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Role of P-glycoprotein in Regulating the Efficacy, Toxicity and Pharmacokinetics of Yunaconitine. P 糖蛋白在调节 Yunaconitine 的药效、毒性和药代动力学中的作用
IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 DOI: 10.2174/0113892002302427240801072910
Xiaocui Li, Qi Liang, Caiyan Wang, Huawei Qiu, Tingting Lin, Wentao Li, Rong Zhang, Zhongqiu Liu, Lijun Zhu

Background: Yunaconitine (YAC) is a hidden toxin that greatly threatens the life safety of patients who are prescribed herbal medicines containing Aconitum species; however, its underlying mechanism remains unclear.

Objective: The objective of this study is to elucidate the functions of P-glycoprotein (P-gp) in regulating the efficacy, toxicity, and pharmacokinetics of YAC.

Methods: The efflux function of P-gp on YAC was explored by using Caco-2 monolayers in combination with the P-gp inhibitor verapamil. The impact of P-gp on regulating the analgesic and anti-inflammatory effects, acute toxicity, tissue distribution, and pharmacokinetics of YAC was determined via male Mdr1a gene knocked-out mice and wild-type FVB mice.

Results: The presence of verapamil significantly decreased the efflux ratio of YAC from 20.41 to 1.07 in Caco- 2 monolayers (P < 0.05). Moreover, oral administration of 0.07 and 0.14 mg/kg YAC resulted in a notable decrease in writhing times in Mdr1a-/- mice by 23.53% and 49.27%, respectively, compared to wild-type FVB mice (P < 0.05). Additionally, the deficiency of P-gp remarkably decreased the half-lethal dose (LD50) of YAC from 2.13 to 0.24 mg/kg (P < 0.05). Moreover, the concentrations of YAC in the tissues of Mdr1a-/- mice were statistically higher than those in wild-type FVB mice (P < 0.05). Particularly, the brain accumulation of YAC in Mdr1a-/- mice significantly increased by 12- and 19-fold, respectively, after oral administration for 30 and 120 min, when compared to wild-type FVB mice (P < 0.05). There were no significant differences in the pharmacokinetic characteristics of YAC between Mdr1a-/- and wild-type FVB mice.

Conclusion: YAC is a sensitive substrate of P-gp. The absence of P-gp enhances the analgesic effect and toxicity of YAC by upregulating its brain accumulation. Co-administration with a P-gp inhibitor may lead to severe YAC poisoning.

背景:云乌头碱(YAC)是一种隐性毒素,极大地威胁着服用含乌头类中药的患者的生命安全,但其潜在机制仍不清楚:本研究旨在阐明P-糖蛋白(P-gp)在调节YAC药效、毒性和药代动力学方面的功能:方法:使用 Caco-2 单层膜结合 P-gp 抑制剂维拉帕米,探讨 P-gp 对雅克的外流功能。通过雄性 Mdr1a 基因敲除小鼠和野生型 FVB 小鼠确定 P-gp 对调节 YAC 的镇痛和抗炎作用、急性毒性、组织分布和药代动力学的影响:结果:维拉帕米的存在明显降低了 YAC 在 Caco- 2 单层细胞中的外流率,从 20.41 降至 1.07(P < 0.05)。此外,与野生型 FVB 小鼠相比,口服 0.07 和 0.14 mg/kg YAC 可使 Mdr1a-/- 小鼠的蠕动时间分别减少 23.53% 和 49.27%(P < 0.05)。此外,P-gp的缺乏还显著降低了YAC的半致死剂量(LD50),从2.13毫克/千克降至0.24毫克/千克(P < 0.05)。此外,Mdr1a-/-小鼠组织中的YAC浓度在统计学上高于野生型FVB小鼠(P < 0.05)。特别是,与野生型FVB小鼠相比,口服YAC 30分钟和120分钟后,Mdr1a-/-小鼠脑内YAC的蓄积量分别显著增加了12倍和19倍(P < 0.05)。Mdr1a-/-和野生型FVB小鼠的YAC药代动力学特征无明显差异:结论:YAC是P-gp的敏感底物。结论:YAC 是一种敏感的 P-gp 底物,P-gp 的缺失会通过上调 YAC 在大脑中的蓄积而增强其镇痛效果和毒性。与 P-gp 抑制剂合用可能会导致严重的 YAC 中毒。
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引用次数: 0
Effect of Salbutamol on the Disposition Kinetics of Levofloxacin in the Plasma and Lung of Rats. 沙丁胺醇对左氧氟沙星在大鼠血浆和肺中的处置动力学的影响
IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 DOI: 10.2174/0113892002314136240816094609
Murat Ali Cicekler, Halis Oguz, Orhan Corum

Background: Antibiotics and bronchodilator drugs can be used together in respiratory distress caused by bacterial infections. Levofloxacin (LVX) and Salbutamol (SLB) can be used simultaneously in respiratory distress. However, there have been no investigations on how the concurrent use of SLB can affect the pharmacokinetics of LVX in rats.

Objective: The purpose of this study was to investigate the influence of SLB on the plasma and lung pharmacokinetics of LVX in rats.

Methods: A total of 132 rats were randomly assigned to two groups: LVX (n=66) and LVX+SLB (n=66). LVX (intraperitoneal) and SLB (oral) were administered to rats at doses of 50 and 3 mg/kg, respectively. The concentrations of LVX in the plasma and lungs were determined through the utilization of high-performance liquid chromatography along with UV. Pharmacokinetic parameters were assessed by non-compartmental analysis.

Results: The area under the curve from 0 to 16 h (AUC0-16), terminal elimination half-life, volume of distribution, total body clearance, and peak concentration of LVX in the plasma were 42.57 h*μg/mL, 2.32 h, 3.91 L/kg, 1.17 L/h/kg, and 23.96 μg/mL, respectively. There were no alterations observed in the plasma and lung pharmacokinetic parameters of LVX when co-administered with SLB. The AUC0-16 lung/AUC0-16 plasma ratios of LVX were 1.60 and 1.39 after administration alone and co-administration with SLB, respectively.

Conclusion: The concentration of LVX in lung tissue was higher than that in plasma. SLB administration to rats did not affect the plasma and lung pharmacokinetics and lung penetration ratio of LVX. There is a need to reveal the change in the pharmacokinetics of LVX after multiple administration of both drugs and after administration of SLB by different routes.

背景:抗生素和支气管扩张药物可同时用于细菌感染引起的呼吸困难。左氧氟沙星(LVX)和沙丁胺醇(SLB)可同时用于呼吸困难。然而,目前还没有研究表明同时使用沙丁胺醇会如何影响大鼠体内左氧氟沙星的药代动力学:本研究旨在探讨 SLB 对大鼠血浆和肺部 LVX 药代动力学的影响:方法:将 132 只大鼠随机分为两组:方法:将 132 只大鼠随机分为两组:LVX 组(n=66)和 LVX+SLB 组(n=66)。腹腔注射 LVX 和口服 SLB 的剂量分别为 50 毫克/千克和 3 毫克/千克。利用高效液相色谱法和紫外线测定血浆和肺中的 LVX 浓度。药代动力学参数通过非室分析法进行评估:血浆中 LVX 的 0 至 16 h 曲线下面积(AUC0-16)、终末消除半衰期、分布容积、总清除率和峰值浓度分别为 42.57 h*μg/mL、2.32 h、3.91 L/kg、1.17 L/h/kg 和 23.96 μg/mL。与 SLB 同时给药时,LVX 的血浆和肺部药代动力学参数没有发生变化。单独给药和与 SLB 联合给药后,LVX 的 AUC0-16 肺/AUC0-16 血浆比分别为 1.60 和 1.39:结论:肺组织中的 LVX 浓度高于血浆中的浓度。结论:肺组织中的 LVX 浓度高于血浆中的浓度。给大鼠服用 SLB 不会影响 LVX 的血浆和肺药代动力学以及肺渗透比。有必要揭示 LVX 在多次给药和通过不同途径给药 SLB 后的药代动力学变化。
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引用次数: 0
Fluoropyrimidine Toxicity: the Hidden Secrets of DPYD. 氟嘧啶的毒性:DPYD 的隐秘。
IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 DOI: 10.2174/0113892002296707240311105527
Vangelis G Manolopoulos, Georgia Ragia

Background: Fluoropyrimidine-induced toxicity is a main limitation of therapy. Currently, polymorphisms in the DPYD gene, which encodes the 5-FU activation enzyme dihydropyrimidine dehydrogenase (DPD), are used to adjust the dosage and prevent toxicity. Despite the predictive value of DPYD genotyping, a great proportion of fluoropyrimidine toxicity cannot be solely explained by DPYD variations.

Objective: We herein summarize additional sources of DPD enzyme activity variability, spanning from epigenetic regulation of DPYD expression, factors potentially inducing protein modifications, as well as drug-enzyme interactions that contribute to fluoropyrimidine toxicity.

Results: While seminal in vitro studies provided evidence that DPYD promoter methylation downregulates DPD expression, the association of DPYD methylation with fluoropyrimidine toxicity was not replicated in clinical studies. Different non-coding RNA molecules, such as microRNA, piwi-RNAs, circular-RNAs and long non-coding RNAs, are involved in post-transcriptional DPYD regulation. DPD protein modifications and environmental factors affecting enzyme activity may also add a proportion to the pooled variability of DPD enzyme activity. Lastly, DPD-drug interactions are common in therapeutics, with the most well-characterized paradigm the withdrawal of sorivudine due to fluoropyrimidine toxicity deaths in 5-FU treated cancer patients; a mechanism involving DPD severe inhibition.

Conclusions: DPYD polymorphisms are the main source of DPD variability. A study on DPYD epigenetics (both transcriptionally and post-transcriptionally) holds promise to provide insights into molecular pathways of fluoropyrimidine toxicity. Additional post-translational DPD modifications, as well as DPD inhibition by other drugs, may explain a proportion of enzyme activity variability. Therefore, there is still a lot we can learn about the DPYD/DPD fluoropyrimidine-induced toxicity machinery.

背景:氟嘧啶引起的毒性是治疗的主要限制因素。目前,编码 5-FU 活化酶二氢嘧啶脱氢酶(DPD)的 DPYD 基因的多态性被用于调整剂量和预防毒性。尽管 DPYD 基因分型具有预测价值,但很大一部分氟嘧啶类药物的毒性并不能完全由 DPYD 变异解释:我们在此总结了 DPD 酶活性变异的其他来源,包括 DPYD 表达的表观遗传调控、可能诱导蛋白质修饰的因素以及导致氟嘧啶毒性的药物-酶相互作用:尽管开创性的体外研究提供了 DPYD 启动子甲基化下调 DPD 表达的证据,但 DPYD 甲基化与氟嘧啶毒性的关联并未在临床研究中得到证实。不同的非编码 RNA 分子,如 microRNA、piwi-RNA、环状 RNA 和长非编码 RNA,参与了转录后 DPYD 的调控。影响酶活性的 DPD 蛋白质修饰和环境因素也可能增加 DPD 酶活性的总体变异性。最后,DPD与药物的相互作用在治疗中很常见,其中最典型的例子是,5-FU治疗的癌症患者因氟嘧啶中毒死亡而停用索立乌丁;其机制涉及DPD的严重抑制:结论:DPYD 多态性是 DPD 变异的主要来源。对 DPYD 表观遗传学(转录和转录后)的研究有望深入了解氟嘧啶毒性的分子途径。DPD翻译后的其他修饰以及其他药物对DPD的抑制可能会解释部分酶活性的变化。因此,关于 DPYD/DPD 氟嘧啶诱导毒性机制,我们还有很多东西可以学习。
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引用次数: 0
Isopsoralen Improves Glucocorticoid-induced Osteoporosis by Regulating Purine Metabolism and Promoting cGMP/PKG Pathway-mediated Osteoblast Differentiation. 异补骨脂素通过调节嘌呤代谢和促进 cGMP/PKG 通路介导的成骨细胞分化改善糖皮质激素诱导的骨质疏松症
IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 DOI: 10.2174/0113892002308141240628071541
Defeng Liu, Lingyun Ma, Jihui Zheng, Zhenqun Zhang, Nana Zhang, Zhongqian Han, Xuejie Wang, Jianyong Zhao, Shuquan Lv, Huantian Cui

Background: The effects of Isopsoralen (ISO) in promoting osteoblast differentiation and inhibiting osteoclast formation are well-established, but the mechanism underlying ISO's improvement of Glucocorticoid- Induced Osteoporosis (GIOP) by regulating metabolism remains unclear.

Methods: This study aims to elucidate the mechanism of ISO treatment for GIOP through non-targeted metabolomics based on ISO's efficacy in GIOP. Initially, we established a GIOP female mouse model and assessed ISO's therapeutic effects using micro-CT detection, biomechanical testing, serum calcium (Ca), and phosphorus (P) level detection, along with histological analyses using hematoxylin and eosin (HE), Masson, and tartrate-resistant acidic phosphatase (TRAP) staining. Subsequently, non-targeted metabolomics was employed to investigate ISO's impact on serum metabolites in GIOP mice. RT-qPCR and Western blot analyses were conducted to measure the levels of enzymes associated with these metabolites. Building on the metabolomic results, we explored the effects of ISO on the cyclic Guanosine Monophosphate (cGMP)/Protein Kinase G (PKG) pathway and its role in mediating osteoblast differentiation.

Results: Our findings demonstrate that ISO intervention effectively enhances the bone microarchitecture and strength of GIOP mice. It mitigates pathological damage, such as structural damage in bone trabeculae, reduced collagen fibers, and increased osteoclasts, while improving serum Ca and P levels in GIOP mice. Non-- targeted metabolomics revealed purine metabolism as a common pathway between the Control and GIOP groups, as well as between the ISO high-dose (ISOH) group and the GIOP group. ISO intervention upregulated inosine and adenosine levels, downregulated guanosine monophosphate levels, increased Adenosine Deaminase (ADA) expression, and decreased cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5) expression. Additionally, ISO intervention elevated serum cGMP levels, upregulated PKGI and PKGII expression in bone tissues, as well as the expression of Runt-related transcription factor 2 (Runx2) and Osterix, and increased serum Alkaline Phosphatase (ALP) activity.

Conclusion: In summary, ISO was able to enhance the bone microstructure and bone strength of GIOP mice and improve their Ca, P, and ALP levels, which may be related to ISO's regulation of purine metabolism and promotion of osteoblast differentiation mediated by the cGMP/PKG pathway. This suggests that ISO is a potential drug for treating GIOP. However, further research is still needed to explore the specific targets and clinical applications of ISO.

背景:异补骨脂素(ISO)具有促进成骨细胞分化和抑制破骨细胞形成的作用,但ISO通过调节代谢改善糖皮质激素诱导的骨质疏松症(GIOP)的机制仍不清楚:本研究旨在根据 ISO 对 GIOP 的疗效,通过非靶向代谢组学阐明 ISO 治疗 GIOP 的机制。首先,我们建立了一个雌性 GIOP 小鼠模型,并使用显微 CT 检测、生物力学测试、血清钙(Ca)和磷(P)水平检测以及苏木精和伊红(HE)、Masson 和耐酒石酸磷酸酶(TRAP)染色进行组织学分析来评估 ISO 的治疗效果。随后,采用非靶向代谢组学研究 ISO 对 GIOP 小鼠血清代谢物的影响。通过 RT-qPCR 和 Western 印迹分析来测量与这些代谢物相关的酶的水平。在代谢组学结果的基础上,我们探讨了 ISO 对环磷酸鸟苷(cGMP)/蛋白激酶 G(PKG)通路的影响及其在介导成骨细胞分化中的作用:结果:我们的研究结果表明,ISO干预能有效改善GIOP小鼠的骨微结构和强度。结果:我们的研究结果表明,ISO干预能有效增强GIOP小鼠的骨微结构和强度,减轻病理损伤,如骨小梁结构损伤、胶原纤维减少和破骨细胞增加,同时改善GIOP小鼠的血清钙和磷水平。非靶向代谢组学发现,嘌呤代谢是对照组和 GIOP 组之间以及 ISO 高剂量组(ISOH)和 GIOP 组之间的共同途径。ISO 干预上调了肌苷和腺苷水平,下调了单磷酸鸟苷水平,增加了腺苷脱氨酶(ADA)的表达,并降低了 cGMP 特异性 3',5'-环磷酸二酯酶(PDE5)的表达。此外,ISO干预还能提高血清cGMP水平,上调骨组织中PKGI和PKGII的表达,以及Runt相关转录因子2(Runx2)和Osterix的表达,并提高血清碱性磷酸酶(ALP)的活性:综上所述,ISO能够增强GIOP小鼠的骨微结构和骨强度,改善其Ca、P和ALP水平,这可能与ISO通过cGMP/PKG途径调节嘌呤代谢和促进成骨细胞分化有关。这表明,ISO 是一种治疗 GIOP 的潜在药物。然而,要探索 ISO 的特定靶点和临床应用,仍需进一步研究。
{"title":"Isopsoralen Improves Glucocorticoid-induced Osteoporosis by Regulating Purine Metabolism and Promoting cGMP/PKG Pathway-mediated Osteoblast Differentiation.","authors":"Defeng Liu, Lingyun Ma, Jihui Zheng, Zhenqun Zhang, Nana Zhang, Zhongqian Han, Xuejie Wang, Jianyong Zhao, Shuquan Lv, Huantian Cui","doi":"10.2174/0113892002308141240628071541","DOIUrl":"10.2174/0113892002308141240628071541","url":null,"abstract":"<p><strong>Background: </strong>The effects of Isopsoralen (ISO) in promoting osteoblast differentiation and inhibiting osteoclast formation are well-established, but the mechanism underlying ISO's improvement of Glucocorticoid- Induced Osteoporosis (GIOP) by regulating metabolism remains unclear.</p><p><strong>Methods: </strong>This study aims to elucidate the mechanism of ISO treatment for GIOP through non-targeted metabolomics based on ISO's efficacy in GIOP. Initially, we established a GIOP female mouse model and assessed ISO's therapeutic effects using micro-CT detection, biomechanical testing, serum calcium (Ca), and phosphorus (P) level detection, along with histological analyses using hematoxylin and eosin (HE), Masson, and tartrate-resistant acidic phosphatase (TRAP) staining. Subsequently, non-targeted metabolomics was employed to investigate ISO's impact on serum metabolites in GIOP mice. RT-qPCR and Western blot analyses were conducted to measure the levels of enzymes associated with these metabolites. Building on the metabolomic results, we explored the effects of ISO on the cyclic Guanosine Monophosphate (cGMP)/Protein Kinase G (PKG) pathway and its role in mediating osteoblast differentiation.</p><p><strong>Results: </strong>Our findings demonstrate that ISO intervention effectively enhances the bone microarchitecture and strength of GIOP mice. It mitigates pathological damage, such as structural damage in bone trabeculae, reduced collagen fibers, and increased osteoclasts, while improving serum Ca and P levels in GIOP mice. Non-- targeted metabolomics revealed purine metabolism as a common pathway between the Control and GIOP groups, as well as between the ISO high-dose (ISOH) group and the GIOP group. ISO intervention upregulated inosine and adenosine levels, downregulated guanosine monophosphate levels, increased Adenosine Deaminase (ADA) expression, and decreased cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5) expression. Additionally, ISO intervention elevated serum cGMP levels, upregulated PKGI and PKGII expression in bone tissues, as well as the expression of Runt-related transcription factor 2 (Runx2) and Osterix, and increased serum Alkaline Phosphatase (ALP) activity.</p><p><strong>Conclusion: </strong>In summary, ISO was able to enhance the bone microstructure and bone strength of GIOP mice and improve their Ca, P, and ALP levels, which may be related to ISO's regulation of purine metabolism and promotion of osteoblast differentiation mediated by the cGMP/PKG pathway. This suggests that ISO is a potential drug for treating GIOP. However, further research is still needed to explore the specific targets and clinical applications of ISO.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"288-297"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Metabolic Pathway of Osilodrostat in Equine Urine Established through High-resolution Mass Spectrometric Characterization for Doping Control. 通过高分辨率质谱分析确定马尿中奥西洛德司他的代谢途径,用于兴奋剂控制。
IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 DOI: 10.2174/0113892002325954240903062440
Hideaki Ishii, Ryo Shigematsu, Shunsuke Takemoto, Yuhiro Ishikawa, Fumiaki Mizobe, Motoi Nomura, Daisuke Arima, Hirokazu Kunii, Reiko Yuasa, Takashi Yamanaka, Sohei Tanabe, Shun-Ichi Nagata, Masayuki Yamada, Gary Ngai-Wa Leung

Objective: Osilodrostat, used to treat Cushing's disease, exhibits an anabolic effect, leading to its classification as a prohibited substance in horseracing and equestrian sports. This study reports the characterization of osilodrostat metabolites in horse urine and elucidates its metabolic pathways for the first time for doping control purposes.

Methods: Osilodrostat was administered nasoesophageally to four thoroughbreds (one gelding and three mares) at a dose of 50 mg each. Potential metabolites were extensively screened via our developed generic approach employing differential analysis to identify metabolites. Specifically, high-resolution mass spectral data were compared between pre- and post-administration samples on the basis of criteria of fold-changes of peak areas and their P values. Potential metabolite candidates were further identified through mass spectral interpretations using product ion scan data.

Results: A total of 37 metabolites were identified after comprehensive analysis. Osilodrostat was predominantly metabolized into a mono-hydroxylated form M1c (~40%) alongside osilodrostat glucuronide M2 (~17%). Given their longest detection time (2 weeks after administration) and the identification of several conjugates of osilodrostat and M1c, including a novel conjugate of riburonic acid, we recommend monitoring both osilodrostat and M1c after hydrolysis during the screening stage. However, only osilodrostat can be used for confirmation because of the availability of a reference material.

Conclusion: It is advisable to screen for both osilodrostat and its mono-hydroxylated metabolite M1c to effectively monitor horse urine for the potential misuse or abuse of osilodrostat. For suspicious samples, confirmation of osilodrostat using its reference material is required.

目的:奥司洛前列素用于治疗库欣氏病,具有合成代谢作用,因此被列为赛马和马术运动中的禁用物质。本研究报告了马尿液中奥司洛前列素代谢物的特征,并首次阐明了其代谢途径,以达到兴奋剂控制的目的:给四匹纯血马(一匹公马和三匹母马)鼻食道注射奥司洛前列素,每匹马的剂量为 50 毫克。通过我们开发的通用方法,采用差分分析鉴定代谢物,对潜在的代谢物进行了广泛筛选。具体来说,根据峰面积的折叠变化标准及其 P 值,比较给药前和给药后样本的高分辨率质谱数据。通过使用产物离子扫描数据进行质谱解释,进一步确定潜在的候选代谢物:结果:经过综合分析,共鉴定出 37 种代谢物。奥司洛司他主要代谢为单羟化形式 M1c(约占 40%)和奥司洛司他葡萄糖醛酸苷 M2(约占 17%)。鉴于奥司洛前列素和 M1c 的检测时间最长(用药后 2 周),而且还发现了奥司洛前列素和 M1c 的多种共轭物,包括核糖醛酸的新型共轭物,我们建议在筛选阶段监测水解后的奥司洛前列素和 M1c。不过,由于有参照物,因此只能使用奥司洛前列素进行确认:结论:最好同时筛查奥司洛前列素及其单羟化代谢物 M1c,以有效监控马尿中可能存在的奥司洛前列素误用或滥用情况。对于可疑样本,需要使用其参考物质对奥司洛前列素进行确认。
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引用次数: 0
A Phase I Clinical Study of the Pharmacokinetics and Safety of Prusogliptin Tablets in Subjects with Mild to Moderate Hepatic Insufficiency and Normal Liver Function. 轻度至中度肝功能不全且肝功能正常受试者服用普格列汀片的药代动力学和安全性 I 期临床研究
IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 DOI: 10.2174/0113892002288120240221111336
Huiting Zhang, Yicong Bian, Weifeng Zhao, Liyan Miao, Hua Zhang, Juanjuan Cui, Xiaofang Zhang, Xueyuan Zhang, Wen Cai

Background: Prusogliptin is a potent and selective DPP-4 inhibitor. In different animal models, Prusogliptin showed potential efficacy in the treatment of type 2 diabetes. However, the knowledge of its pharmacokinetics and safety in patients with liver dysfunction is limited.

Objectives: The present study evaluated the pharmacokinetics and safety of Prusogliptin in subjects with mild or moderate hepatic impairment compared with healthy subjects.

Methods: According to the liver function of the subjects, we divided them into a mild liver dysfunction group, a moderate liver dysfunction group and a normal liver function group. All subjects in three groups received a single oral dose of Prusogliptin 100-mg tablets. Pharmacokinetics and safety index collection was carried out before and after taking the drug. Plasma pharmacokinetics of Prusogliptin were evaluated, and geometric least- -squares mean (GLSM) and associated 90% confidence intervals for insufficient groups versus the control group were calculated for plasma exposures.

Results: After a single oral administration of 100 mg of Prusogliptin tablets, the exposure level of Prusogliptin in subjects with mild liver dysfunction was slightly higher than that in healthy subjects. The exposure level of Prusogliptin was significantly increased in subjects with moderate liver dysfunction. There were no adverse events in this study.

Conclusion: The exposure level of Prusogliptin in subjects with liver dysfunction was higher than that in healthy subjects. No participant was observed of adverse events. Prusogliptin tablets were safe and well tolerated in Chinese subjects with mild to moderate liver dysfunction and normal liver function.

背景介绍普格列汀是一种强效的选择性 DPP-4 抑制剂。在不同的动物模型中,普鲁格列汀显示出治疗 2 型糖尿病的潜在疗效。然而,人们对其在肝功能异常患者中的药代动力学和安全性了解有限:本研究评估了普鲁格列汀在轻度或中度肝功能损害受试者与健康受试者中的药代动力学和安全性:根据受试者的肝功能,我们将其分为轻度肝功能障碍组、中度肝功能障碍组和正常肝功能组。三组所有受试者均口服单剂量普鲁格列汀 100 毫克片剂。服药前后均进行了药代动力学和安全性指标收集。评估了普鲁格列汀的血浆药代动力学,并计算了不足组与对照组血浆暴露量的几何最小二乘法平均值(GLSM)和相关的 90% 置信区间:单次口服 100 毫克普格列汀片后,轻度肝功能异常受试者的普格列汀暴露水平略高于健康受试者。中度肝功能异常受试者的普鲁格列汀暴露水平明显升高。本研究未发现不良反应:结论:普鲁列汀在肝功能异常受试者中的暴露水平高于健康受试者。没有参与者出现不良反应。普格列汀片在轻度至中度肝功能异常和肝功能正常的中国受试者中安全且耐受性良好。
{"title":"A Phase I Clinical Study of the Pharmacokinetics and Safety of Prusogliptin Tablets in Subjects with Mild to Moderate Hepatic Insufficiency and Normal Liver Function.","authors":"Huiting Zhang, Yicong Bian, Weifeng Zhao, Liyan Miao, Hua Zhang, Juanjuan Cui, Xiaofang Zhang, Xueyuan Zhang, Wen Cai","doi":"10.2174/0113892002288120240221111336","DOIUrl":"10.2174/0113892002288120240221111336","url":null,"abstract":"<p><strong>Background: </strong>Prusogliptin is a potent and selective DPP-4 inhibitor. In different animal models, Prusogliptin showed potential efficacy in the treatment of type 2 diabetes. However, the knowledge of its pharmacokinetics and safety in patients with liver dysfunction is limited.</p><p><strong>Objectives: </strong>The present study evaluated the pharmacokinetics and safety of Prusogliptin in subjects with mild or moderate hepatic impairment compared with healthy subjects.</p><p><strong>Methods: </strong>According to the liver function of the subjects, we divided them into a mild liver dysfunction group, a moderate liver dysfunction group and a normal liver function group. All subjects in three groups received a single oral dose of Prusogliptin 100-mg tablets. Pharmacokinetics and safety index collection was carried out before and after taking the drug. Plasma pharmacokinetics of Prusogliptin were evaluated, and geometric least- -squares mean (GLSM) and associated 90% confidence intervals for insufficient groups versus the control group were calculated for plasma exposures.</p><p><strong>Results: </strong>After a single oral administration of 100 mg of Prusogliptin tablets, the exposure level of Prusogliptin in subjects with mild liver dysfunction was slightly higher than that in healthy subjects. The exposure level of Prusogliptin was significantly increased in subjects with moderate liver dysfunction. There were no adverse events in this study.</p><p><strong>Conclusion: </strong>The exposure level of Prusogliptin in subjects with liver dysfunction was higher than that in healthy subjects. No participant was observed of adverse events. Prusogliptin tablets were safe and well tolerated in Chinese subjects with mild to moderate liver dysfunction and normal liver function.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"140-151"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ceftobiprole and Cefiderocol for Patients on Extracorporeal Membrane Oxygenation: The Role of Therapeutic Drug Monitoring. 用于体外膜氧合患者的头孢比普洛和头孢克洛:治疗药物监测的作用。
IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 DOI: 10.2174/0113892002331260240919055056
Diana Morales Castro, John Granton, Eddy Fan

Introduction: Limited data exist on therapeutic ranges for newer antimicrobials in the critically ill, with few pharmacokinetic studies including patients undergoing renal replacement therapy or extracorporeal membrane oxygenation (ECMO).

Case representation: These interventions can potentially alter the pharmacokinetic profile of antibiotics, resulting in therapeutic failures, antimicrobial resistance, or increased toxicity. In this report, we present two ECMO patients treated with cefiderocol and ceftobiprole, where therapeutic drug monitoring (TDM) aided in the successful treatment of severe infections. Antibiotic trough concentrations in both cases were consistent with previously reported therapeutic levels in critically ill and ECMO patients, meeting minimal inhibitory concentrations recommended by the European Committee on Antimicrobial Susceptibility Testing for the respective pathogens.

Conclusion: Treatment might be suboptimal if doses are not adjusted based on physicochemical properties and extracorporeal support. In an era marked by highly resistant pathogens, these cases highlight the importance of timely access to real-time TDM for optimizing and individualizing antimicrobial treatment.

简介:关于新型抗菌药物在重症患者中的治疗范围的数据有限,包括接受肾脏替代疗法或体外膜氧合(ECMO)的患者在内的药代动力学研究很少:这些干预措施可能会改变抗生素的药代动力学特征,导致治疗失败、抗菌药耐药性或毒性增加。在本报告中,我们介绍了两名接受头孢哌酮和头孢噻吩治疗的 ECMO 患者,他们在治疗药物监测(TDM)的帮助下成功治疗了严重感染。两个病例的抗生素谷浓度与之前报道的重症患者和 ECMO 患者的治疗水平一致,达到了欧洲抗菌药物敏感性检测委员会针对相应病原体推荐的最小抑菌浓度:结论:如果不根据理化特性和体外支持调整剂量,治疗可能达不到最佳效果。在病原体高度耐药的时代,这些病例凸显了及时进行实时 TDM 以优化和个性化抗菌治疗的重要性。
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引用次数: 0
Innovative Nanoscale Drug Delivery Strategies for Breast Carcinoma: A Comprehensive Exploration. 乳腺癌的创新纳米级给药策略:全面探索。
IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 DOI: 10.2174/0113892002298034240802110752
S Jaishree, Selvaraj Kousalya, S Prakash, D Vineesh

Breast cancer (BC) is one of the major causes of poor health in women and the most devastating disease after lung cancer. The term "cancer" refers to a collection of problems resulting from abnormal cell proliferation, particularly cells that can spread to other parts of the body. Surgery, followed by chemotherapy or radiotherapy, is now accepted for BC-related cancers. However, chemotherapy and radiotherapy are rarely effective in the treatment of BC due to the adverse effects of these treatments on healthy tissues and organs. Consequently, the use of NPs in targeted Drug Delivery Systems (DDSs) has emerged as a promising strategy for BC treatment. This review provides a summary of recent clinical investigations of nanoparticle-mediated DDS that offer a novel therapeutic strategy commonly used for the treatment of breast cancer.

乳腺癌(BC)是导致女性健康不良的主要原因之一,也是继肺癌之后最具破坏性的疾病。癌症 "一词是指细胞异常增殖导致的一系列问题,尤其是会扩散到身体其他部位的细胞。对于 BC 相关的癌症,目前接受的治疗方法是手术,然后进行化疗或放疗。然而,由于化疗和放疗会对健康组织和器官产生不良影响,因此很少能有效治疗 BC。因此,在靶向给药系统(DDS)中使用 NPs 已成为治疗 BC 的一种有前途的策略。本综述概述了纳米粒子介导的 DDS 的最新临床研究,这些研究提供了一种常用于治疗乳腺癌的新型治疗策略。
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引用次数: 0
Drug Metabolizing Enzymes: An Exclusive Guide into Latest Research in Pharmaco-genetic Dynamics in Arab Countries. 药物代谢酶:阿拉伯国家药物基因动态最新研究独家指南》。
IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 DOI: 10.2174/0113892002323910240924145310
Laith Al Eitan, Iliya Yacoub Khair, Saif Alahmad

Drug metabolizing enzymes play a crucial role in the pharmacokinetics and pharmacodynamics of therapeutic drugs, influencing their efficacy and safety. This review explores the impact of genetic polymorphisms in drug-metabolizing genes on drug response within Arab populations. We examine the genetic diversity specific to Arab countries, focusing on the variations in key drug-metabolizing enzymes such as CYP450, GST, and UGT families. The review highlights recent research on polymorphisms in these genes and their implications for drug metabolism, including variations in allele frequencies and their effects on therapeutic outcomes. Additionally, the paper discusses how these genetic variations contribute to the variability in drug response and adverse drug reactions among individuals in Arab populations. By synthesizing current findings, this review aims to provide a comprehensive understanding of the pharmacogenetic landscape in Arab countries and offer insights into personalized medicine approaches tailored to genetic profiles. The findings underscore the importance of incorporating pharmacogenetic data into clinical practice to enhance drug efficacy and minimize adverse effects, ultimately paving the way for more effective and individualized treatment strategies in the region.

药物代谢酶在治疗药物的药代动力学和药效学中起着至关重要的作用,影响着药物的疗效和安全性。本综述探讨了阿拉伯人群中药物代谢基因的遗传多态性对药物反应的影响。我们研究了阿拉伯国家特有的遗传多样性,重点是 CYP450、GST 和 UGT 家族等关键药物代谢酶的变异。综述重点介绍了这些基因多态性的最新研究及其对药物代谢的影响,包括等位基因频率的变化及其对治疗效果的影响。此外,论文还讨论了这些基因变异如何导致阿拉伯人群中个体间药物反应和药物不良反应的差异。通过综合目前的研究结果,本综述旨在提供对阿拉伯国家药物遗传学状况的全面了解,并为针对遗传特征的个性化医疗方法提供真知灼见。研究结果强调了将药物基因数据纳入临床实践的重要性,以提高药物疗效并最大限度地减少不良反应,最终为该地区制定更有效的个性化治疗策略铺平道路。
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引用次数: 0
Comparative Analysis of Machine Learning Algorithms Evaluating the Single Nucleotide Polymorphisms of Metabolizing Enzymes with Clinical Outcomes Following Intravenous Paracetamol in Preterm Neonates with Patent Ductus Arteriosus. 评估患有动脉导管未闭的早产新生儿体内代谢酶单核苷酸多态性的机器学习算法与静脉注射扑热息痛临床结果的比较分析
IF 2.1 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 DOI: 10.2174/0113892002289238240222072027
Kannan Sridharan, George Priya Doss C, Hephzibah Cathryn R, Thirumal Kumar D, Muna Al Jufairi
<p><strong>Aims: </strong>Pharmacogenomics has been identified to play a crucial role in determining drug response. The present study aimed to identify significant genetic predictor variables influencing the therapeutic effect of paracetamol for new indications in preterm neonates.</p><p><strong>Background: </strong>Paracetamol has recently been preferred as a first-line drug for managing Patent Ductus Arteriosus (PDA) in preterm neonates. Single Nucleotide Polymorphisms (SNPs) in CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4 have been observed to influence the therapeutic concentrations of paracetamol.</p><p><strong>Objectives: </strong>The purpose of this study was to evaluate various Machine Learning Algorithms (MLAs) and bioinformatics tools for identifying the key genotype predictor of therapeutic outcomes following paracetamol administration in neonates with PDA.</p><p><strong>Methods: </strong>Preterm neonates with hemodynamically significant PDA were recruited in this prospective, observational study. The following SNPs were evaluated: CYP2E1*5B, CYP2E1*2, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, CYP3A5*11, CYP1A2*1C, CYP1A2*1K, CYP1A2*3, CYP1A2*4, CYP1A2*6, and CYP2D6*10. Amongst the MLAs, Artificial Neural Network (ANN), C5.0 algorithm, Classification and Regression Tree analysis (CART), discriminant analysis, and logistic regression were evaluated for successful closure of PDA. Generalized linear regression, ANN, CART, and linear regression were used to evaluate maximum serum acetaminophen concentrations. A two-step cluster analysis was carried out for both outcomes. Area Under the Curve (AUC) and Relative Error (RE) were used as the accuracy estimates. Stability analysis was carried out using <i>in silico</i> tools, and Molecular Docking and Dynamics Studies were carried out for the above-mentioned enzymes.</p><p><strong>Results: </strong>Two-step cluster analyses have revealed CYP2D6*10 and CYP1A2*1C to be the key predictors of the successful closure of PDA and the maximum serum paracetamol concentrations in neonates. The ANN was observed with the maximum accuracy (AUC = 0.53) for predicting the successful closure of PDA with CYP2D6*10 as the most important predictor. Similarly, ANN was observed with the least RE (1.08) in predicting maximum serum paracetamol concentrations, with CYP2D6*10 as the most important predictor. Further MDS confirmed the conformational changes for P34A and P34S compared to the wildtype structure of CYP2D6 protein for stability, flexibility, compactness, hydrogen bond analysis, and the binding affinity when interacting with paracetamol, respectively. The alterations in enzyme activity of the mutant CYP2D6 were computed from the molecular simulation results.</p><p><strong>Conclusion: </strong>We have identified CYP2D6*10 and CYP1A2*1C polymorphisms to significantly predict the therapeutic outcomes following the administration of paracetamol in preterm neonates with PDA. Prospective studies are required
目的:药物基因组学被认为在决定药物反应方面发挥着至关重要的作用。本研究旨在确定影响扑热息痛对早产新生儿新适应症治疗效果的重要遗传预测变量:背景:最近,扑热息痛已成为治疗早产新生儿动脉导管未闭(PDA)的一线药物。据观察,CYP1A2、CYP2A6、CYP2D6、CYP2E1 和 CYP3A4 中的单核苷酸多态性(SNPs)会影响扑热息痛的治疗浓度:本研究旨在评估各种机器学习算法(MLA)和生物信息学工具,以确定预测 PDA 新生儿服用扑热息痛后治疗效果的关键基因型:这项前瞻性观察研究招募了患有血流动力学显著性 PDA 的早产新生儿。对以下 SNPs 进行了评估:CYP2E1*5B、CYP2E1*2、CYP3A4*1B、CYP3A4*2、CYP3A4*3、CYP3A5*3、CYP3A5*7、CYP3A5*11、CYP1A2*1C、CYP1A2*1K、CYP1A2*3、CYP1A2*4、CYP1A2*6 和 CYP2D6*10。在这些工作重点中,人工神经网络(ANN)、C5.0 算法、分类和回归树分析(CART)、判别分析和逻辑回归被用来评估 PDA 的成功关闭。广义线性回归、ANN、CART 和线性回归用于评估血清对乙酰氨基酚的最大浓度。对这两种结果进行了两步聚类分析。曲线下面积(AUC)和相对误差(RE)被用作准确度估计值。使用硅学工具进行了稳定性分析,并对上述酶进行了分子对接研究(MDS):结果:两步聚类分析显示,CYP2D6*10 和 CYP1A2*1C 是预测新生儿 PDA 成功关闭和血清中扑热息痛最大浓度的关键因素。ANN 预测 PDA 成功关闭的准确率最高(AUC = 0.53),CYP2D6*10 是最重要的预测因子。同样,在预测血清中扑热息痛的最高浓度时,ANN 的 RE 最低(1.08),而 CYP2D6*10 是最重要的预测因子。进一步的 MDS 证实,与 CYP2D6 蛋白的野生型结构相比,P34A 和 P34S 在稳定性、灵活性、紧凑性、氢键分析以及与扑热息痛相互作用时的结合亲和力方面分别发生了构象变化。根据分子模拟结果计算了突变体 CYP2D6 酶活性的变化:我们发现 CYP2D6*10 和 CYP1A2*1C 多态性可显著预测患有 PDA 的早产新生儿服用扑热息痛后的治疗效果。要在易感人群中证实这些发现,还需要进行前瞻性研究。
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引用次数: 0
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Current drug metabolism
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