【文章內(nèi)容簡(jiǎn)介】 mple, the bacteriacide殺菌劑 prontosil百浪多息 , discovered in 1935, is not active but is metabolized to the antibacterial殺菌的 sulphanilamide磺胺 . 24 前藥是指一些在體外 活性 較小或者無(wú)活性的 化合物 ，在體內(nèi)經(jīng)過 酶 的 催化 或者非酶作用，釋放出 活性物質(zhì) 從而發(fā)揮其藥理作用的化合物，其常常指將活性藥物（原藥）與某種無(wú)毒性化合物以 共價(jià)鍵 相連接而生成的新化學(xué)實(shí)體。 硬藥 是指具有發(fā)揮藥物作用所必需的結(jié)構(gòu)特征的化合物，該化合物在生物體內(nèi)不發(fā)生代謝或轉(zhuǎn)化，可避免產(chǎn)生某些毒性代謝產(chǎn)物。 軟藥 是指本身具有治療作用的藥物，在生物體內(nèi)作用后常轉(zhuǎn)變成無(wú)活性和無(wú)毒性的化合物。 25 Metabolism ? Drug metabolism is the biotransformation生物轉(zhuǎn)化 of the drug into other pounds referred to as metabolites代謝物 . These biotransformations occur mainly in the liver but they can also occur in blood and other ans such as the brain, lungs肺 and kidneys腎 . Metabolism of a drug usually reduces the concentration of that drug in the systemic全身的，系統(tǒng)的 circulation循環(huán) , which normally leads to either a lowering or a plete suppression抑制 of the pharmacological action and toxic effects of that drug. Exceptions are prodrugs, such as prontosil, where metabolism produces the active form of the drug. 26 ? Metabolism usually involves more than one route and results in the formation of a sucession消長(zhǎng) of metabolites. Each of these metabolites may have a different or similar activity to the parent drug. Consequently, the activities of all the metabolites of a drug must be considered in the development of a potential drug. Metabolites are frequently more water soluble than their parent drug and because of this are usually excreted排泄 in the urine尿液 . 27 生物轉(zhuǎn)化分兩步進(jìn)行，第一步為氧化、還原或水解，第二步為結(jié)合。第一步反應(yīng)使多數(shù)藥物滅活，但少數(shù)例外反而活化，故生物轉(zhuǎn)化不能稱為解毒過程。第二步與體內(nèi)物質(zhì)結(jié)合后總是使藥物活性降低或滅活并使極性增加。各藥在體內(nèi)轉(zhuǎn)化過程不同，有的只經(jīng)一步轉(zhuǎn)化，有的完全不變自腎排出，有的經(jīng)多步轉(zhuǎn)化生成多個(gè)代謝產(chǎn)物。 28 Factors affect metabolism ?Biological factors affecting metabolism: Age, Sex, Geic variations ?Environmental factors affecting metabolism ?Species and metabolism 29 Biological factors affecting metabolism ? The metabolic differences found within a species are believed to be due to variations in age, sex, geics遺傳學(xué) and diseases. In particular, diseases that affect the liver will have a large effect on drug metabolism. Diseases of ans, such as the kidneys and lungs, that are less important centres for metabolism will also affect the excretion of metabolic products. Consequently, when testing new drugs, it is essential to design trials to cover all these aspects of metabolism. 30 1. Age ? The ability to metabolize drugs is lower in the very young (under 5) and the elderly (over 60). However, it is emphasized that the quoted引證的 ages are approximate and the actual changes will vary according to the individual and their lifestyle. In the foetus胎兒 and the very young (neonates新生兒 ), many metabolic routes are not fully developed. This is because the enzymes required by metabolic processes are not produced in sufficient quantities until several months after birth. Children (above 5) and teenagers青少年 usually have the same metabolic routes as adults. ? However, their smaller body volume means that smaller doses are required to achieve the desired therapeutic effect 31 2. Sex ? The metabolic pathway followed by a drug is normally the same for both males and females. However, some sex related differences in the metabolism of anxiolytics抗焦慮藥 , hypnotics催眠的 and a number of other drugs have been observed. Pregnant women will also exhibit changes in the rate of metabolism of some drugs. For example, the metabolism of both the analgesic鎮(zhèn)痛劑 pethidine哌替啶 and the antipsychotic安定藥 chlorpromazine氯丙嗪 are reduced during pregnancy. 32 3. Geic variations ? Variations in the geic codes of individuals can result in the absence of enzymes, low concentrations of enzymes or the formation of enzymes with reduced activity. These differences in enzyme concentration and activity result in individuals exhibiting different metabolic rates and in some cases different pharmacological responses for the same drug. An individual’s inability to metabolize a drug could result in that drug accumulating in the body. This could give rise to unwanted effects. 33 Environmental factors affecting metabolism ? The metabolism of a drug is also affected by lifestyle. Poor diet, drinking, smoking and drug abuse濫用 may all have an influence on the rate of metabolism. ? The use of overthecounter (OTC) selfmedicaments may also affect the rate of metabolism of an endogenous內(nèi)生的 ligand or a prescribed規(guī)定的 drug. Since the use of overthecounter medicaments is widespread, it can be difficult to assess the results of some large scale clinical trials. 34 Species and metabolism ? Different species often respond differently to a drug. This is believed to be due to