摘要
配伍是中药运用的主要形式,是中药的特色和优势,也是中药学研究的重点和难点。而细胞色素代谢酶P450(CYP450)作为人体重要的Ⅰ相药物代谢酶系统,在研究药物代谢和药物间相互作用方面存在着重要价值。故通过分析中药配伍后对CYP450的诱导或抑制作用,对阐明配伍的科学内涵,以及继承和发展中医药理论有着深远意义。
本文理论部分整理和阐释了七情配伍中,存在药物间相互作用关系的相须、相使、相畏、相杀、相恶、相反六种配伍关系的基本涵义;并结合中药基本理论的性味、归经、升降浮沉以及临床配伍运用经验,以半夏药对为例,对其内涵进行进一步的阐述和挖掘;同时,通过分析CYP450在药物相互作用中的重要地位,总结CYP1A2、CYP3A4及CYP2E1在药物转化中的主要作用,阐明了以半夏药对为切入点,引入CYP450酶,对研究中药配伍的深远意义。
实验研究分别以半夏-生姜、半夏-黄连、半夏-附子及半夏-甘草四组药对为研究对象,采用Cocktail探针药物法,通过分析探针药物代谢的药动学参数的变化,评价各组药物对CYP450酶的影响。结果表明给予半夏-甘草组的大鼠CYP1A2及3A4的水平显著高于对照组,CYP2E1水平没有显著变化。其余各配伍给药组对CYP450酶3种亚型水平均无影响。结论是从CYP450酶角度来看,半夏与甘草配伍对CYP1A2及3A4具有显著地诱导作用,故推测作为CYP1A2及3A4诱导剂的甘草,可促进与之配伍的半夏毒性成分的代谢。提示我们在临床上应用毒性中药时,可在辩证施治的情况下,适当这种“相须相畏”配伍方式;半夏附子配伍对三种亚型活性无明显作用,印证了“半夏并不反附子”之说;而半夏生姜与半夏黄连配伍对CYP450酶三种亚型不产生诱导或抑制作用,表明这两组药对配伍应用时既不影响其他药物药效的发挥,也不会产生药物毒性成分的蓄积,为“相畏相杀”及“相须相使”是临床“可用”、“当用”之配伍提供理论基础,并为临床安全合理使用该配伍形式提供参考。
The compatibility is the main clinical application forms of traditional chinese medicine,which is not only the feature and dominance of traditional chinese medicine,but also the emphasis and nodus of this field of science research.As an important phase I drug-metabolizing enzyme system in the human body,cytochrome P450 enzymes has significant value during the study of drug metabolism and drug-drug interaction.Therefore,it has far-reaching significance in researching the connotation of compatibility,as well as inheriting and developing the theory of traditional chinese medicine by analyzing the induction or inhibition effect of CYP450 in different compatibility of traditional chinese medicine.
Through investigated on ancient literature and modern clinical experience, systematically sorted out and interpreted six kinds of medicinal compatibility, including the mutual reinforcement,mutual assistant,mutual detoxication,mutual restraint,mutual inhibition and antagonism,belonged to the core part of the theory of medicinal compatibility,namely the seven prescriptions.Meanwhile,taking the commonly used couplet medicines(pinellia tuber-ginger,pinellia tuber-aconite, pinellia tuber-golden thread,pinellia tuberliquorice root) as examples,expounded and explored the connotation of seven prescriptions,integrating property and flavor, meridian distribution,lifting,lowering,floating and sinking,and clinical experience,which belonged to traditional Chinese medicine fundamental theory.in order to identify and expand it.Then,through analyzed the significance of the metabolic enzyme CYP450 in the interaction of compatibility of Chinese Herbs,and summarized major functions of CYP1A2,CYP3A4 and CYP2E1 in transformation of drug,finally,we put forward to establish the research mode of compatibility of Chinese herbs on the basis of studying on the effect of CYP450's activity in different compatibility of Chinese herbs.
The part of empirical study is on the basis of reseashing the four pairs of couplet medicines(pinellia tuber-ginger,pinellia tuber-aconite,pinellia tuber-golden thread, pinellia tuber-liquorice root) on the basis of studying on the effect of CYP450's activity in different compatibility of Chinese herbs by cocktail approach.Result is the level of CYP1A2 and CYP3A4 after received the aqueous extract of pinellia tuber -liquorice root was enhanced,but the level of CYP2E1 was not changed.But the other Chinese drug pairs groups have not effect the subtype enzymes of CYP450 either.So we can draw the conclusions from the directions of CYP450,that is pinellia tuber -liquorice root could induce CYP1A2 and CYP3A4,CYP2E1 was hardly affected.we presumed that liquorice root is the inductor of CYP1A2 and CYP3A4,so that it could promote the metabolism of pinellia tuber's toxicity compositions.this indicated that we can used this kind of compatibility mode under the circumstances of determine the treatment based on differentiation of symptoms and signs when utilizing the traditional Chinese medicine with toxicity.Pinellia tuber-aconite has no effect to the levis of subtype enzymes,which confirmed the debate of pinellia tuber and aconite have no relations of antagonism.Althouge the groups of pinellia tuber-ginger and pinellia tuber-golden thread could not induce or inhibite the activity of subtype enzymes,it still manifested that they would not effect the pharmacodynamic action of other drugs which mixed used during the clinical practice,but would not occur cumulation of toxicity compositions.These conclusions supplied rationale to the theory of "the the mutual reinforcement and mutual assistant should be used in the process of clinic ","utual detoxication and mutual restraint can used in the process of clinic",furthmore,provided for references in order to ues durg securely and rationally.
引文
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