Background Pharmacokinetics provides a scientific basis for drug product design, dosage regimen planning, understanding the body's action on the drug, and relating the time course of the drug in the body to its pharmacodynamics and/or toxic effects. Recently, naringin, a natural flavonoid, was approved for clinical trials as a first-class new drug product by the China Food and Drug Administration, owing to its nonclinical efficacy in relieving cough, reducing sputum, and low toxicity. Previous reports focused on the pharmacokinetic studies of naringin or its active metabolite naringenin in rats, which were scattered and insufficient because naringin was coadministered with mixtures such as herbs, fruits, and other traditional medicines. The purpose of this study was to evaluate the pharmacokinetics and metabolism of naringin and naringenin, following oral and intravenous administration of naringin in rats, dogs, and humans, which can be beneficial for new drug development. Methods Separate bioanalytical methods were developed and validated to determine the concentrations of naringin and its active metabolite naringenin in biological samples obtained from rats, dogs, and humans. Comprehensive nonclinical and clinical data were used to estimate the pharmacokinetic parameters of naringin and naringenin. Experiments included single-dose studies (oral and intravenous administration), multiple-dose studies, and an assessment of food-effects. Furthermore, the metabolism of naringin and naringenin was studied in rat and human liver and kidney microsomes. All biological samples were analyzed using liquid chromatography-tandem mass spectrometry. Results The pharmacokinetic parameters of naringin and naringenin were calculated and the results show an insignificant influence of high-fat diet and insignificant accumulation of the drugs after multiple dosing. Twelve metabolites were detected in the liver and kidney microsomes of rats and humans; naringin metabolism was a complex process simultaneously catalyzed by multiple human enzymes. All evaluated species demonstrated differences in the pharmacokinetics and metabolism of naringin and naringenin. Conclusion The results can be used to design a dosage regimen, deepen understanding of mechanisms, and accelerate new drug development. Clinical Trial Registration http://www.chinadrugtrials.org.cn/eap/main, identifiers CTR20130704 and CTR20190127.

: The clinical application of herbal medicines is increasing, but there is still a lack of comprehensive safety data and in-depth research into mechanisms of action. The composition of herbal medicines is complex, with each herb containing a variety of chemical components. Each of these components may affect the activity of metabolizing enzymes, which may lead to herb-drug interactions. It has been reported that the combined use of herbs and drugs can produce some unexpected interactions. Therefore, this study reviews the progress of research on safety issues caused by the effects of herbs on metabolizing enzymes with reference to six categories of drugs, including antithrombotic drugs, non-steroidal anti-inflammatory drugs, anti-diabetic drugs, statins lipid-lowering drugs, immunosuppressants, and antineoplastic drugs. Understanding the effects of herbs on the activity of metabolizing enzymes could help avoid the toxicity and adverse drug reactions resulting from the co-administration of herbs and drugs, and help doctors to reduce the risk of prescription incompatibility.

目的 总结归纳药物性肝损伤机制的最新研究进展,为深入了解药物性肝损伤机制提供参考.方法 通过文献检索和归纳,总结了四类易致肝损伤的药物:非甾体抗炎药、抗生素和抗真菌药物、神经系统药物、中草药的肝损伤作用机制.结果 该类药物肝损伤机制涉及线粒体功能障碍和氧化应激、患者的基因多态性、活性代谢物、免疫反应等.结论 应该进一步加强药物性肝损伤机制的研究和总结,以最大限度地规避药物性肝损伤的发生,指导相关药物的合理应用.

目的 为了提高对药源性肾损伤的认识,对药源性肾损伤的发展机制研究进展进行分析综合,为预防药源性肾损伤提供参考.方法 通过检索Pubmed、ScienceDirect等权威数据库,总结国内外最新文献对发病原因、药源性肾损伤的机制、典型疾病及药物安全性评价方法等进行综述.结果 药源性肾损伤临床表型分为急性肾损伤、肾小球损伤、肾小管损伤及肾结石四类;药源性肾损伤发生机制主要涉及直接作用、氧化应激作用、免疫炎症作用、酸碱平衡紊乱、药物影响转运蛋白五类;临床上典型的药源性肾损伤主要有血栓性微血管病、马兜铃酸肾病和范可尼综合征;还需要更加敏感的药源性肾损伤的安全性评价方法.结论 应该加深对药源性肾损伤的临床表型、发生机制和典型疾病的认识,研究和发展全面可靠的药物安全性评价方法,从而促进提高对药源性肾损伤的防控水平.

Honokiol, the main bioactive component of Magnolia officinalis, has a variety of pharmacological actions. However, its toxicity has rarely been reported. According to previous studies performed in our laboratory, honokiol microemulsion has embryo developmental toxicity. For further exploration, Zebrafish embryos were exposed to different doses of honokiol microemulsion to record the rates of mortality, malformation, and hatching. We found that high doses of honokiol microemulsion (0.6 and 0.9 μg/ml) increased mortality, inhibited hatching, caused malformation and reduced swimming activities. The low-dose group (0.15 and 0.30 μg/ml) had decreased production of reactive oxygen species (ROS), but the high-dose group had inhibited superoxide dismutase (SOD) enzyme activity and increased ROS content. The mRNA expression of sod1, sod2, catalase(cat), and heme oxygenase 1 (ho1) was up-regulated at low doses but down-regulated at high doses. The nuclear factor E2-related factor 2 (Nrf2) mRNA expression increased at low doses but decreased at high doses. After knocking down Nrf2 in zebrafish embryos, the rates of mortality and malformation were markedly increased and the hatching rate was significantly decreased. These results suggest that honokiol has antioxidative effects at low doses but causes embryo-developmental toxicity at high doses, and the Nrf2 gene may play a pivotal role in regulating these processes.

With the rapid development of medicinal chemistry, bioscience, molecular biology and molecular pharmacology, there are many anti-tumor drugs under research, coming into clinical trials or having been approved. With the discovery of disease-associated mutation sites and signaling pathways, therapeutic approaches to these mutations and signaling pathways have emerged, which is named targeted therapies. Targeted therapies are more accurate than conventional drugs with few side effects, good applicability, and high specificity. However, a series of toxicities associated with therapeutic targets have also emerged. According to the mechanism of action of drugs, this article has summarized the target related toxicity of anti-tumor drugs, and hopes to provide some ideas and suggestions for the safety evaluation of targeted therapy.

Nifurtimox has been an important treatment for trypanosomiasis for many years, but new research indicates that the drug may also be an effective therapy for malignant neuroblastoma. However, there have been few published reports evaluating the toxicity of nifurtimox in different species. Therefore, to further understand its toxicity and toxicokinetic profiles, Sprague Dawley rats and beagle dogs were orally administered nifurtimox at 0, 25, 75 and 150 mg kg(-1) day(-1), and 0, 30, 60 and 120 mg kg(-1) day(-1), respectively, for 28 days, which was followed by a 28-day recovery period. Significant decreases in the body weight and food consumption were observed in rats given 75 and 150 mg kg(-1) day(-1), but no significant difference was observed in either body weight or food consumption in dogs. No notable gender difference was observed in the rats in our study. The mean C-max and AUC(0-t) increased with the exposure time in rats, and systemic exposure on day 28 was notably higher than that on day 1 for each dosing group. In contrast, in dogs the mean Cmax and AUC0-t increased significantly in the 120 mg kg(-1) day(-1) group only. Other findings in rats included a dose-dependent increase in total bilirubin and urea, a significant increase in the kidney organ coefficient, a decrease in heart and thymus weights, and a decrease in the weight of testes and epididymides tissue in males administered 75 and 150 mg kg(-1) day(-1), with dead sperms observed in the epididymides and a loss of necrotic cells. Furthermore, the brains of rats administered 150 mg kg(-1) day(-1) nifurtimox revealed cerebral tissue softening. In dogs there were no treatment-related changes in organ weights during the dosing period. However, deciduous spermatoblasts were observed in the seminiferous tubules and there was a lack of long sperms in the epididymides. The findings from this study demonstrate inter-species differences in nifurtimox toxicity and toxicokinetics. These results are relevant to the evaluation of the wider clinical applications of this drug.

目的 建立测定氨酚伪麻那敏分散片中对乙酰氨基酚、盐酸伪麻黄碱及马来酸氯苯那敏溶出度的方法.方法 色谱柱为Agilent HC-C18柱(4.6 mm×250 mm,5μm),测定对乙酰氨基酚的流动相为甲醇-0.05 mol· L-1-磷酸二氢钾溶液-三乙胺(20:80∶0.02,V/V);检测波长为244 nm;测定盐酸伪麻黄碱与马来酸氯苯那敏的流动相为乙腈-0.5％十二烷基磺酸钠溶液-三乙胺(57∶43∶0.06,V/V)(磷酸调至pH 4.0);检测波长为260 nm.结果 对乙酰氨基酚、盐酸伪麻黄碱及马来酸氯苯那敏分别在4～ 820 μg· mL-1、3～ 466 μg· mL-1和0.2～ 62 μg· mL-1的浓度范围内线性良好.3个主药成分的回收率均良好.来自两个厂家的5批样品在溶出15 min取样检测时溶出度均在85％以上.结论 建立的方法专属性强,可用于氨酚伪麻那敏分散片中3个有效成分溶出度的质量控制.

A rapid, specific and high-throughput stable isotope-dilution LC-MS/MS method was developed and validated with high sensitivity for the quantification of R-phencynonate (a eutomer of phencynonate racemate) in rat and dog plasma. Plasma samples were deproteinized using acetonitrile and then separated on a C8 column with an isocratic mobile phase containing acetonitrile-water-formic acid mixture (60:40:0.1, v/v/v) at a flow rate of 0.2 mL/min. Each sample had a total run time of 3 min. Quantification was performed using triple quadrupole mass spectrometry in selected reaction monitoring mode with positive electrospray ionization. The method was shown to be highly linear (r2  > 0.99) and to have a wide dynamic range (0.1-100 ng/mL) with favourable accuracy and precision. No matrix effects were observed. The detailed pharmacokinetic profiles of R-phencynonate at therapeutic doses in rats and dogs were characterized by rapid oral absorption, quick clearance, high volume of distribution and poor absolute bioavailability. R-Phencynonate lacked dose proportionality over the oral dose range, based on the power model. However, the area under concentration-time curve and the maximum plasma concentration increased linearly in a dose-dependent manner in both animal models. The absolute bioavailability of R-phencynonate was 16.6 ± 2.75 and 4.78 ± 1.26% in dogs and rats, respectively.

目的 考察灌胃给药华卟啉钠在大鼠体内的主要代谢产物和代谢途径.方法 收集华卟啉钠灌胃后大鼠的血浆、尿液和粪便,采用Thermo Q Exactive Orbitrap四极杆-轨道阱高分辨质谱仪对大鼠尿、粪及血浆中的代谢产物进行研究,通过获得的精确分子量、二级碎片图谱,推断SD大鼠尿、粪及血浆中的代谢物,并绘制华卟啉钠在SD大鼠体内的代谢途径.结果 在大鼠的尿、粪及血浆样品中共检测到10个代谢产物,主要为两卟啉之间的醚键断裂后的产物及其进一步加氢、N-甲基化和O-甲基化产物.结论 华卟啉钠在大鼠体内以Ⅰ相代谢产物为主.

目的：探讨大鼠口服放射性氚标记盐酸川丁特罗（[3H]SPFF）后经尿、粪和胆汁的排泄动力学特征。方法采用化学法合成[3H]SPFF，并进行放化纯度鉴定。粪尿排泄实验观察SD大鼠经口45.5 MBq·kg-1（1 mg·kg-1）给药后168 h内经尿和粪累积放射性排出率。胆汁排泄实验观察胆汁引流模型大鼠给药后，72 h内胆汁累积放射性排出率。HPLC-放射性检测法鉴定单只大鼠尿和胆汁中放射性成分组成。结果化学法合成获得5 mL[3H]SPFF甲醇溶液（比活度403 GBq·g-1），化学纯度＞96%，放化纯＞97%。粪尿排泄实验的结果表明，经口给药后，SD大鼠体内放射性物质经泌尿系统排出较快，168 h经尿粪累积排出率达84.74%，其中尿回收56.63%，粪回收28.10%。胆汁排泄实验显示，给药后3 d，经胆汁放射性累积排出率为29.3%。放射性组成分析结果显示，单只SD大鼠给药后72 h尿液中累积总放射性排出量占给药量的48.61%，其中原型占4.71%，产物占42.62%。72 h胆汁中累积总放射性排出量占给药量的28.14%，其中原型占9.51%，产物占18.63%。结论大鼠经口盐酸川丁特罗后吸收完全，主要经尿液以代谢物形式排泄。

目的 建立硝呋莫司与SD大鼠、比格犬、食蟹猴和人血浆蛋白结合率的测定方法,计算硝呋莫司与4个不同种属的血浆蛋白结合率.方法 采用体外快速平衡透析法,将透析后的血浆和缓冲液分别加入对应的空白基质,用乙酸乙酯萃取后采用HPLC法测定.结果 硝呋莫司在样品中的线性范围为0.1～5 μg ·ml-1,在不同血浆中的色谱方法专属性良好,提取回收率为(73.64±1.00)％ ～ (81.20±0.66)％.硝呋莫司在人、犬、大鼠、猴中的血浆蛋白结合率范围为46.0％ ～58.2％、40.7％ ～42.6％、38.7％ ～ 43.8％、30.8％ ～42.8％.结论 硝呋莫司与4种血浆蛋白的结合率中等,且在不同种属的血浆蛋白结合率随药物浓度不同存在一定种属差异.

提出了中药活性成分发现与成药性研究的基本思路,并重点介绍了以岭南特色中药化橘红、田基黄等为基源的新药发现及成药性研究实例,对促进岭南特色中药的创新发展具有积极意义和实用价值.

Naringin is a pharmacologically active compound extracted and purified from Citri Grandis Ex-ocarpium ( Huajuhong) .During the past more than ten years, naringin has been developed into a classⅠinnovative drug to treat cough by our group.The Drug Clinical Trial Approval of naringin was issued by China Food and Drug Administration.As such, this review aims to summarize all of pre-clinical studies of naringin from our laboratory, including pharmacological effects and acting mechanisms, non-clinical pharmacokinetics and toxicological evaluation.

目的:建立毛细管气相色谱法(GC),测定复方薄荷脑滴鼻液中薄荷脑、樟脑的含量.方法:采用色谱柱为DB-WAXetr弹性石英毛细管柱(固定相:键合交联聚乙二醇,30 m×0.25 mm×0.25 μm),载气为N2,程序升温,检测器为氢焰离子化检测器(FID),对6家医院6批产品进行了测定.结果:薄荷脑在18.94～132.58tg/ml,樟脑在14.60～102.20 μg/ml范围内呈良好的线性关系,相关系数r＞0.999,样品的绝对回收率为97％～103％.各制剂样品的测定结果显示,薄荷脑和樟脑的含量均在标示量的90％～110％之间.结论:本方法简便、准确,重复性好,可快速测定制剂中薄荷脑和樟脑的含量,适用于提高该制剂的质控标准.

BACKGROUND AND AIM:The cryptand Kryptofix 2.2.2 is used extensively as a phase-transfer reagent in the preparation of [18F]fluoride-labelled radiopharmaceuticals. However, it has considerable acute toxicity. The aim of this study was to develop and validate a method for rapid (within 1 min), specific and sensitive quantification of Kryptofix 2.2.2 at trace levels. METHODS:Chromatographic separations were carried out by rapid-resolution liquid chromatography (Agilent ZORBAX SB-C18 rapid-resolution column, 2.1 × 30 mm, 3.5 μm). Tandem mass spectra were acquired using a triple quadrupole mass spectrometer equipped with an electrospray ionization interface. Quantitative mass spectrometric analysis was conducted in positive ion mode and multiple reaction monitoring mode for the m/z 377.3 → 114.1 transition for Kryptofix 2.2.2. The external standard method was used for quantification. RESULTS:The method met the precision and efficiency requirements for PET radiopharmaceuticals, providing satisfactory results for specificity, matrix effect, stability, linearity (0.5-100 ng/ml, r(2)=0.9975), precision (coefficient of variation < 5%), accuracy (relative error < ± 3%), sensitivity (lower limit of quantification=0.5 ng) and detection time (<1 min). Fluorodeoxyglucose (n=6) was analysed, and the Kryptofix 2.2.2 content was found to be well below the maximum permissible levels approved by the US Food and Drug Administration. CONCLUSION:The developed method has a short analysis time (<1 min) and high sensitivity (lower limit of quantification=0.5 ng/ml) and can be successfully applied to rapid quantification of Kryptofix 2.2.2 at trace levels in fluorodeoxyglucose. This method could also be applied to other [18F]fluorine-labelled radiopharmaceuticals that use Kryptofix 2.2.2 as a phase-transfer reagent.

Agrobacterium tumefaciens-mediated transformation of tobacco leaves (Nicotiana tabacum) is used to study gene expression in a heterologous genetic background. Here, the Cre-loxP recombination system was used to detect T-DNA transfer by two A. tumefaciens cells harboring different binary vectors. Cre, under the control of the CaMV 35S promoter, was cloned into one vector, and a loxP cassette into another vector. A mixture of A. tumefaciens, in which each cell contained either a Cre- or loxP-vector, was co-infiltrated into tobacco leaves. After two days, excision of loxP-flanked DNA was detected by PCR and used as an estimate for co-transformation events. Strongest excision (> 50%) was observed when the loxP cassette was cloned into vector pPZP112 and Cre into pISV2678. This fast and easy technique can be used to assess the co-transformation efficiency of tobacco cells in future studies.

A sensitive rapid resolution liquid chromatography–tandem mass spectrometry method was developed to determine the pharmacokinetics of ginsenoside Rb1, Rb2, and Rb3 in rats, after oral administration (50mg/kg) and intravenous administration (10mg/kg) of Rb1, Rb2, and Rb3, respectively. The plasma samples were extracted by saturated N-butanol with Rg2 as internal standard. Chromatographic separation was performed on a Zorbax SB-C18 column (50mm×4.6mm, 1.8μm) with a mobile phase consisting of methanol and 1mM ammonium formate (74:26, v/v). Multiple reaction monitoring mode was performed using the fragmentation transitions of m/z 1107.7→m/z 178.9, m/z 1077.7→m/z 148.6, and m/z 1077.7→m/z 783.4 for Rb1, Rb2, and Rb3, respectively. Calibration curves were recovered over a concentration range of 20–1000ng/ml for Rb1 and Rb2, and 50–2500ng/ml for Rb3. The limits of detection were 3.0ng/ml, 4.0ng/ml, and 6.5ng/ml. Both intra-day and inter-day variances were less than 15% and the accuracy was within 86–114% for the three ginsenosides. All three ginsenosides had poor oral bioavailability (0.78%, 0.08%, and 0.52% for Rb1, Rb2, and Rb3, respectively). The value of Rb1 is higher than that of Rb2 or Rb3, indicating that ginsenosides with hexose and hydroxyl groups (Rb1) could present better pharmacokinetic behaviors than those with pentose groups in the same glycosylation site by oral administration.

Toxicokinetic characteristics of naringin and its metabolite naringenin were investigated in beagle dogs after oral administration of naringin at the doses of 20, 100, or 500 mg/kg/day in a repeated-dose study for 1, 30, 90, and 180 days. Plasma concentrations of naringin and naringenin were determined by a rapid resolution liquid chromatography/electrospray ionization/tandem mass spectrometric method. The results showed that no differences in systemic exposure were observed between male and female beagle dogs. Systematic exposure exhibited dose-dependent increase for both naringin and naringenin. No significant accumulations were observed. Results would be taken into consideration for the interpretation of toxicology findings and provide a reference for clinical safety assessment.