药物代谢与药物动力学基础研究展望

1　药物代谢与药物动力学的战略地位药物在体内的吸收、分布、代谢和排泄统称为药物的体内过程 ,其中吸收、分布、排泄过程又称机体对药物的转运 ,代谢过程又称机体对药物的转化。药物代谢与药物动力学是研究药物体内过程动态规律的科学 ,药物代谢 (ｄｒｕｇｍｅｔａｂｏｌｉｓｍ)探讨药物分子的化学结构在体内以不同规模发生的生物转化 ,药物动力学 ( ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ)的核心是阐明体内药物及其代谢产物的浓度随时间变化的动态过程[1～ 4 ] 。几乎所有的生物体均对外源性的化学物质 (ｘｅｎｏ ｂｉｏｔｉｃａ)具有转运和…     

常见药物转运体基因多态性对药动学影响及研究进展

药物转运体在体内药物的吸收（absorption）、分布（distribution）、代谢（metabolism）及排泄（excretion）的过程（ADME）中发挥着关键的作用。转运体在各组织器官的不同分布以及其基因多态性,导致某些药物的吸收、分布、代谢和排泄过程产生明显的个体差异。随着药物基因组学的快速发展,关于转运体基因多态性的研究报道越来越多。本文对近年来人体主要药物转运体基因多态性在药动学和药效学中的影响研究进行综述。     

发育药理学--药物在小儿体内的作用特点

小儿不同年龄阶段发育的变化,对药物的体内处置有极大影响,本文引用“发育药理学”这一较新的概念,从药物在小儿体内吸收、分布、代谢和排泄的药物动力学全过程,综述药物在小儿体内的作用特点。     

转运体介导的食物-药物相互作用

食物与药物之间的相互作用普遍存在,且作用机制也多种多样。目前,研究较多的是单个食物或食物中的某些营养成分通过调节药物转运体或代谢酶的功能从而影响药物的体内过程。食物对药物体内过程的影响包括吸收、分布、代谢、排泄四个方面,并且主要是调节其中参与的药物转运体和代谢酶的功能。转运体介导的食物对药物体内吸收的影响主要是通过调节肠上皮摄取型和外排型的转运体,从而影响药物的吸收;对分布的影响主要是通过调节体内一些屏障中的转运体;对代谢的影响主要是同时调节药物代谢酶和转运体;对排泄的影响是通过调节肾脏和肝脏胆汁排泄的药物转运体,从而影响药物的清除率。因此,转运体介导的食物与药物相互作用直接影响药物治疗的效果。     

鬼针草中黄酮类化学成分的药代动力学研究进展

鬼针草是我国的传统中药材,现代药学研究发现有抗炎、抗氧化、抗纤维化等药理活性,临床用于肝炎、风湿等疾病。黄酮类是其主要活性部位,从鬼针草中提取的鬼针草总黄酮（TFB）具有良好的临床应用前景。近年来其中一些成分在体内的药代动力学研究资料不断丰富,为了进一步明确鬼针草中黄酮类成分在体内的吸收、分布、代谢、排泄过程,该文就近年来鬼针草中含有的黄酮类化学成分的药代动力学研究进展进行综述,为相关研究提供参考。     

肾功能不全病人的药物剂量调整

肾功能不全病人的药物剂量调整宋钟娟，顾金林（上海市华东医院２０００４０）药物在体内要经过吸收、分布、代谢、排泄四个主要的动力学过程，影响药物清除的主要二大组织是肝脏和肾脏。许多药物以原形从肾脏排泄，甚至一些有活性或毒性的代谢产物也经肾脏排泄。当肾功能...     

肠道“药物代谢酶-外排转运体偶联”对黄酮类化合物生物利用度影响的研究进展

黄酮类化合物为广泛存在于食物和药物中的一类多酚化合物，具有多种药理作用，但其生物利用度低限制了其临床应用，这与其肠道吸收和代谢密切相关。黄酮类化合物主要在肠道吸收，并经Ⅱ相药物代谢酶：葡萄糖醛酸转移酶（UGTs），硫酸转移酶（SULTs）和谷胱甘肽-S-转移酶（GSTs）广泛代谢为Ⅱ相代谢产物，其极性增加，难以通过被动扩散穿透肠上皮细胞膜。肠道外排转运体P-糖蛋白（P-gp）、乳腺癌耐药蛋白（BCRP）、多药耐药相关蛋白（MRPs）作为一个"旋转门"，可调控肠上皮细胞内Ⅱ相代谢物外排至肠腔或进入体循环。本文对黄酮类化合物在肠道处置以及肠道药物代谢酶-外排转运体偶联进行了探究，这种偶联作用可显著影响黄酮类化合物生物利用度，进而影响其临床疗效与毒副作用。阐明肠道代谢酶-外排转运体偶联作用及其机制，将为提高黄酮类化合物体内生物利用度和增加其临床疗效奠定基础。     

计算模拟技术在化合物代谢特征预测中的应用

近年来已经发现,具有良好的药代动力学特征的候选药物方有临床应用价值和前景,因此在新药研发的过程中应尽早引入对药物吸收、分布、代谢和排泄的评价。细胞色素P450（CYP450）是药物体内代谢中一类至关重要的酶系,若能较准确地对化合物的CYP450代谢特征,如其是否为CYP450的底物、抑制剂和诱导剂等进行预测,就有可能提高新药研发的成功率,故以此为例,介绍目前有关计算模拟技术在预测化合物代谢特征方面的应用研究进展。     

建国以来中草药有效成分的药物代谢动力学研究

药物代谢是研究药物的体内过程—吸收、分布、结构转化和排泄。药物代谢动力学(简称药代动力学)是用数学模式定量研究药物体内过程的动态变化。药物体内过程及其动力学研究对于指导临床合理用药有特殊重要的意义。本文评述了建国35年来中草药有效成分、包括其合成品和衍生物或有效部位的体内过程及药代动力学研究的情况,并试图对研究前景作一展望。     

天然环烯醚萜类化合物的药动学研究进展

环烯醚萜类化合物是存在于多种中药材里的一类重要成分,具有多种生物活性。从吸收、分布、代谢、排泄4个方面对常见的环烯醚萜类化合物（栀子苷、胡黄连苷、獐牙菜苦苷等）在动物体内的药动学研究进行整理和综述,发现这类化合物具有在体内快速吸收,在肾、肝等组织脏器中广泛分布,经水解和葡萄糖醛酸化等多种代谢过程后迅速排泄出体外的药动学特点,为提高该类化合物的生物利用度以及新药研发提供参考。     

黄酮类化合物磷脂复合物的制备与功能活性研究进展

黄酮类化合物具有诸多生物活性,但因其脂溶性差、生物利用度低等问题,严重制约了在生物医药领域的应用。近年来对黄酮类化合物改性技术及开发备受关注,例如黄酮磷脂复合物的制备可显著增强黄酮的脂溶性,促进其在消化道中的吸收,提高黄酮类的生物利用度。本文对国内外黄酮磷脂复合物的制备、药代动力学及功能活性方面的应用研究进行综述,旨在为日后对黄酮类化合物临床应用价值的开发提供依据。     

Comparison of effects of natural or artificial rodent diet on etoposide absorption in rats

The oral administration of etoposide has erratic absorption and low bioavailability. P-glycoprotein (Pgp) located in the intestinal brush-border membrane may pump out orally absorbed etoposide and thus decrease etoposide's absorption. Since flavonoids are abundant in food, we speculated that the common natural rodent diet may contain some flavonoid-related constituents which influence etoposide absorption. We therefore compared the absorption of etoposide's in the everted gut sacs of rats pretreated for 30 minutes with two different diets, natural rodent diet or artificial rodent diet. The effect of quercetin, one of the plant derived flavonoids with Pgp modulating activity, on etoposide's absorption was also compared. The addition of natural rodent diet or quercetin increased etoposide's absorption in everted sacs of jejunum or ileum, in comparison to those added with artificial rodent diet. The enhancing effect of quercetin was compatible with the effect of natural rodent diet in the jejunum and was higher in the ileum. These in vitro data supported the hypothesis that certain dietary components, possibly flavonoid-related compounds, may influence Pgp's function in intestine and thus increase etoposide's absorption. However, when fed with natural rodent diet for one week, a lower enhancing effect on absorption was observed. This may be due to the metabolism of the ingredients with modulating activity to their inactive forms, thus reducing the effect of natural rodent diet on etoposide absorption. The results proved that feeding rats with natural or artificial rodent diet had no obvious effect on etoposide absorption in vivo.     

山楂叶总黄酮磷脂复合物大鼠在体肠吸收动力学研究

目的研究山楂叶总黄酮磷脂复合物的大鼠在体小肠吸收动力学特征。方法采用大鼠在体肠单向灌流模型,以山楂叶总黄酮原料药为对照,采用分光光度法测定灌流液中总黄酮含量,计算肠吸收速率常数（Ka值）与单位时间吸收转化率（A值）,考察药物浓度与pH值对山楂叶总黄酮磷脂复合物肠吸收的影响。结果浓度为0．1mg·mL^-1的山楂叶总黄酮和山楂叶总黄酮磷脂复合物,Ka值与A值分别为0．0109h^-1,1．20％和0．0391h^-1,3．73％;药物浓度为0．1mg．mL^-1,pH为6．0,7．4,8．0的肠循环液,山楂叶总黄酮和山楂叶总黄酮磷脂复合物的Ka值分别为0．0076．0．0109．0．0056h^-1和0．0376,0．0391,0．0305h^-1,A值分别为0．69％,1．20％,0．42％和3．19％,3．73％,2．81％;表明在总黄酮浓度和溶液pH相同条件下,山楂叶总黄酮磷脂复合物的大鼠在体肠吸收明显优于山楂叶总黄酮。结论磷脂固体分散技术可改善山楂叶总黄酮的小肠吸收。     

Flavonoid antioxidants

In order to ascertain the role of dietary flavonoids as antioxidants in vivo it is necessary to understand the chemical nature of the absorbed forms in the circulation in vivo and how the multiplicity of research findings in vitro reflect the bioactivity of flavonoids in vivo. Only when we gain adequate information on the circulating forms can we begin to understand the targeting to the tissues, whether flavonoids cross the blood-brain barrier, for example, and in what forms. Flavonoids are powerful antioxidants in vitro, but their overall function in vivo has yet to be clarified, whether antioxidant, anti-inflammatory, enzyme inhibitor, enzyme inducer, inhibitor of cell division, or some other role. It should also be emphasised that the reducing properties of flavonoids might contribute to redox regulation in cells, independently of their antioxidant properties, and thus might protect against cell ageing, for example, by working together with the intracellular reductant network. To gain understanding of these issues the factors influencing the absorption of flavonoids in the gastrointestinal tract needs to be established, namely the questions of: de-glycosylation before absorption, conjugation in the small intestine through glucuronidation, sulphation or methylation etc, metabolism and degradation in the colon to smaller phenolic molecules. The forms in which they circulate in vivo will influence their polarity and, thus, their localization and bioactivities in vivo. Finally if antioxidant activities are important, the elucidation of how such properties in vitro relate to the potential for conjugates and metabolites in vivo to act as antioxidants is required. The absorbed flavonoid components might function in the aqueous phase (like vitamin C) or in the lipophilic milieu (as vitamin E) in vivo. This will depend on their polarity properties on uptake, how they are metabolised on absorption, and their resulting structural forms in the circulation.     

桑叶中黄酮类成分在大鼠体内分布特征研究

目的:研究桑叶中黄酮类成分的归经特征。方法:采用有效成分的组织分布分析桑叶中黄酮类成分与归经的关系。结果:芦丁和总黄酮在大鼠各组织中分布广泛,芦丁在胃中分布最多,其余脏器中大部分有二次分布特点;总黄酮在肝中分布最多,在大肠中分布较多。结论:桑叶总黄酮的分布特征与桑叶归肝、肺经相符合。     

Segment-selective absorption of lysozyme in the intestine

Absorption of fluorescein isothiocyanate-labeled lysozyme (FITC-lysozyme) was examined in rat small intestine. Messenger RNA of megalin, an endocytic receptor for lysozyme in the kidney, was expressed in the lower but not in the upper intestine. In in situ closed loop and recirculation methods, absorption of FITC-lysozyme from the upper intestine was much higher than from the lower intestine. The absorption rate of FITC-lysozyme in the upper intestine was significantly higher than FITC-dextran and was inhibited by unlabeled lysozyme in a concentration-dependent manner. The absorption of FITC-lysozyme was also inhibited by spermine and phenylarsine oxide. These results indicate that the intestinal absorption of lysozyme is segment-selective and occurs preferentially from the upper intestine. Megalin expressed in the lower intestine appears not to have a significant role in the absorption of lysozyme. In the upper intestine, lysozyme appears to be absorbed by an endocytic pathway, and cationic charge may be important for lysozyme absorption.     

黄葵醇提物中黄酮类成分在体肠吸收研究

为了研究黄葵黄酮类成分的肠吸收机制,进行了黄葵醇提物不同浓度、不同肠段大鼠在体肠吸收研究。采用HPLC法测定循环液中药物浓度,分析了黄葵6种黄酮类成分的肠吸收,开展了P-gp抑制剂对黄葵黄酮类成分吸收影响的研究。结果显示:黄葵各黄酮成分在不同浓度下,Ka值没有明显差异(P>0.05),吸收呈一级动力学过程,提示为被动扩散吸收;各黄酮成分之间的吸收有差异性,苷类成分的Ka值小于苷元类成分;各成分在不同肠段均有吸收,金丝桃苷和杨梅素的最佳吸收部位分别为空肠和十二指肠;P-gp抑制剂维拉帕米可促进异槲皮苷、金丝桃苷、杨梅素和槲皮素3'-O-葡萄糖苷的吸收。     

Intestinal absorption of sodium cefoxitin in rats: effect of formulation

The absorption of cefoxitin from rat intestine, rectum and small intestine was greater when the powdered form was administered than when an aqueous solution was given. Cefoxitin absorption from the small intestine was significantly increased after its administration in suppository form prepared with a triglyceride base, although rectal absorption from the suppository did not differ from that of the drug in powdered form. The increase in absorption by the small intestine from the suppository form may be due to fatty acids produced from triglyceride by lipase.     

在体单向灌流法研究加巴喷丁的大鼠肠吸收

采用在体单向灌流法考察加巴喷丁的大鼠肠吸收特性.结果表明,加巴喷丁在小肠各段(十二指肠段、空肠段和回肠段)和结肠均有吸收.低、中浓度(1和10 mmol/L)时药物在小肠各段的吸收速率常数(Ka)和有效渗透系数(Peff)显著大于结肠段(P＜0.05),高浓度(50 mmol/L)时十二指肠段的吸收显著大于结肠段(P＜0.05).加巴喷丁浓度对其在小肠各段的吸收有显著影响,低浓度组小肠各段药物的Ka和Peff显著大于高浓度组(P＜0.05),而药物浓度对结肠段的吸收无显著影响.