜在的有益健康作用:药代动力学带来的困惑显示文摘白藜芦醇(Resveratrol,3,5,4'-三羟基-反式-二苯乙烯)最早在植物白藜芦(Veratrum grandiflorum O.Loes)的根中被发现。白藜芦醇引起关注最初与“法国悖论”有关,该化合物不仅存在于红葡萄酒中,而且还展现出与红葡萄酒保护心血管作用相关的生物活性。除保护心血管方面的作用外,白藜芦醇还在抗代谢性疾病、抗肿瘤和预防神经退行性疾病等方面表现出有益的作用。为了将这些潜在的有益健康作用向临床转化,人们对白藜芦醇开展了药代研究。本文作者从进入体循环的系统暴露和体内过程两个方面,总结了目前已知的口服后白藜芦醇的人体药代特征及围绕提高其系统暴露水平所做的多种尝试。然而,既有的药代动力学结果给白藜芦醇潜在作用的临床转化带来了困惑,包括:白藜芦醇展现有益健康的体外生物活性的物质形式(原形化合物)与口服后被机体利用的体内暴露形式(以代谢物为主)显著不同、药代研究测出的口服后白藜芦醇体内暴露水平明显低于其展现活性所需的浓度、根据白藜芦醇产生体内效应时所用的剂量推导出的体内暴露水平常明显低于研究其作用机制所用的浓度。为了更好地与白藜芦醇有益健康作用的研究相结合、促进其临床转化,作者建议从三方面进一步开展白藜芦醇的药代研究:(1)全面研究白藜芦醇代谢物的系统暴露、体内靶标到达及在靶细胞中的代谢,(2)研究口服后白藜芦醇的肠腔暴露,(3)开展红葡萄酒多成分药代研究。 | 王亚亚 褚子璇 杨军令 Olajide E.Olaleye 贺容容 李木子 程晨 李川 | 2021 | 中国临床药理学与治疗学2021，26，8： | 3 |
| 5 | Multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines显示文摘Traditional medicine has provided a basis for health care and disease treatment to Chinese people for millennia,and herbal medicines are regulated as drug products in China.Chinese herbal medicines have two features.They normally possess very complex chemical composition.This makes the identification of the constituents that are together responsible for the therapeutic action of an herbal medicine challenging,because how to select compounds from an herbal medicine for pharmacodynamic study has been a big hurdle in such identification efforts.To this end,a multi-compound pharmacokinetic approach was established to identify potentially important compounds(bioavailable at the action loci with significant exposure levels after dosing an herbal medicine)and to characterize their pharmacokinetics and disposition.Another feature of Chinese herbal medicines is their typical use as or in combination therapies.Coadministration of complex natural products and conventional synthetic drugs is prevalent worldwide,even though it remains very controversial.Natural product–drug interactions have raised wide concerns about reduced drug efficacy or safety.However,growing evidence shows that incorporating Chinese herbal medicines into synthetic drug-based therapies delivers benefits in the treatment of many multifactorial diseases.To address this issue,a drug-combination pharmacokinetic approach was established to assess drug–drug interaction potential of herbal medicines and degree of pharmacokinetic compatibility for multi-herb combination and herbal medicine–synthetic drug combination therapies.In this review we describe the methodology,techniques,requirements,and applications of multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines and to discuss further development for these two types of pharmacokinetic research. | Chuan Li Wei-wei Jia Jun-ling Yang Chen Cheng Olajide E.Olaleye | 2022 | Acta Pharmacologica Sinica2022，43，12： | 2 |
| 6 | Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study显示文摘Methyl(S)-4-(6-amino-9 H-purin-9-yl)-2-hydroxybutanoate(DZ2002) is a potent reversible inhibitor of S-adenosyl-L-homocysteine hydrolase(SAHH). Due to its ester structure, DZ2002 is rapidly hydrolyzed in rat blood to 4-(6-amino-9 H-purin-9-yl)-2-hydroxybutyric acid(DZA) during and after blood sampling from rats; this hampers accurate determination of the circulating DZ2002 and its acid metabolite DZA in rats. To this end, a method for determining the blood concentrations of DZ2002 and DZA in rats was developed by using methanol to immediately deactivate blood carboxylesterases during sampling. The newly developed bioanalytical assay possessed favorable accuracy and precision with lower limit of quantification of 31 nM for DZ2002 and DZA. This validated assay was applied to a rat pharmacokinetic study of DZ2002. After oral administration, DZ2002 was found to be extensively converted into DZA. The level of systemic exposure to DZ2002 was significantly lower than that of DZA. The apparent oral bioavailability of DZ2002 was 90%–159%. The mean terminal half-lives of DZ2002 and DZA were 0.3–0.9 and 1.3–5.1 h, respectively. The sample preparation method illustrated here may be adopted for determination of other circulating ester drugs and their acid metabolites in rodents. | Weiwei Jia Jing Li Feifei Du Yan Sun Fang Xu Fengqing Wang Olajide E.Olaleye Danghui Chen Wei Tang Jianping Zuo Chuan Li | 2019 | Journal of Pharmaceutical Analysis2019，9，1： | 0 |
| 7 | Novel assays for quality evaluation of XueBiJing:Quality variability of a Chinese herbal injection for sepsis management显示文摘XueBiJing is an intravenous five-herb injection used to treat sepsis in China.The study aimed to develop a liquid chromatography-tandem mass spectrometry(LC-MS/MS)-or liquid chromatography-ultraviolet(LC-UV)-based assay for quality evaluation of XueBiJing.Assay development involved identifying marker constituents to make the assay therapeutically relevant and building a reliable one-point calibrator for monitoring the various analytes in parallel.Nine marker constituents from the five herbs were selected based on XueBiJing's chemical composition,pharmacokinetics,and pharmacodynamics.A selectivity test(for“similarity of response”)was developed to identify and minimize interference by nontarget constituents.Then,an intercept test was developed to fulfill“linearity through zero”for each analyte(absolute ratio of intercept to C response,<2%).Using the newly developed assays,we analyzed samples from 33 batches of XueBiJing,manufactured over three years,and found small batch-to-batch variability in contents of the marker constituents(4.1%-14.8%),except for senkyunolide I(26.5%). | Xuan Yu Wei Niu Ya-Ya Wang Olajide E.Olaleye Jia-Nan Wang Meng-Yuan Duan Jun-Ling Yang Rong-Rong He Zi-Xuan Chu Kai Dong Gui-Ping Zhang Chang-Xiao Liu Chen Cheng Chuan Li | 2022 | Journal of Pharmaceutical Analysis2022，12，4： | 0 |
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