药物非临床毒代动力学研究进展

药物非临床毒代动力学是药代动力学在全身暴露评价中的延伸,或为非临床毒性研究的一部分,或为某一专设支持性研究,可为药物临床试验或应用提供安全性依据。目前毒代动力学已由最初的解释毒性试验结果逐渐扩展至毒性机制研究,成为在药物非临床和临床研究间的桥梁,同时其研究范围也扩展至药物代谢产物等的安全性评价中。本文就毒代动力学的实施、复合因素以及国内外研究进展进行综述,并展望其发展新方向。

Chemical constituents from Portulaca oleracea and their bioactivities

In the present study, we aimed to intensively study the chemical constituents, especially organic acids from a medicinal plant Portulaca oleracea L., and screen their anti-inflammatory and quinone reductase （QR, a phase II detoxyfication enzyme） inductive activity. A total of 20 compounds were isolated and identified based on spectroscopic methods, as succinic acid （1）, mono-methyl succinate （2）, L-malic acid （3）, L-l-methyl malate （4）, L-4-methyl malate （5）, L-dimethyl malate （6）, L-6-ethyl citrate （7）, L-1-methyl citrate （8）, L-1,5-dimethyl citrate （9）, 4-hydroxy-5-methylfuran-3-carboxylic acid （10）, 5-hydroxymethyl-furoic acid （11）, stearic acid （12）, L-pyroglutamic acid （13）, cyclo-（tyrosine-leucine） （14）, L-isoleucine （15）, （-）-dehydrovomifoliol （16）, （-）-epiloliolide （17）, 3,4-dihydroxyphenylethanol （18）, succinimide （19）, and uracil （20）. Among them, 14 compounds （2, 4-8, 10, 11, 13-18） were isolated from P. oleracea for the first time. Compotmd 18 （12.5 μM） exhibited potent anti-inflammatory effect in lipopolysaccharide （LPS）-induced macrophage cells （RAW264.7） by reducing NO production, and it also increased QR activity in Hepa lclc7 cells. Compound 16 （50 μM） showed weak QR inductive activity. None of other compounds showed anti-inflammatory or QR inductive activities.

Pharmacokinetic and pharmacodynamic comparison between Glucophage~? and a generic metformin in a rat model

In the present study, we aimed to compare the pharmacokinetics and pharmacodynamics between Glucophage~? and a generic metformin formulation in a diabetic rat model in order to assess the bioequivalence of the generic formulation. Adult male Zucker diabetes fatty rats received Glucophage~? or the generic metformin through gastric gavage at a dose of 180 mg/kg(n = 6 per condition). Both pharmacokinetic parameters(AUC0–t, AUC0–∞, Cmax) of metformin and plasma glucose levels were compared between the two groups. For pharmacodynamics, rats received Glucophage~? or the generic metformin at doses of 180 and 300 mg·kg–1·d–1 for 6 weeks. The measurements included body weight, fasting plasma glucose, glycosylated serum protein(GSP) and serum insulin. Data were analyzed with SPSS 22.0 and Prism 7. The level of statistical significance was set at P<0.05. In single dosing experiments, pharmacokinetic parameters(t1/2, AUC0–t and Cmax) did not differ between Glucophage~? and the generic metformin(P>0.05). However, plasma glucose was significantly higher in the generic metformin group at 2 h(P = 0.03) and 4 h(P = 0.04) after drug treatment. In repeated dosing experiments, fasting glucose, HOMA-IR and body weight in rats receiving high-dose Glucophage~? were significantly lower at the end of the 6-week treatment period than those in rats receiving high-dose generic metformin(P<0.05 for all). GSP and serum insulin did not differ significantly between the two groups. In rats receiving low-dose metformin, fasting glucose was lower in the Glucophage~? group. HOMA-IR and body weight did not differ between the two groups. Moreover, blood lipids did not differ significantly between the two groups. The generic metformin used in the current study did not differ significantly in pharmacokinetic characteristics with Glucophage~?. However, Glucophage~? was superior in terms of glucose control, body weight loss and insulin sensitivity in repeated administration.

Synthesis and biological evaluation of indeno[1, 2-b]indole derivatives as dual topoisomerase Ⅰ & Ⅱ inhibitors: novel multidrug resistant reversal anticancer agents

A single compound able to inhibit both TopoⅠandⅡmay present the advantage of improving anti-proliferative activity,with reduced toxic side effects,with respect to the combination of two inhibitors.We designed and synthesized 28 compounds of indeno[1,2-b]indole derivatives as a new class of TopoⅠandⅡinhibitor and successfully identified compound 2-3 j,which showed the most potent cell growth inhibition with IC50=0.74μM against HCT-116 cell line.Compound 2-3 j was also evaluated as a potent topoisomeraseⅠandⅡinhibitor and can induce apoptosis in human colon cancer cells.2-3 j showed potency against a small panel of drug sensitive and multidrug resistant(MDR)cell lines,and it reversed the MDR of K562/A02,MCF-7/Adr,and KB/Vcr cells at 0.5μM,with reversal fold values of 3.2,10.1,and 5.8,respectively.2-3 j might inhibit the function of ABCG2 to increase intracellular drug accumulation and enhance the sensitivity of conventional chemotherapeutic agents for MDR cells.2-3 j could be a promising lead for the development of a new class of antitumor drug acting as inhibitors of TopoⅠ&Ⅱand ABCG2.