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Bioavailability and dose proportionality of a highly lipophilic phenolic antioxidant.
IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pub Date : 2025-03-19 DOI: 10.1080/00498254.2025.2465237
Elena A Yanovskaya, Galina A Frelikh, Alexander P Lakeev, Vera I Smolyakova, Galina A Chernysheva

IBP (2,6-diisobornyl-4-methylphenol) is a camphene derivative with unique pharmacological properties and low toxicity. It exhibits pronounced antioxidant and membrane-protective effects, making it a promising cardio- and neuroprotector.The aim of the study was investigating the pharmacokinetics of IBP in rats after intravenous (1 mg/kg) and oral administration at three doses (10, 25, 50 mg/kg). Specifically, we focused on assessing the bioavailability and dose proportionality following oral administration.Blood samples were collected via a jugular vein catheter, and plasma samples were analysed using a validated HPLC-MS/MS method. The calculation of pharmacokinetic parameters was performed by both non-compartmental and compartmental approaches. The proposed dosage form for intravenous administration was a multicomponent mixture containing N-methyl-2-pyrrolidone.Concentration of IBP in the body after intravenous administration decreased over time, exhibiting bi-exponential decay kinetics. IBP reached peak concentrations immediately and was rapidly distributed into the peripheral compartment after intravenous administration. The systemic exposure after oral administration was proportional to the dose. The calculated absolute oral bioavailability of IBP was no more than 20%.The value of the average half-life of IBP after intravenous administration exceeded similar values after oral administration by 1.5-1.6 times.

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引用次数: 0
Inhibition of ABC transporters by sorafenib and lenvatinib: implications for drug-induced cholestasis.
IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pub Date : 2025-03-17 DOI: 10.1080/00498254.2025.2475501
Getahun Befirdu Abza, Kristof De Vos, Pieter Annaert
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引用次数: 0
Development of eugenol fortified fisetin loaded nano-invasomes gel.
IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pub Date : 2025-03-13 DOI: 10.1080/00498254.2025.2478928
Abdul Ahad, Mohammad Raish, Yousef A BinJardan, Abdullah M Al-Mohizea, Fahad I Al-Jenoobi

1. The goal of current investigation was to develop eugenol fortified fisetin nano-invasomes. Fisetin loaded invasomes were prepared using thin film hydration procedure and evaluated for various parameters. Additionally, the optimized fisetin invasomes formulation (F5) was converted to fisetin invasomes gel using Carbopol® as gelling agent and evaluated for pH, spreadability, homogeneity, drug content, in vitro fisetin release, antioxidant activity and stability study.2. Prepared optimized fisetin invasomes formulation (F5) demonstrated vesicles size, PDI, zeta potential and entrapment efficiency of 153.85 ± 14.32 nm, 0.208 ± 0.042, -12.67 ± 1.08 mV and 72.10 ± 6.36%. The TEM image indicated that the prepared invasomes vesicles are intact, spherical and found in the range of nanosized scale. Prepared fisetin invasomes gel showed better spreadability and in vitro fisetin released in contrast to fisetin control gel. Substantial improvement in the DPPH radical scavenging activity of fisetin invasomes gel 44.70% (3.1 µM) and 83.94% (50 µM), was noted as compared to the control gel at 39.47% (3.1 µM) and 79.10% at (50 µM). The prepared fisetin invasomes gel formulation was found stable at 4 °C.3. Based on the results, prepared invasomes gel formulation was found as a viable method for the better delivery of bioactive compound(s) including fisetin.

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引用次数: 0
Nrf2 signaling pathway studies in Drosophila melanogaster: parallel roles in human health and insect environmental responses.
IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-23 DOI: 10.1080/00498254.2025.2465239
Jingyi Li, Shushen Sun, Ying Li, Mengzhe Tian, Xinyi Li, Suxia Ren, Zengyi Huang, Yiwen Wang, Shaoshan Du

The Nrf2 signalling pathway is crucial for cellular defense against oxidative stress and xenobiotic toxicity, highlighting its importance in both human health and environmental responses.This review focuses on the dual role of Drosophila melanogaster in Nrf2 research: we utilised the PubMed database to collect and summarised research articles on fruit fly Nrf2 studies published in the past decade, using keywords such as 'Nrf2', 'CncC', and 'Drosophila'.We found that Drosophila melanogaster, as a classical model organism for studying human diseases such as neurodegenerative disorders, cancers, and diabetes, and as an insect model for investigating xenobiotic responses and pesticide resistance, is particularly well-suited for exploring the diverse and complex functions of Nrf2 pathway.Additionally, Natural products such as curcumin and quercetin can modulate Nrf2 activity for cytoprotection. Utilising D. melanogaster's genetic tools and short life cycles, researchers can discover new therapeutics and study their mechanisms.This twofold exploration not only advances our understanding of Nrf2 in human health but also provides insights into pest control strategies through enhanced insect resistance mechanisms. Continued research in this area is essential for developing innovative treatments and effective pest management approaches.

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引用次数: 0
Dolutegravir metabolism: impact of genetic variations on uridine diphosphate glucuronosyltransferase subfamilies. 多替格拉韦代谢:遗传变异对尿苷二磷酸葡萄糖醛酸转移酶亚家族的影响。
IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-20 DOI: 10.1080/00498254.2025.2453983
Kouji Tagawa, Yoshihiro Maruo

Dolutegravir (DTG) is a key drug used to treat human immunodeficiency virus type-1 (HIV-1) infections. Adverse events (AEs) of DTG treatment, including headache, anxiety, depression, insomnia, and abnormal dreams, are influenced by sex, body weight, age, and serum bilirubin levels. DTG is mainly metabolised by members of the uridine diphosphate glucuronosyltransferase 1A subfamilies (UGT1As), especially UGT1A1.Some studies suggest a relationship between UGT1A1 variants and AEs. The aim of this study was to identify UGT1A isoforms that exhibit DTG glucuronidation activity and determine the relationship between UGT1A variants and DTG glucuronidation in vitro.UGT1A1, UGT1A3, UGT1A9, and UGT1A10 exhibited DTG glucuronidation activity, of which UGT1A1 was the most active. Furthermore, variants of these isoforms showed decreased DTG glucuronidation activity. The different variants of UGT1As, such as UGT1A1.6, UGT1A1.7, UGT1A1.35, UGT1A1.63, UGT1A3.5, UGT1A9.2, UGT1A10M59I, and UGT1A10T202I, showed reduced glucuronidation activity towards DTG in comparison with the wild-type UGT1As.This study elucidates the relationship between UGT1A variants and the levels of glucuronidation associated with each variant.Checking for UGT1As may be helpful in predicting potential toxicities and adverse effects related to DTG treatment.

Dolutegravir (DTG)是治疗人类免疫缺陷病毒1型(HIV-1)感染的关键药物。DTG治疗的不良事件(ae),包括头痛、焦虑、抑郁、失眠和梦异常,受性别、体重、年龄和血清胆红素水平的影响。二甘油三酯主要由尿苷二磷酸葡萄糖醛酸转移酶1A亚家族(UGT1As)成员代谢,尤其是UGT1A1。一些研究表明UGT1A1变异与ae之间存在关系。本研究的目的是鉴定具有DTG糖醛酸化活性的UGT1A亚型,并确定UGT1A变体与体外DTG糖醛酸化之间的关系。UGT1A1、UGT1A3、UGT1A9和UGT1A10表现出DTG糖醛酸化活性,其中UGT1A1活性最强。此外,这些异构体的变体显示DTG糖醛酸化活性降低。UGT1As的不同变异体UGT1A1.6、UGT1A1.7、UGT1A1.35、UGT1A1.63、UGT1A3.5、UGT1A9.2、UGT1A10M59I和UGT1A10T202I对DTG的糖醛酸化活性均低于野生型UGT1As。本研究阐明了UGT1A变体与每种变体相关的糖醛酸化水平之间的关系。检查ugt1a可能有助于预测与DTG治疗相关的潜在毒性和不良反应。
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引用次数: 0
Inorganic mercury pharmacokinetics in man: a hybrid model. 无机汞在人体内的药代动力学:一个混合模型。
IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2025-01-22 DOI: 10.1080/00498254.2024.2448979
Fred Farris, Ayda Awaness, Joe Su

A four-compartment model is presented that simulates inorganic mercury [Hg(II)] pharmacokinetics in blood, tissue, and excreta over a 70-day period. Simulations are validated against data collected from five human subjects, and previously analyzed.In the model, two compartments simulate Hg(II) in blood: one for mobile-Hg(II) and the other for immobile-Hg(II). Two corresponding compartments simulate Hg(II) in tissue. Mobile-Hg(II) represents Hg(II) available for transport across cell membranes. Immobile-Hg(II) represents Hg(II) that is not easily transported.Following dosing, blood total-Hg(II) droped rapidly in all subjects. Blood mobile-Hg(II) also droped rapidly with a concomitant rise in blood immobile-Hg(II). For four subjects, immobile-Hg(II) became the dominant Hg(II) species in blood by day 4. For subject five, mobile-Hg(II) remained dominant in blood for the study duration.Tissue mobile-Hg(II) declined rapidly for four of the subjects, with a simultaneous rapid rise in tissue immobile-Hg(II). In subject 5, tissue mobile-Hg(II) declined linearly, and immobile-Hg(II) accumulated slowly in tissue. For all subjects, tissue mobile-Hg(II) is the primary source of fecal Hg(II). The major source for Hg(II) excreted into the urine is immobile-Hg(II) from tissue.

提出了一个四室模型,模拟了70天内血液、组织和排泄物中的无机汞[Hg(II)]药代动力学。模拟是根据从五个人类受试者中收集的数据进行验证的,并在之前进行了分析(Farris, f.f., A. Kaushal, and J.G. Strom. 2008)。无机汞在人体中的药代动力学:一个双室模型。环境科学与技术,2009(5):527 - 531。在该模型中,两个隔室模拟血液中的汞(II):一个用于移动汞(II),另一个用于固定汞(II)。两个相应的区室模拟组织中的Hg(II)。Mobile-Hg(II)表示可以跨细胞膜运输的汞(II)。不可移动汞(II)表示不易运输的汞(II)。给药后,所有受试者血液中总汞(II)迅速下降。血液流动汞(II)也迅速下降,同时血液固定汞(II)升高。对于四名受试者,固定汞(II)在第4天成为血液中主要的汞(II)种类。对于受试者5,在研究期间,移动汞(II)在血液中仍占主导地位。四名受试者的组织移动汞(II)迅速下降,同时组织固定汞(II)迅速上升。在受试者5中,组织活动汞(II)呈线性下降,而固定汞(II)在组织中缓慢积累。对于所有受试者,组织移动汞(II)是粪便汞(II)的主要来源。排泄到尿液中的汞(II)的主要来源是来自组织的固定汞(II)。
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引用次数: 0
Noise - an insidious stressor affecting xenobiotic metabolism? 噪音——影响异种生物代谢的潜在压力源?
IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-12-18 DOI: 10.1080/00498254.2024.2441675
Rosemary Waring, Stephen Mitchell
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引用次数: 0
Effects of CYP3A5 polymorphism and renal impairment on the drug interaction between venetoclax and fluconazole in acute myeloid leukaemia patients. CYP3A5多态性与肾损害对急性髓系白血病患者维妥乐与氟康唑药物相互作用的影响。
IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-12-20 DOI: 10.1080/00498254.2024.2442431
Takahiro Kobayashi, Honami Sato, Yumiko Akamine, Yayoi Fukushi, Naoto Takahashi, Masatomo Miura

The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukaemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C0) of venetoclax and the fluconazole C0 were obtained from plasma samples on day 7 after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C0 values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC0-24 and C0 of venetoclax were not associated with fluconazole C0; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C0 and fluconazole C0 (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C0. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C0 is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.

本研究旨在探讨30例急性髓系白血病患者肾功能及CYP3A5多态性对维妥乐与氟康唑药物相互作用的影响。在venetoclax与氟康唑联合用药200mg /d后第7天的血浆样品中测定venetoclax与氟康唑的血药浓度-时间曲线下面积(AUC)和谷浓度(C0)。中度和重度肾功能损害患者氟康唑C0值显著高于正常和轻度肾功能损害患者(中位数分别为7037、6234和4813 ng/mL, P = 0.026)。在CYP3A5*3/*3基因型患者中,venetoclax的AUC0-24和C0与氟康唑C0无相关性;而在CYP3A5*1等位基因患者中,venetoclax C0与氟康唑C0呈显著正相关(r = 0.782, P = 0.004)。即使在低氟康唑浓度下,CYP3A4对venetoclax的代谢也受到抑制。在CYP3A5*1等位基因患者中,高氟康唑C0引起肾功能损害时,CYP3A5被抑制。在接受venetoclax治疗的严重肾功能损害患者中,氟康唑的预防剂量可为100mg。
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引用次数: 0
The impact of CYP3A5, NR1I2, and POR polymorphisms on tacrolimus dose-adjusted concentration and clinical outcomes in adult allogeneic haematopoietic stem cell transplantation. CYP3A5、NR1I2和POR多态性对成人异基因造血干细胞移植中他克莫司剂量调整浓度和临床结果的影响
IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2025-01-07 DOI: 10.1080/00498254.2024.2448967
Yuan Gao, Jingjing Ma

Polymorphisms in genes related to drug-metabolising enzymes may affect tacrolimus exposure. This study aimed to assess the influence of CYP3A5, NR1I2, and POR polymorphisms on tacrolimus pharmacokinetics and outcomes in allogeneic haematopoietic stem cell transplantation (HSCT).Forty-six adult patients receiving oral tacrolimus at an initial dose of 0.03 mg/kg/day for acute graft versus host disease (GVHD) prophylaxis after allogeneic HSCT were enrolled in this retrospective study. Genetic polymorphisms were detected in relation to concentration/dose (C/D) ratios of tacrolimus and the incidence of acute GVHD and acute kidney injury (AKI).The CYP3A5 *3/*3 genotype and co-administration of voriconazole were significantly associated with increased C/D ratios of tacrolimus (p < 0.05). NR1I2 8055CC presents a significantly higher tacrolimus C/D ratio compared with carriers of 8055CT and 8055TT genotypes in allogeneic HSCT recipients with the CYP3A5*1 allele (p = 0.033). Younger age and recipients with the CYP3A5*1 allele were significantly associated with higher incidence of II-IV acute GVHD post-transplantation.CYP3A5*3, NR1I2 8055C > T, and concomitant use of voriconazole are important determinants affecting tacrolimus pharmacokinetics. Moreover, CYP3A5*1 allele and younger age are independent risk factors for II-IV acute GVHD in HSCT recipients.

1. 与药物代谢基因相关的基因多态性可能影响他克莫司暴露。本研究旨在评估CYP3A5、NR1I2和POR多态性对他克莫司药代动力学和异基因造血干细胞移植(HSCT)结果的影响。这项回顾性研究纳入了46名成年患者,他们在同种异体造血干细胞移植后接受口服他克莫司,初始剂量为0.03mg/kg/天,用于预防急性移植物抗宿主病(GVHD)。他克莫司浓度/剂量比(C/D)与急性GVHD和急性肾损伤(AKI)发生率之间存在遗传多态性。CYP3A5* 3/*3基因型和同时给药voriconazole与他克莫司C/D比值升高有显著相关性(CYP3A5*1等位基因的同种异体HSCT接受者中,P NR1I2 8055CC比8055CT和8055TT基因型携带者的他克莫司C/D比值显著升高(P = 0.033)。年龄较小和携带CYP3A5*1等位基因的受体与移植后II-IV期急性GVHD的发生率显著相关。CYP3A5*3、NR1I2 8055 C > T及合用伏立康唑是影响他克莫司药代动力学的重要因素。此外,CYP3A5*1等位基因和年龄较小是HSCT受者II-IV期急性GVHD的独立危险因素。
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引用次数: 0
Optimising pirfenidone dosage regimens in idiopathic pulmonary fibrosis: towards a guide for personalised treatment.
IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2025-01-26 DOI: 10.1080/00498254.2025.2450440
Nastia Tsyplakova, Georgios Ismailos, Vangelis D Karalis

Idiopathic Pulmonary Fibrosis (IPF) is a chronic respiratory disorder for which pirfenidone is the recommended first-line anti-fibrotic treatment. While pirfenidone has demonstrated efficacy in slowing the progression of IPF, its use is associated with several challenges and unresolved issues that impact patient outcomes. Pirfenidone administration can result in gastrointestinal side effects, photosensitivity reactions, and significant drug interactions, particularly in patients with hepatic impairment. For those who experience intolerable side effects, dose reductions or temporary discontinuations are frequently employed. However, there is limited data on the efficacy of reduced doses, creating uncertainty about the balance between tolerability and therapeutic benefit.The aim of this study is to evaluate the currently proposed dosage adjustments and to develop new dosage regimens tailored to the needs of patients. Simulations were conducted to explore pirfenidone pharmacokinetics under various challenging conditions, including dose titration, withdrawal, retitration, moderate and severe hepatic impairment, co-administration of moderate (e.g. omeprazole) and strong (e.g. smoking) inducers of the CYP1A2 enzyme, gastrointestinal adverse events, and photosensitivity reactions.Simulations led to specific recommendations for physicians regarding dosage regimens in each condition. The recommended dosage adjustments are designed to maintain concentrations within acceptable levels, ensuring both safe and effective treatment.

{"title":"Optimising pirfenidone dosage regimens in idiopathic pulmonary fibrosis: towards a guide for personalised treatment.","authors":"Nastia Tsyplakova, Georgios Ismailos, Vangelis D Karalis","doi":"10.1080/00498254.2025.2450440","DOIUrl":"10.1080/00498254.2025.2450440","url":null,"abstract":"<p><p>Idiopathic Pulmonary Fibrosis (IPF) is a chronic respiratory disorder for which pirfenidone is the recommended first-line anti-fibrotic treatment. While pirfenidone has demonstrated efficacy in slowing the progression of IPF, its use is associated with several challenges and unresolved issues that impact patient outcomes. Pirfenidone administration can result in gastrointestinal side effects, photosensitivity reactions, and significant drug interactions, particularly in patients with hepatic impairment. For those who experience intolerable side effects, dose reductions or temporary discontinuations are frequently employed. However, there is limited data on the efficacy of reduced doses, creating uncertainty about the balance between tolerability and therapeutic benefit.The aim of this study is to evaluate the currently proposed dosage adjustments and to develop new dosage regimens tailored to the needs of patients. Simulations were conducted to explore pirfenidone pharmacokinetics under various challenging conditions, including dose titration, withdrawal, retitration, moderate and severe hepatic impairment, co-administration of moderate (e.g. omeprazole) and strong (e.g. smoking) inducers of the CYP1A2 enzyme, gastrointestinal adverse events, and photosensitivity reactions.Simulations led to specific recommendations for physicians regarding dosage regimens in each condition. The recommended dosage adjustments are designed to maintain concentrations within acceptable levels, ensuring both safe and effective treatment.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"25-36"},"PeriodicalIF":1.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047748","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
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Xenobiotica
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