Safety evaluation and drug development based on biological fate of drugs -efforts made to overcome drug interaction in drug development-.
Safety evaluation and drug development based on biological fate of drugs -efforts made to overcome drug interaction in drug development-.
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DOI：
10.2133/dmpk.17.379
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发表时间：
2002
影响因子：
2.1
通讯作者：
T. Matsubara
中科院分区：
文献类型：
--
作者：
T. Matsubara
1.通过测定肝脏样品中细胞色素P450含量及其活性，建立了检测毒理学样品中药物相互作用的测定方法。7-烷氧基香豆素的O-脱烷基化反应反映了P450分子形式的变化，并且通过使用所建立的方法可以容易地检测毒理样品中的酶诱导或抑制。2.在450191-S或睡眠诱导剂利马扎酮的毒理学研究期间，在动物中观察到肝脏药物代谢酶的苯巴比妥型诱导，大鼠和犬之间诱导所需的剂量显著不同。酶诱导由450191-S的某些特定代谢产物引起，当在两只动物中产生酶诱导时，这些代谢产物的血浆浓度相当。3.非甾体化合物480156-S对大鼠微粒体药物代谢活性显示轻微或无影响。另一方面，对人体重复给予该化合物导致480156-S的氧化代谢显著降低，随后该化合物的血浆浓度显著增加。当志愿者在接受480156-S后再接受几种药物（如甲苯磺丁脲）时，血浆清除率显著延迟，表明存在严重的药物相互作用。4.属于CYP 2C家族的细胞色素P450在大鼠和人肝微粒体中均参与480156-S的氧化代谢。微粒体与480156-S的预孵育导致大鼠和人体中CYP 2C依赖性甲苯磺丁脲羟基化反应的浓度依赖性抑制。对480156-S抑制作用的敏感性存在明显的种属差异，抑制大鼠CYP 2C所需的浓度几乎是人体所需浓度的10倍。5.在3 '-位取代有N-甲基四唑乙硫醚（NMTT）的头孢类抗生素被证明抑制线粒体低K（m）醛脱氢酶（ALDH），并在酒精代谢过程中产生双硫仑样（Antabuse）反应。药代动力学研究表明，抗生素在胆管或肠道中释放的NMTT引起抑制作用，随后发生双硫仑样反应。6.人们曾试图通过改变3 ′-位取代基的化学结构来开发缺乏双硫仑样反应的新头孢烯抗生素，发现羟乙基四唑乙硫醚不抑制该酶。在此基础上，结合抗菌活性，我们开发了一种新的氧头孢类抗生素氟氧头孢（6315-S）。氟氧头孢在大鼠和人体中均未出现双硫仑样反应。
1. Assay methods to detect drug interaction in toxicological samples were established by determining cytochrome P450 content and its activity in liver samples. The O-dealkylation reaction of 7-alkoxycoumarin was indicated to reflect changes in the molecular forms of P450s, and the enzyme induction or inhibition in the toxicological samples was easily detected by using the established methods. 2. During toxicological studies of 450191-S or the sleep inducer rilmazafone, a phenobarbital type-induction of hepatic drug metabolizing enzymes was observed in animals, and the doses required for the induction differed markedly between rats and dogs. Enzyme induction was caused by some specific metabolites of 450191-S, and the plasma concentrations of these metabolites were comparable when the enzyme induction was developed in both animals. 3. A nonsteroidal antiinflammatory compound 480156-S showed a slight or no effect on microsomal drug metabolizing activity in rats. On the other hand, repeated administration of this compound to humans resulted in a marked decrease in the oxidative metabolism of 480156-S, followed by a marked increase in the plasma concentrations of the compound. When volunteers were given 480156-S followed by several drugs, such as tolubutamide, the plasma clearance was delayed remarkably, indicating a severe drug interaction. 4. Cytochrome P450 belonging to the CYP2C family was indicated to participate in the oxidative metabolism of 480156-S in both rat and human liver microsomes. The preincubation of microsomes with 480156-S caused a concentration-dependent inhibition of CYP2C-dependent tolubutamide hydroxylation reaction in both rats and humans. There was a marked species difference in the susceptibility to the inhibitory effect of 480156-S, and the concentration required to inhibit rat CYP2C was almost 10 times higher than that required in humans. 5. The cephem antibiotics having N-methyltetrazolethiol (NMTT) at the 3'-position substituent were demonstrated to inhibit mitochondrial low K(m) aldehyde dehydrogenase (ALDH), and produced disulfiram-like (Antabuse) reaction during alcohol metabolism. Pharmacokinetic studies indicated that NMTT released from the antibiotics in bile duct or intestine cause the inhibitory action followed by the development of disulfiram-like reaction. 6. Attempts had been made to develop new cephem antibiotics lacking the disulfiram-like reaction by changing the chemical structure of 3'-position substituents, and a hydroxyethyltetrazolethiol was found not to inhibit the enzyme. Based on this result, together with the antibacterial activity, we have developed a new oxacephem antibiotic flomoxef (6315-S). Flomoxef showed no disulfiram-like reaction both in rats and human.