| 1 | Drug Metab. Dispos. 2003 Jan 31: 60-6 |
|---|---|
| PMID | 12485954 |
| Title | Differences in cytochrome P450 forms involved in the metabolism of N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a novel sigma ligand, in human liver and intestine. |
| Abstract | N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100) has been developed to treat subjects withschizophrenia。This drug is mainly excreted in the form of oxidative metabolites. In the present study, identification of p450 forms involved in the metabolism was carried out using human livers and intestinal microsomes (HLM and HIM). Eadie-Hofstee plots for NE-100 disappearance in HLM were biphasic, thus indicating the involvement of at least two p450 forms. The metabolism of NE-100 was mediated with recombinantCYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. A significant correlation was observed between activities of NE-100 metabolism and dextromethorphan O-demethylation (a specific activity for CYP2D6) or testosterone 6beta-hydroxylation (a specific activity for CYP3A4) in HLM. The activity of NE-100 metabolism was inhibited by approximately 80% by an anti-CYP2D6 antibody and only by quinidine among the p450-selective inhibitors at a low substrate concentration (0.1 microM). In contrast, with a high substrate concentration (10 microM), the activity was inhibited by an anti-CYP3A4 antibody and by ketoconazole. On the other hand, in HIM, the Eadie-Hofstee plots for NE-100 disappearance were monophasic, and the metabolism was strongly inhibited by an anti-CYP3A4 antibody and by ketoconazole but not by other inhibitors used. These results strongly suggest that NE-100 has different profiles regarding metabolism between liver and intestine. During absorption, NE-100 is mainly metabolized by CYP3A4 in the intestine and thereafter by CYP2D6 in the liver in the presence of therapeutic doses. |
| SCZ关键字 | schizophrenia |
| 2 | Arch. Toxicol. 2014 Mar 88: 691-9 |
| PMID | 24352538 |
| Title | Inhibition of tumour spheroid-induced prometastatic intravasation gates in the lymph endothelial cell barrier by carbamazepine: drug testing in a 3D model. |
| Abstract | Metastatic breast cancer is linked to an undesired prognosis. One early and crucial metastatic step is the interaction of cancer emboli with adjacent stroma or endothelial cells, and understanding the mechanisms of this interaction provides the basis to define new targets as well as drugs for therapy and disease management. A three-dimensional (3D) co-culture model allowing the examination of lymphogenic dissemination of breast cancer cells was recently developed which facilitates not only the study of metastatic processes but also the testing of therapeutic concepts. This 3D setting consists of MCF-7 breast cancer cell spheroids (representing a ductal and hormone-dependent subtype) and of hTERT-immortalised lymph endothelial cell (LEC; derived from foreskin) monolayers. Tumour spheroids repel the continuous LEC layer, thereby generating "circular chemorepellent-induced defects" (CCIDs) that are reminiscent to the entry gates through which tumour emboli intravasate lymphatics. We found that the ion channel blocker carbamazepine (which is clinically used to treat epilepsy,schizophrenia和其他神经系统疾病）抑制了CCID的形成。这种作用与抑制NF-？B的活性有关，该活性导致细胞运动，以及迁移蛋白MLC2，MyPT1和FAK的失活，这对于LEC迁移是必需的。NF-？B活性和细胞运动是CCID形成的先决条件。另一方面，运动蛋白帕西林和NF-依赖性粘附介质ICAM-1的表达没有变化。ALOX12的活性也不受影响。ALOX12是主要酶合成12（s） - hete，然后触发CCID的形成。抑制的相关性CYP1A1, which is also involved in the generation of mid-chain HETEs such as 12(S)-HETE, by carbamazepine remains to be established, because the constitutive level of 12(S)-HETE did not change upon carbamazepine treatment. Nevertheless, the effect of carbamazepine on the inhibition of CCID formation as an early step of breast cancer metastasis was significant and substantial (~30 %) and achieved at concentrations that are found in the plasma of carbamazepine-treated adults (40-60 ?M). The fact that carbamazepine is a drug approved by the US Food and Drug Administration facilitates a "from-bench-to-bedside" perspective. Therefore, the here presented data should undergo scrutiny in vivo. |
| SCZ关键字 | schizophrenia |
| 3 | Int Clin Psychopharmacol 2015 Mar 30: 82-8 |
| PMID | 25025989 |
| Title | Pharmacogenetics of quetiapine in healthy volunteers: association with pharmacokinetics, pharmacodynamics, and adverse effects. |
| Abstract | Quetiapine is an atypical antipsychotic used for treatment ofschizophrenia。对该药物的响应变异性可能与药物遗传学有关。这项研究的目的是鉴定与喹硫平的药代动力学，药效学和不良反应有关的遗传标记。该研究人群包括来自两项生物等效试验的79名健康志愿者，这些试验旨在鉴定编码酶，受体和转运蛋白的基因中的多态性。使用高性能液相色谱/质谱法对喹硫平血浆水平进行定量。通过间接化学发光检测催乳素血浆水平。在整个研究过程中记录了可能的不良影响。在单变量分析中，p值为0.1或更少的因素包括在多元回归分析（不良反应的逻辑回归）中。曲线下的面积和喹硫平的清除率分别受到CYP1A2和DRD3的多态性的影响。与女性相比，曲线下的喹硫平面积较低。 Prolactin iC(max) was higher in volunteers harboring polymorphisms in CYP2C19 and AGT. An association was detected between polymorphisms inCYP1A1CYP2C9和嗜睡。几个多态性re responsible for differences in the pharmacokinetics, pharmacodynamics, and safety of quetiapine in healthy individuals. |
| SCZ关键字 | schizophrenia |