| 1 | Ther Drug Monit 2006年10月28日：599-602 |
|---|---|
| PMID | 17038872 |
| 标题 | Effect of adjunctive lamotrigine treatment on the plasma concentrations of clozapine, risperidone and olanzapine in patients with schizophrenia or bipolar disorder. |
| Abstract | 这effect of lamotrigine on the steady-state plasma concentrations of the atypical antipsychotics clozapine, olanzapine, and risperidone was investigated in patients with精神分裂症或用氯氮平（200-500 mg/day; n = 11），利培酮（3-6 mg/day; n = 10）或奥氮平（10-20 mg/day; n = 14）），利培酮（3-6 mg/day; n = 10），在慢性治疗中稳定的双相情感障碍。。在8周内，将拉莫三嗪滴定至200 mg/天的最终剂量，并在基线时和治疗第6和第10周进行药代动力学评估，分别在100和200 mg/day的Lamotrigine剂量下进行。氯氮平，Norclozapine，利培酮和9-羟基瑞菌酮的血浆浓度在用Lamotrigine治疗期间没有显着变化。奥氮平的平均血浆浓度为基线时为31 +/- 7 ng/ml，第6周时为32 +/- 7 ng/ml，第10周，第10周，第10周和基线之间的差异为36 +/- 9 ng/ml具有统计学意义（p <0.05）。辅助拉莫三嗪治疗在所有组中均得到很好的耐受性。这些发现表明，在建议用作情绪稳定剂的剂量下，拉莫三嗪不会影响氯氮平，利培酮及其活性代谢物的血浆水平。血浆奥氮平浓度的适度升高，可能是由于抑制UGT1A4-mediated olanzapine glucuronidation, is unlikely to be of clinical significance. |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 2 | 这r Drug Monit 2008 Feb 30: 35-40 |
| PMID | 18223460 |
| 标题 | 基于药物遗传学的临床症状反应与血浆奥氮平浓度的反应之间的关系：后龙大学精神分裂症项目（JUSP）。 |
| Abstract | 这monitoring of plasma olanzapine concentrations has been found to be an important and useful tool for optimizing psychiatric treatment. The present study investigated the effect that clinical factors, such as smoking and age, and functional polymorphisms ofUGT1A4，CYP1A2和CYP2D6基因对血浆奥氮平浓度具有以及血浆奥氮平浓度对日本的影响精神分裂症patients' clinical symptoms. The subjects included 51 chronic精神分裂症patients whose symptoms were not controlled with chronic conventional antipsychotics and therefore were switched to olanzapine. Male smokers had a significantly lower olanzapine concentration-dose ratio and olanzapine/4'-N-desmethyl olanzapine ratio (which reflects CYP1A2 activity) than male nonsmokers and female nonsmokers. The results of a 2-way analysis of covariance showed that smoking had the main effect, rather than gender or age. The functional gene polymorphisms that were studied had no effect on the plasma olanzapine and metabolite concentrations. An improved total Brief Psychiatric Rating Scale (BPRS) score was not correlated with the plasma olanzapine concentration, but individual BPRS scores related to improvement of suspiciousness, hallucinations, and blunted affect were significantly correlated with plasma olanzapine concentration. Clinical factors, especially smoking, were more important modulators of olanzapine metabolism than the functional genotypes. Long-term olanzapine treatment with adequate plasma olanzapine concentrations could be more effective in improving some symptoms than treatment with conventional antipsychotics. |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 3 | 这r Drug Monit 2008 Feb 30: 35-40 |
| PMID | 18223460 |
| 标题 | 基于药物遗传学的临床症状反应与血浆奥氮平浓度的反应之间的关系：后龙大学精神分裂症项目（JUSP）。 |
| Abstract | 这monitoring of plasma olanzapine concentrations has been found to be an important and useful tool for optimizing psychiatric treatment. The present study investigated the effect that clinical factors, such as smoking and age, and functional polymorphisms ofUGT1A4，CYP1A2和CYP2D6基因对血浆奥氮平浓度具有以及血浆奥氮平浓度对日本的影响精神分裂症patients' clinical symptoms. The subjects included 51 chronic精神分裂症patients whose symptoms were not controlled with chronic conventional antipsychotics and therefore were switched to olanzapine. Male smokers had a significantly lower olanzapine concentration-dose ratio and olanzapine/4'-N-desmethyl olanzapine ratio (which reflects CYP1A2 activity) than male nonsmokers and female nonsmokers. The results of a 2-way analysis of covariance showed that smoking had the main effect, rather than gender or age. The functional gene polymorphisms that were studied had no effect on the plasma olanzapine and metabolite concentrations. An improved total Brief Psychiatric Rating Scale (BPRS) score was not correlated with the plasma olanzapine concentration, but individual BPRS scores related to improvement of suspiciousness, hallucinations, and blunted affect were significantly correlated with plasma olanzapine concentration. Clinical factors, especially smoking, were more important modulators of olanzapine metabolism than the functional genotypes. Long-term olanzapine treatment with adequate plasma olanzapine concentrations could be more effective in improving some symptoms than treatment with conventional antipsychotics. |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 4 | Eur. J. Clin. Pharmacol. 2010 May 66: 465-74 |
| PMID | 20143052 |
| 标题 | UGT1A4 142T> G基因变体的载体易于减少奥氮平的暴露 - 类似于男性性别或精神分裂症患者吸烟的影响。 |
| Abstract | 的影响UGT1A4在奥氮平血浆水平上，与其他个体因素（例如性别，吸烟状况，体重和年龄）相关的奥氮平血浆水平上的MDR1遗传变异。精神分裂症。 总共从斯德哥尔摩县的精神病学院门诊病患者招募了121名患者。奥氮平血浆浓度是通过高性能液相色谱测定的。基因分型是通过PCR限制片段长度多态性或微型定量进行的，并使用专门的计算机软件在人群遗传学上分析了单倍型。进行了多元回归分析，以研究患者特征和基因型/单倍型对每日剂量校正后血浆lanzapine的综合作用。 In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of theUGT1A4142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact. At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry theUGT1A4142T>G SNP compared to a smoking man treated with the same dose but heterozygous forUGT1A4142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established. |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 5 | Eur. J. Clin. Pharmacol. 2010 May 66: 465-74 |
| PMID | 20143052 |
| 标题 | UGT1A4 142T> G基因变体的载体易于减少奥氮平的暴露 - 类似于男性性别或精神分裂症患者吸烟的影响。 |
| Abstract | 的影响UGT1A4在奥氮平血浆水平上，与其他个体因素（例如性别，吸烟状况，体重和年龄）相关的奥氮平血浆水平上的MDR1遗传变异。精神分裂症。 总共从斯德哥尔摩县的精神病学院门诊病患者招募了121名患者。奥氮平血浆浓度是通过高性能液相色谱测定的。基因分型是通过PCR限制片段长度多态性或微型定量进行的，并使用专门的计算机软件在人群遗传学上分析了单倍型。进行了多元回归分析，以研究患者特征和基因型/单倍型对每日剂量校正后血浆lanzapine的综合作用。 In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of theUGT1A4142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact. At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry theUGT1A4142T>G SNP compared to a smoking man treated with the same dose but heterozygous forUGT1A4142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established. |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 6 | Pharmacogenet。基因组学2011年9月21日：539-51 |
| PMID | 21750471 |
| 标题 | Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants. |
| Abstract | 奥氮平是用于治疗的抗精神病药精神分裂症，躁郁症和耐药性抑郁症。UDP-葡萄糖基转移酶（UGT）酶家族的葡萄糖醛酸化是奥氮平代谢的主要方式，这些酶中的多态性可能有助于奥氮平代谢和治疗反应的大区差异。 过表达单个UGT酶的细胞系用于确定哪些UGT具有针对奥氮平的酶促活性，表征了这种反应的动力学，并检查了UGT变体对奥氮平代谢的影响。使用105个人肝微粒体（HLM）的库进行表型基因型研究，比较了葡萄糖醛酸苷化活性与UGT基因型。 过表达单个UGTS 1A4和2B10的细胞系对奥氮平表现出葡萄糖醛酸化活性。这UGT1A4variant exhibited a 3.7-fold (P<0.0001) higher Vmax/KM for the formation of the olanzapine-10-N-glucuronide isomer 1, and a 4.3-fold (P<0.0001) higher Vmax/KM for the formation of the olanzapine-10-N-glucuronide isomer 2 than wild-typeUGT1A4。这UGT2B10 variant exhibited no glucuronidation activity against olanzapine. In a screening of 105 HLM specimens, there was a 2.1-fold (P=0.04) and 1.6-fold (P=0.0017) increase in the rate of olanzapine-10-N-glucuronide isomer 1 and olanzapine-4'-N-glucuronide formation, and a 2-fold (P=0.02) increase in the overall olanzapine glucuronidation formation, in HLM with theUGT1A4（*3/*3）/ugt2b10（*1/*1）基因型与HLM相比UGT1A4（*1/*1）/ugt2b10（*1/*1）基因型。Olanzapine-10-N-葡萄糖苷的两种异构体的形成下降了1.9倍（P <0.003），奥氮平（P <0.0001）的Olanzapine-4'-N-N-N-葡萄糖苷形成和2.7倍（P <0.0001）降低。HLM中至少一个UGT2B10*2等位基因的HLM中总olanzapine葡萄糖醛酸形成的2.1倍（P = 0.0002）降低。在回归分析中UGT1A4*3（p <0.02）和ugt2b10*2（p <0.002）等位基因是所有奥氮平葡萄糖醛酸异构体形成的重要预测指标。 ugt 1 a4和2 b10 glucuronidate奥氮平和functional variants of these UGTs significantly alter olanzapine glucuronidation in vitro. These data suggest that theUGT1A4*3和UGT2B10*2等位基因对奥氮平代谢的个体变异性有显着贡献。 |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 7 | Pharmacogenet。基因组学2012年8月22日：561-76 |
| PMID | 22565219 |
| 标题 | 第二代抗精神病药氯氮平及其活性代谢产物N-脱甲基甲基二氯氮平的葡萄糖醛酸化。UGT1A1 A（TA）和UGT1A4 L48V多态性的潜在重要性。 |
| Abstract | Clozapine (CLZ) is an FDA approved second-generation antipsychotic for refractory精神分裂症, and glucuronidation is an important pathway in its metabolism. The aim of this study was to fully characterize the CLZ glucuronidation pathway and examine whether polymorphisms in active glucuronidating enzymes could contribute to variability in CLZ metabolism. Cell lines overexpressing wild-type or variant uridine diphosphate-glucuronosyltransferase (UGT) enzymes were used to determine which UGTs show activity against CLZ and its major active metabolite N-desmethylclozapine (dmCLZ). Human liver microsomes (HLM) were used to compare hepatic glucuronidation activity against the UGT genotype. 包括1A1和1A4在内的几个UGT对CLZ具有活性。只要UGT1A4显示了针对DMCLZ的活性。UGT1A1显示出2.1倍（p <0.0001）的V（max）/k（m），用于CLZ-N？ - 葡萄糖醛酸的形成UGT1A4;UGT1A4是唯一可以确定CLZ-5-N-葡萄糖醛酸动力学的UGT。这UGT1A4(24Pro/48Val) variant showed a 5.2-, 2.0-, and 3.4-fold (P < 0.0001 for all) higher V(max)/K(M) for the formation of CLZ-5-N-glucuronide, CLZ-N?-glucuronide, and dmCLZ-5-N-glucuronide, respectively, as compared with that of wild-typeUGT1A4(24Pro/48Leu). There was a 37% (P< 0.05) decrease in the rate of CLZ-N?-glucuronide formation in HLM with the UGT1A1 (*28/*28)/UGT1A4(*1/*1) genotype, and a 2.2- and 1.8-fold (P < 0.05 for both) increase in the formation of CLZ-5-N-glucuronide and CLZ-N?-glucuronide in UGT1A1 (*1/*1)/UGT1A4(*3/*3) HLM compared with UGT1A1 (*1/*1)/UGT1A4（*1/*1）HLM。UGT1A1*28等位基因是Clz-N？ - 葡萄醛酸形成的显着（p = 0.045）。这UGT1A4*3等位基因是CLZ-5-N-N-葡萄糖醛酸和DMCLZ-葡萄糖醛酸形成的显着（P <0.0001）预测指标。 这些数据表明UGT1A1*28和UGT1A4*3 alleles contribute significantly to the interindividual variability in CLZ and dmCLZ metabolism. |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 8 | Clin. Pharmacol. Ther. 2012 Aug 92: 221-7 |
| PMID | 22713701 |
| 标题 | UGT1A4*3 encodes significantly increased glucuronidation of olanzapine in patients on maintenance treatment and in recombinant systems. |
| Abstract | 奥氮平是抗精神病药的世界领导者，用于治疗精神分裂症和躁郁症。其肝间隙有很大的室内变异性。尿苷二磷酸葡萄糖糖基转移酶1A4对奥氮平的多态葡萄糖醛酸化（UGT1A4) was investigated retrospectively in patient samples taken for routine therapeutic drug monitoring (TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed that patients who were heterozygous as well as those who were homozygous for theUGT1A4*3等位基因变体在血清中的主要代谢产物10-N-葡萄糖苷的浓度明显更高（ +38％（P = 0.011）和 +246％（P <0.001））。这一发现与重组观察到的奥氮平的葡萄糖醛酸化活性显着增加UGT1A4。3 (Val-48) as compared withUGT1A4.1（Leu-48）（1.3倍差，p <0.001）。相比之下，父母药物的血清浓度没有显着影响UGT1A4基因型。因此，我们的发现表明UGT1A4- 介导的新陈代谢并不是奥氮平水平室内变异性的主要因素。但是，关于其他药物UGT1A4在清除中具有主要作用UGT1A4*3可能会影响亚治性药物暴露的风险。 |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 9 | 专家Opin Drug Drug Metab Toxicol 2014 Jun 10：893-903 |
| PMID | 24793403 |
| 标题 | Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism. |
| Abstract | Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of精神分裂症和双极躁狂/混合发作。 这篇综述的目的是描述Asenapine的化学，药效学和药代动力学。 Asenapine具有复杂的药效学特征，在多巴胺，5-羟色胺，组胺和？ - 肾上腺素受体处有亲和力，它们都可以作为拮抗剂。舌下Asenapine片在口腔粘膜中吸收，TMAX发生在30至90分钟之间。终端半衰期约为24小时。Asenapine具有多种非活性代谢物，通过直接葡萄糖醛酸化产生（主要是通过UGT1A4), demethylation, and oxidative metabolism (primarily via CYP1A2). Hepatic and renal routes contribute approximately equally to the elimination of asenapine and its metabolites. Two notable drug-drug interactions are evident: asenapine (an inhibitor of CYP2D6) can increase plasma levels of paroxetine, and fluvoxamine (a CYP1A2 inhibitor) can increase plasma levels of asenapine. Caution is required when coadministering asenapine with drugs that are both substrates and inhibitors of CYP2D6. |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 10 | Drug Metab. Dispos. 2015 Nov 43: 1806-14 |
| PMID | 26329789 |
| 标题 | In Vitro Characterization of the Human Liver Microsomal Kinetics and Reaction Phenotyping of Olanzapine Metabolism. |
| Abstract | Olanzapine (OLZ) is an atypical antipsychotic used in the treatment of精神分裂症和相关的精神病。的新陈代谢OLZ是有限公司mplex and incompletely characterized. This study aimed to elucidate the enzymes and pathways involved in the metabolism of OLZ and to determine the kinetics of OLZ oxidation and glucuronidation by human liver microsomes, recombinant cytochrome P450 (rP450) enzymes, and recombinant UDP-glucuronosyltransferase (rUGT) enzymes. An ultra-performance liquid chromatography-mass spectrometry method was developed and validated to quantify OLZ, its four oxidative metabolites (N-desmethyl-OLZ, 2-hydroxymethyl-OLZ, 7-hydroxy-OLZ, and OLZ-N-oxide), and two N-glucuronides (OLZ-10-N-glucuronide and OLZ-4'-N-glucuronide). Consistent with previous reports,UGT1A4, CYP1A2, and flavin-containing monooxygenase 3 play major roles in catalyzing the formation of OLZ-10-N-glucuronide, 7-hydroxy-OLZ, and OLZ-N-oxide, respectively. In addition, a previously uncharacterized major contribution of CYP2C8 to OLZ-N-demethylation was demonstrated. The kinetics of OLZ metabolite formation (Km and Vmax) by human liver microsomes, rP450 enzymes, and rUGT enzymes were characterized in the presence of bovine serum albumin [2% (w/v)]. Consistent with the known effect of bovine serum albumin on CYP1A2, CYP2C8, andUGT1A4活动，此处报告的KM值低于先前报道的OLZ代谢途径值。除了CYP1A2介导的OLZ-N-二甲基化外，这些结果还表明，其他P450酶，尤其是CYP2C8，通过催化OLZ-N-甲基化来对氧化OLZ代谢产生显着贡献。 |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 11 | 这r Drug Monit 2015 Apr 37: 152-60 |
| PMID | 25090458 |
| 标题 | CYP1A2 *1D和 *1F多态性对奥氮平血清浓度有重大影响。 |
| Abstract | 尽管几个olanzapine-metab多态性olizing enzymes have been identified, the clear role and benefit for pharmacotherapy remain uncertain. The aim of the study was to investigate the potential influence of polymorphisms in the CYP1A2 gene (*1D,*1F), in theUGT1A4基因（*3）和POR基因（RS2302429）在奥氮平血清浓度和临床结果上。 回顾性调查中包括了至少4周接受奥氮平的一部分，他们接受奥氮平的一部分。此外，建立了接受奥氮平或氯氮平的209个住院患者的样本，以研究相关多态性CYP1A2 *1F， *1D和CYP1A2诱导剂对临床结果的影响。 三角形（*1D）的载体显着更高剂量校正的奥氮平血清浓度（协方差分析； p <0.001，delt + deltdelt：3.1，tt：1.6 ng.ml.mg，性别，基线重量，CYP1A2*1F基因型和伴随的CYP1A2诱导剂）。此外，根据协方差模型的分析，CYP1A2*1F（AA）基因型也对奥氮平血清浓度产生了重大影响（p = 0.028; cc + ca：2.05，aa：1.44 ng.ml.mg）。研究的其他多态性没有明显影响。关于反应和不良影响，可以在精神分裂症Paranoid Depressive Scale (responder: +5.7 vs nonresponder: +1.8 kg; P = 0.007) and Clinical Global Impression responders (4.6 vs 1.8 kg; P = 0.017). No direct correlation between olanzapine serum concentrations and response or weight gain could be detected. Patients with at least 2 factors promoting higher serum concentrations (no CYP1A2 inducer, *1D deltT-allele, or *1F C-allele) showed a better response according to the Paranoid Depressive Scale (P = 0.002) and a significant correlation with the Clinical Global Impression Scale-2 after 4 weeks (n = 193, r = -0.177; P = 0.005). 我们首次确定了CYP1A2中多态性与CYP1A2诱导剂状态对临床结果的重大影响。因此，CYP1A2 *1D和 *1F的基因分型可能是优化和鉴定高危患者的有用工具。在基于基因型的剂量建议可以帮助接受CYP1A2代谢药物治疗的患者之前，需要进一步的研究。 |
| SCZ Keywords | 精神分裂症, schizophrenic |
| 12 | J. Pharmacol。经验。ther。2015年2月352日：358-67 |
| PMID | 25503386 |
| 标题 | A UGT2B10 splicing polymorphism common in african populations may greatly increase drug exposure. |
| Abstract | RO5263397 [(S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine], a new compound that showed promising results in animal models of精神分裂症，主要通过N-葡萄糖醛酸化代谢在人类中。酶研究，使用（当时）可用的商业尿苷5'-二磷酸 - 葡萄糖糖基转移酶（UGT），表明UGT1A4负责其共轭。在第一次临床试验中，RO5263397被口服给健康的人类志愿者，在其中一位参与者中发现了对父母大院的平均水平高于平均水平的136倍。在这项试验中，进一步的管理确定了另外两个这样的不良代谢物，这是非洲三个起源。重组UGT的其他体外研究表明，UGT2B10对RO5263397葡萄糖醛酸化的贡献远高于UGT1A4at clinically relevant concentrations. DNA sequencing in all of these poor metabolizers identified a previously uncharacterized splice site mutation that prevents assembly of full-length UGT2B10 mRNA and thus functional UGT2B10 protein expression. Further DNA database analyses revealed the UGT2B10 splice site mutation to be highly frequent in individuals of African origin (45%), moderately frequent in Asians (8%) and almost unrepresented in Caucasians (<1%). A prospective study using hepatocytes from 20 individual African donors demonstrated a >100-fold lower intrinsic clearance of RO5263397 in cells homozygous for the splice site variant allele. Our results highlight the need to include UGT2B10 when screening the human UGTs for the enzymes involved in the glucuronidation of a new compound, particularly when there is a possibility of N-glucuronidation. Moreover, this study demonstrates the importance of considering different ethnicities during drug development. |
| SCZ Keywords | 精神分裂症, schizophrenic |