Drug Metabolism and Pharmacokinetics最新文献_第2页

A novel quantitative assessment of formed reactive metabolites by double trapping with [3H]glutathione and [14C]cyanide [3H]谷胱甘肽和[14C]氰化物双捕获形成的反应性代谢物的一种新的定量评估。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-12-01 DOI: 10.1016/j.dmpk.2025.101504

Tomoyuki Kawachi , Tatsuki Fukami , Miki Nakajima

Drug-induced liver injury often arises from reactive metabolites (RMs) produced in the liver, making it crucial to assess RM formation rates from drug candidates. Conventional assays using glutathione (GSH) effectively trap soft electrophilic RMs but fail to detect hard electrophiles. To address this, we developed a double trapping assay employing [³H]GSH and [¹⁴C]cyanide as soft and hard nucleophilic reagents, respectively. This assay was applied to 25 drugs chosen based on safety profiles. Eight drugs were exclusively trapped by [³H]GSH, while 11 were trapped by [¹⁴C]cyanide or both reagents, demonstrating that a double trapping assay provides a more comprehensive detection method for both soft and hard RMs. Multiplying RM formation rates by daily doses allowed almost complete differentiation between withdrawn/black boxed warning drugs and safer ones. Radio-LCMS analysis provided detailed insights into the substructures of drug candidates responsible for RM production. Interestingly, it was discovered that GSH-based assays sometimes fail to detect certain RMs due to the presence of dithiothreitol in commercial [³H]GSH. This study highlights the efficacy of the double trapping assay using [³H]GSH and [¹⁴C]cyanide in accurately and comprehensively detecting RMs. Furthermore, it offers valuable structural information to minimize RM formation during early drug discovery.

药物性肝损伤通常由肝脏产生的反应性代谢物（RM）引起，因此评估候选药物的RM形成率至关重要。使用谷胱甘肽（GSH）的常规检测方法可以有效捕获软亲电均方根，但无法检测硬亲电均方根。为了解决这个问题，我们开发了一种双捕获实验，分别使用[3H]GSH和[14C]氰化物作为软亲核试剂和硬亲核试剂。该方法应用于25种基于安全性特征选择的药物。8种药物完全被[3H]GSH捕获，11种药物被[14C]氰化物捕获或同时被两种试剂捕获，表明双捕获法为软硬均方根提供了更全面的检测方法。将RM形成率乘以每日剂量，几乎可以完全区分停药/黑框警告药物和更安全的药物。无线电- lcms分析提供了对负责原料药生产的候选药物亚结构的详细见解。有趣的是，研究发现，基于谷胱甘肽的检测有时无法检测到某些有效值，因为在商业[3H]谷胱甘肽中存在二硫苏糖醇。本研究强调了[3H]GSH和[14C]氰化物双捕集法准确、全面地检测均方根值的有效性。此外，它提供了有价值的结构信息，以减少早期药物发现过程中RM的形成。

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引用次数: 0

The rational use of PBPK to assess the changing DDI liability in pediatrics: Model qualification and the move towards best practice 合理使用PBPK评估儿科不断变化的DDI责任：模型资格和走向最佳实践。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-11-26 DOI: 10.1016/j.dmpk.2025.101509

Trevor N. Johnson , Jean Dinh , Roz Southall , Amin Rostami-Hodjegan

Many drug-drug interactions (DDIs) in the pediatric population are managed based on data generated in adults, however this is done with little clinical evidence and the assumption of DDIs being similar between adults and pediatric may not be correct. Physiologically Based Pharmacokinetic models have been used extensively to predict DDIs in adults and this evidence is now being accepted by regulators worldwide and in certain cases information from PBPK is feeding directly into the drug labels. Because pediatric PBPK models account for age related changes in physiology and biochemistry they are ideally placed to extrapolate DDI liability from adults to children. However, marrying together all relevant system factors such as ontogeny of enzymes and hepatic blood flow with drug related factors e.g. extraction ratio and fraction unbound is important and is an active area of research. This review will highlight the need for dynamic rather than static PBPK pediatric DDI predictions with a view to recommending the best practice approach.

儿童人群中的许多药物-药物相互作用（ddi）是基于成人数据进行管理的，然而这是在很少的临床证据的基础上完成的，并且成人和儿童之间ddi相似的假设可能是不正确的。基于生理的药代动力学模型已被广泛用于预测成人的ddi，这一证据现在已被世界各地的监管机构所接受，在某些情况下，PBPK的信息直接输入到药物标签中。由于儿童PBPK模型考虑了与年龄相关的生理和生物化学变化，因此它们是推断成人对儿童DDI责任的理想选择。然而，将所有相关的系统因素（如酶的个体发生和肝血流）与药物相关因素（如提取率和未结合分数）结合起来是重要的，也是一个活跃的研究领域。本综述将强调动态而非静态PBPK儿科DDI预测的必要性，以推荐最佳实践方法。

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引用次数: 0

Cytochrome P450 reaction phenotyping: State of the art 细胞色素P450反应表型：最新进展。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-11-10 DOI: 10.1016/j.dmpk.2025.101508

Elaine Tseng, R. Scott Obach

Cytochrome P450 reaction phenotyping refers to the in vitro experimental approach that estimates the quantitative contributions of individual P450 enzymes to the metabolism of a drug. Methods for this are well-established and have existed for over three decades and include the use of selective inhibitors, individually expressed P450 enzymes, and human-derived in vitro systems such as liver microsomes and hepatocytes. The results from P450 reaction phenotyping experiments are used to inform patient safety, clinical trial designs, and physiologically-based pharmacokinetic models, and this information is an expectation from government regulatory authorities when developing a new drug candidate. Despite widespread use, P450 reaction phenotyping methods possess shortcomings. These include sub-optimal selectivity of P450 inhibitors, scaling factors that can differ among substrates, challenges measuring low turnover substrates, and considerations of non-P450 routes of drug clearance (e.g. active transport, other drug metabolizing enzyme families). A recently described “sequential qualitative-then-quantitative” approach to P450 reaction phenotyping is described along with a more comprehensive experimental design that considers incomplete selectivity of P450 inhibitors. This approach addresses some of the aforementioned shortcomings, however it is still important to consider the contribution of P450 enzymes to the overall dispositional profile that is obtained from in vivo studies, such as radiolabel human absorption/distribution/metabolism/excretion (ADME) studies.

细胞色素P450反应表型是指体外实验方法，估计单个P450酶对药物代谢的定量贡献。这方面的方法已经建立并存在了30多年，包括使用选择性抑制剂、单独表达的P450酶和人类来源的体外系统，如肝微粒体和肝细胞。P450反应表型实验的结果用于为患者安全性、临床试验设计和基于生理的药代动力学模型提供信息，这些信息是政府监管机构在开发新的候选药物时的期望。尽管广泛使用，P450反应表型方法有缺点。其中包括P450抑制剂的次优选择性，底物之间的比例因子可能不同，测量低周转底物的挑战，以及非P450药物清除途径的考虑（例如主动运输，其他药物代谢酶家族）。最近描述了一种“连续定性-然后定量”的P450反应表型方法，以及一种考虑P450抑制剂不完全选择性的更全面的实验设计。这种方法解决了前面提到的一些缺点，但是考虑P450酶对体内研究（如放射性标记人体吸收/分布/代谢/排泄（ADME）研究）获得的整体配置概况的贡献仍然很重要。

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引用次数: 0

Analysis of blood-brain barrier permeability of drugs using forensically obtained human cerebrospinal fluid and plasma in Japan 日本利用法医获得的人脑脊液和血浆分析药物的血脑屏障渗透性

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-10-30 DOI: 10.1016/j.dmpk.2025.101507

Tomoyoshi Hariba , Kenta Mizoi , Saori Takahashi , Hiroki Sunakawa , Yoshimichi Sai , Junichi Furumiya , Masahiko Zuka , Takuo Ogihara

Distribution coefficient the cerebrospinal fluid (CSF) concentration ratios of unbound drugs to serum (K_s,uu,CSF) were calculated from drugs detected in serum and CSF obtained at forensic autopsies in Japan, and documented values of serum protein binding rates of the drugs. Of the 39 compounds detected in 51 specimens, 21 drugs with a case number of 2 or more were included in the analysis. The calculated liposolubility parameter (cLogP) of each drug was corrected for the square root of the molecular weight to calculate the Log [Pc × MW^−1/2] value. A tendency for drugs with higher liposolubility to have higher permeability into the cerebral spinal fluid was observed. The K_s,uu,CSF values were particularly high for diphenhydramine and haloperidol, which are substrates for transporters in the uptake system. When the correlation between K_s,uu,CSF and Log [Pc × MW^−1/2] was examined after excluding diphenhydramine and haloperidol, a significant positive correlation (R = 0.465, p < 0.05) was found. It is planned to publish a database of these individual values and update it whenever new drug data becomes available to make these data widely available to other researchers.

根据日本法医尸检中检测到的血清和脑脊液中检测到的药物，计算未结合药物的脑脊液（CSF）浓度比（Ks、uu、CSF）的分布系数，并记录药物的血清蛋白结合率值。在51份标本中检测到的39种化合物中，21种病例数为2或更多的药物被纳入分析。将计算出的每种药物的脂溶性参数（cLogP）校正为分子量的平方根，计算Log [Pc × MW−1/2]值。观察到高脂溶性药物在脑脊液中具有较高的渗透性。对于苯海拉明和氟哌啶醇，Ks,uu，CSF值特别高，它们是摄取系统中转运体的底物。排除苯海拉明和氟哌啶醇后，检测Ks、uu、CSF与Log [Pc × MW−1/2]的相关性，发现两者呈正相关（R = 0.465, p < 0.05）。计划公布这些个别值的数据库，并在有新的药物数据时进行更新，以便使这些数据广泛地提供给其他研究人员。

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引用次数: 0

Cytochrome P450 inhibition correlates with hepatotoxicity of pesticides: Analysis using repeated-dose toxicity data in rats 细胞色素P450抑制与农药肝毒性相关：使用大鼠重复剂量毒性数据分析。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-10-24 DOI: 10.1016/j.dmpk.2025.101505

Minami Shibata, Nana Uchida, Akira Ooka, Ryota Shizu, Kouichi Yoshinari

Drug-induced liver injury (DILI) remains a significant challenge in drug development and safety assessment, requiring a deeper understanding of its underlying mechanisms. We recently reported that the inhibition of cytochrome P450 (P450) enzymes CYP1A1 and CYP1B1 is associated with DILI; however, it is unclear whether this association extends to non-pharmaceutical chemicals with structurally and pharmacologically diverse properties. In this study, we aimed to clarify the relationship between P450 inhibition and the hepatotoxicity of pesticides by using the results of rat repeated-dose toxicity studies and in vitro assays. A test set of 126 pesticides was evaluated for inhibitory activity against six rat P450s using recombinant enzymes and luminescent substrates. Statistical analyses revealed that the inhibition of CYP1A1 and CYP2C6 was significantly (p < 0.05) associated with liver hypertrophy-related findings, including weight increase and centrilobular hepatocyte hypertrophy, and dyslipidemia characterized by elevated blood cholesterol levels. In addition, simple regression analysis demonstrated that CYP2C6-inhibitory activity correlated with the lowest observed adverse effect level (LOAEL) values for the hypertrophy and dyslipidemia in carbamates. These results suggest that hepatotoxicity associated with CYP1A1 inhibition is a common phenomenon across chemical classes, and that CYP2C6 inhibition is specifically linked to liver hypertrophy and dyslipidemia in pesticides.

药物性肝损伤（DILI）仍然是药物开发和安全性评估中的一个重大挑战，需要对其潜在机制有更深入的了解。我们最近报道了细胞色素P450 （P450）酶CYP1A1和CYP1B1的抑制与DILI有关；然而，尚不清楚这种关联是否延伸到具有结构和药理学不同性质的非药物化学物质。在本研究中，我们旨在通过大鼠重复给药毒性研究和体外实验的结果来阐明P450抑制与农药肝毒性之间的关系。利用重组酶和发光底物对126种农药对6种大鼠p450的抑制活性进行了评价。统计分析显示，CYP1A1和CYP2C6的抑制显著(p

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引用次数: 0

Metabolism of simvastatin by Streptomyces griseolus CYP105A1 and its variants for the production of human simvastatin metabolites 灰色链霉菌CYP105A1及其变异对辛伐他汀的代谢及其对人类辛伐他汀代谢物的产生

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-10-24 DOI: 10.1016/j.dmpk.2025.101506

Sachiyo Yoneda , Kaori Yasuda , Bunzo Mikami , Teisuke Takita , Kiyoshi Yasukawa , Masahiro Hamada , Hiromasa Imaishi , Toshiyuki Sakaki , Shinichi Ikushiro

Streptomyces griseolus CYP105A1 showed hydroxylation activity at 25- and 1α-positions of vitamin D₃ to produce an active form of vitamin D₃. We have succeeded in dramatically increasing its activity by site-directed mutagenesis. We also found that CYP105A1 and its mutants metabolize various non-steroidal anti-inflammatory drugs. In this study, we attempted to metabolize simvastatin (SV), an HMG-CoA reductase inhibitor, by CYP105A1 mutants, and compared their metabolism with that by human CYP3A4. The SV was converted into multiple metabolites by the CYP105A1 variants CYP105A1-R84A and CYP105A1-R84A/M239A, with the latter exhibiting significantly higher activity than the former. The metabolites were estimated to be 6′-hydroxy-SV, 3′-hydroxy-SV, 3″-hydroxy SV, 3′,5′-dihydrodiol SV, and 6′-exomethylene SV. In addition, 6′-hydroxy-SV was non-enzymatically converted to 3′-hydroxy-SV under acidic conditions. The X-ray crystal structure of SV-bound CYP105A1-R84A suggested the formation of a 3′,4′-epoxide intermediate, from which 3′-hydroxy and 3′,5′-dihydrodiol SV were presumed to be generated non-enzymatically. It is noted that all of these metabolites have either been reported as SV metabolites formed by human CYP3A4 or were detected in the present study. Thus, CYP105A1-R84A/M239A appears to be highly useful for the production of human metabolites of SV.

灰色链霉菌CYP105A1在维生素D3的25-和1α-位点显示羟基化活性，产生活性形式的维生素D3。我们已经成功地通过定点诱变极大地增加了它的活性。我们还发现CYP105A1及其突变体代谢各种非甾体抗炎药。在本研究中，我们试图通过CYP105A1突变体代谢HMG-CoA还原酶抑制剂辛伐他汀（SV），并将其与人类CYP3A4的代谢进行比较。SV被CYP105A1变异CYP105A1- r84a和CYP105A1- r84a /M239A转化为多种代谢物，后者的活性明显高于前者。代谢产物估计为6 ' -羟基SV， 3 ' -羟基SV， 3″-羟基SV， 3 ',5 ' -二氢二醇SV和6 ' -外甲基SV。此外，6′-羟基- sv在酸性条件下非酶转化为3′-羟基- sv。SV结合的CYP105A1-R84A的x射线晶体结构表明形成了一个3 ',4 ' -环氧化物中间体，由此推定3 ' -羟基和3 ',5 ' -二氢二醇SV是非酶促生成的。值得注意的是，所有这些代谢物要么被报道为人类CYP3A4形成的SV代谢物，要么在本研究中被检测到。因此，CYP105A1-R84A/M239A似乎对人体SV代谢产物的产生非常有用。

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引用次数: 0

Japanese medicinal drug labeling for use in the clinical setting as informed by pharmacogenomic data on cytochrome P450 enzymes obtained from in silico studies. 根据从计算机研究中获得的细胞色素P450酶的药物基因组学数据，用于临床环境的日本药品标签。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-10-01 Epub Date: 2025-05-29 DOI: 10.1016/j.dmpk.2025.101496

Yoichi Tanaka, Makiko Shimizu, Yoshiro Saito, Hiroshi Yamazaki

Although the United States Food and Drug Administration has disclosed a list of drugs with pharmacogenomic biomarkers for drug labeling, there is limited information regarding pharmacogenomic-associated drugs in Japan. Such associations include genetic variants of uridine diphosphate glucuronosyltransferase 1A1 for irinotecan, nudix hydrolase 15 for thiopurine drugs, and cytochrome P450 (P450) 2C9 for siponimod. The effects of such genetic variants on drug concentrations are similar to those from drug interactions. Because of race and dosage differences, the relevance of pharmacogenomic associations in Asian populations requires confirmation. This white paper proposes that in vitro pharmacogenomic information can be used to predict human pharmacokinetics and to describe in drug labels the changes in blood concentrations by genetic variants. For P450 variants CYP2C9∗3, CYP2C19∗2, CYP2C19∗3, CYP2D6∗10, and CYP3A4∗16, we propose using the enzymatic activity parameters obtained from in vitro functional analysis of the drug-metabolizing enzymes for multiple substrate drugs to predict the effects of these variants on human pharmacokinetics. Consequently, in patients prescribed only a single drug, anything more than a "moderate effect" on plasma exposure should be mentioned as a caution in the drug labels; such effects are likely caused by enzyme polymorphisms resulting in similar effects to drug-drug interactions.

尽管美国食品和药物管理局已经公布了一份药物标签上带有药物基因组生物标记物的药物清单，但在日本，关于药物基因组相关药物的信息有限。这些关联包括伊立替康的尿苷二磷酸葡萄糖醛基转移酶1A1、硫嘌呤类药物的嘌呤水解酶15和西泊尼莫德的细胞色素P450 (P450) 2C9的遗传变异。这些基因变异对药物浓度的影响与药物相互作用的影响相似。由于种族和剂量的差异，亚洲人群中药物基因组关联的相关性需要证实。本白皮书提出体外药物基因组学信息可用于预测人体药代动力学，并在药物标签上描述遗传变异引起的血药浓度变化。对于P450变体CYP2C9∗3，CYP2C19∗2,CYP2C19∗3，CYP2D6∗10和CYP3A4∗16，我们建议使用从多种底物药物代谢酶的体外功能分析中获得的酶活性参数来预测这些变体对人体药代动力学的影响。因此，对于只服用一种药物的患者，任何对血浆暴露超过“中等影响”的情况都应在药物标签上注明注意事项；这种影响可能是由酶多态性引起的，导致类似于药物-药物相互作用的影响。

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引用次数: 0

Important role of OATP in the liver disposition of ezetimibe and its consequent glucuronidation metabolite OATP在依泽可米及其后续糖醛酸化代谢产物的肝脏处理中的重要作用。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-09-18 DOI: 10.1016/j.dmpk.2025.101503

Ying Su , Xinyi Zhang , Yiguo Jiang , Cheng Wang , Jianqing Ruan

Ezetimibe is a widely used antilipemic agent that lowers LDL-C and raises HDL-C by inhibiting intestinal cholesterol absorption. However, the mechanisms governing the hepatic transport of ezetimibe and its glucuronide metabolite remain unclear. In this study, we demonstrated that ezetimibe is rapidly metabolized to its glucuronide in mouse, rat, and human liver microsomes, with UGT1A1 showing the highest catalytic activity, followed by UGT1A3. In vitro transport assays revealed that human OATP1B1 and OATP1B3 selectively mediate the uptake of ezetimibe-glucuronide, but not parent ezetimibe. Using Slco1b2 knockout mice, an in vivo model for hepatic OATP deficiency, we found that knockout significantly increased the plasma AUC and decreased the liver-to-plasma ratio of ezetimibe-glucuronide, without affecting parent ezetimibe. These results indicate that OATP-mediated hepatic uptake is key to the disposition of ezetimibe-glucuronide, which may influence the pharmacokinetics and clinical efficacy of ezetimibe.

依折替米贝是一种广泛使用的降脂剂，通过抑制肠道胆固醇吸收来降低LDL-C和升高HDL-C。然而，依折麦布及其葡萄糖醛酸代谢产物的肝脏转运机制尚不清楚。在本研究中，我们证明依折麦比在小鼠、大鼠和人的肝微粒体中被快速代谢为葡萄糖醛酸盐，其中UGT1A1的催化活性最高，其次是UGT1A3。体外转运实验显示，人OATP1B1和OATP1B3选择性地介导依zetimibe-glucuronide的摄取，而不是亲本依zetimibe。使用肝脏OATP缺乏的体内模型Slco1b2敲除小鼠，我们发现敲除显著增加血浆AUC，降低依zetimibe-glucuronide的肝-血浆比值，而不影响亲本依zetimibe。这些结果表明ooatp介导的肝脏摄取是依zetimibe-glucuronide处置的关键，可能影响依zetimibe的药代动力学和临床疗效。

引用次数: 0

Tyrosine kinase inhibitors, nilotinib and radotinib, suppress both catalytic function and mRNA expression of human cytochrome P450 2J2 and 2C8 酪氨酸激酶抑制剂尼罗替尼和拉多替尼抑制人细胞色素P450 2J2和2C8的催化功能和mRNA表达

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-08-29 DOI: 10.1016/j.dmpk.2025.101501

Ayaka Kojima , Masayuki Nadai , Hiroshi Yamazaki , Miki Katoh

Cytochrome P450 (P450 or CYP) 2J2, which metabolizes exogenous medicines and endogenous arachidonic acid to 14,15-epoxyeicosatrienoic acid (14,15-EET), is expressed in various organs and cancer cells. Additionally, CYP2C8 catalyzes the synthesis of 14,15-EET, a vasodilator that promotes cancer cell proliferation. However, the effect of tyrosine kinase inhibitors (TKIs) used in leukemia treatment on CYP2J2 and CYP2C8 remains unclear. This study investigated the effects of 16 TKIs used for leukemia treatment on recombinant CYP2J2-and CYP2C8-mediated processes. Among the TKIs, nilotinib and radotinib strongly inhibited CYP2J2-dependent astemizole O-demethylation and rivaroxaban hydroxylation, and CYP2C8-mediated paclitaxel 6α-hydroxylation (<20 %), with competitive inhibition constants of 0.41 and 0.22 μM, respectively (for astemizole O-demethylation). Nilotinib and radotinib suppressed CYP2J2-and CYP2C8-catalyzed arachidonic acid epoxidation and decreased their mRNA expression in Huh-7 cells (possibly via the peroxisome proliferator-activated receptor α pathway). Given that their inhibition constants are lower than their reported plasma concentrations, both may substantially suppress CYP2J2 and CYP2C8 functional enzyme levels and enzymatic activities in clinical settings. This suppression could potentially alter vasodilation by affecting 14,15-EET production, influencing CYP2J2 and CYP2C8-mediated drug-disease (conditions) and drug-drug interactions.

细胞色素P450 (P450或CYP) 2J2在各器官和癌细胞中表达，将外源性药物和内源性花生四烯酸代谢为14,15-环氧二碳三烯酸（14,15- eet）。此外，CYP2C8催化1415 - eet的合成，1415 - eet是一种促进癌细胞增殖的血管扩张剂。然而，用于白血病治疗的酪氨酸激酶抑制剂（TKIs）对CYP2J2和CYP2C8的影响尚不清楚。本研究探讨了16种用于白血病治疗的TKIs对重组cyp2j2和cyp2c8介导过程的影响。在TKIs中，尼罗替尼和拉多替尼对cyp2j2依赖性阿司咪唑o -去甲基化和利伐沙班羟化，以及cyp2c8介导的紫杉醇6α-羟化具有较强的抑制作用（< 20%），竞争抑制常数分别为0.41 μM和0.22 μM（对阿司咪唑o -去甲基化）。尼罗替尼和拉多替尼抑制了cyp2j2和cyp2c8催化的花生四烯酸环氧化，并降低了Huh-7细胞中它们的mRNA表达（可能通过过氧化物酶体增殖物激活受体α途径）。鉴于它们的抑制常数低于其报道的血浆浓度，两者都可能在临床环境中实质性地抑制CYP2J2和CYP2C8功能酶水平和酶活性。这种抑制可能通过影响14,15- eet的产生，影响CYP2J2和cyp2c8介导的药物-疾病（状况）和药物-药物相互作用来潜在地改变血管舒张。

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引用次数: 0

L-Type amino acid transporter 1-mediated developmental change of cerebral gabapentin distribution across the rat blood-brain barrier l型氨基酸转运蛋白1介导的脑加巴喷丁血脑屏障分布的发育变化。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-08-29 DOI: 10.1016/j.dmpk.2025.101502

Hiroki Endo , Takeshi Sugouchi , Otaro Kobayashi , Yuma Tega , Yoshiyuki Kubo , Ken-ichi Hosoya , Shin-ichi Akanuma

Gabapentin is an anticonvulsant used in the pharmacotherapy of pediatric epilepsy. Differences in transporter-mediated cerebral drug/compound distribution across the blood-brain barrier (BBB) have been reported between neonates/infants, and adults. The purpose of our study was to comprehensively elucidate the transport of gabapentin across the BBB during childhood and its regulatory molecular systems. The cerebral distribution of [³H]gabapentin in 7-day-old rats was significantly lower than that in 42-day-old adult rats, suggesting weaker gabapentin transport in the BBB of neonates/infants than in adults. In vivo brain uptake and in vitro transport studies have indicated the involvement of transporters that accept large neutral amino acids in the cerebral gabapentin distribution across the BBB. In particular, an in vitro study using RNA interference suggested a major contribution of L-type amino acid transporter 1 (LAT1) to gabapentin transport across the BBB. In the brains of 7-day-old rats, the mRNA expression of LAT1 and the heavy chain of the 4F2 antigens (4F2hc), which forms a complex with LAT1, was reduced compared to that of 42-day-old rats. Consequently, it is suggested that a decrease in gabapentin distribution to the brain across the BBB contributes to the transcriptional reduction of cerebral LAT1 and 4F2hc.

加巴喷丁是一种用于小儿癫痫药物治疗的抗惊厥药。转运体介导的脑药物/化合物在血脑屏障（BBB）中的分布在新生儿/婴儿和成人之间存在差异。我们研究的目的是全面阐明儿童时期加巴喷丁在血脑屏障中的转运及其调控分子系统。加巴喷丁[3H]在7日龄大鼠脑内的分布明显低于42日龄成年大鼠，表明新生儿/婴儿加巴喷丁在血脑屏障中的转运比成人弱。体内脑摄取和体外转运研究表明，接受大量中性氨基酸的转运体参与了加巴喷丁在脑血脑屏障中的分布。特别是，一项使用RNA干扰的体外研究表明，l型氨基酸转运蛋白1 （LAT1）对加巴喷丁在血脑屏障中的转运起着重要作用。在7日龄大鼠的大脑中，与42日龄大鼠相比，LAT1和与LAT1形成复合物的4F2抗原重链（4F2hc）的mRNA表达减少。因此，这表明加巴喷丁在脑血脑屏障中的分布减少有助于大脑LAT1和4F2hc的转录减少。

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引用次数: 0