Xenobiotica最新文献_第2页

Qualitative and quantitative status of cytochrome P450s after the administration of a liposomal platelet substitute in rat liver. 在大鼠肝脏中施用脂质体血小板替代物后细胞色素 P450s 的定性和定量状况。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-09 DOI: 10.1080/00498254.2024.2385535

Kazuaki Taguchi, Mai Hashimoto, Masahiro Tokuno, Shinji Takeoka, Toru Maruyama, Keishi Yamasaki, Masaki Otagiri

{"title":"Qualitative and quantitative status of cytochrome P450s after the administration of a liposomal platelet substitute in rat liver.","authors":"Kazuaki Taguchi, Mai Hashimoto, Masahiro Tokuno, Shinji Takeoka, Toru Maruyama, Keishi Yamasaki, Masaki Otagiri","doi":"10.1080/00498254.2024.2385535","DOIUrl":"10.1080/00498254.2024.2385535","url":null,"abstract":"In the process of the drug development, studies on the cytochrome P450 (CYP) profiles after its administration provided fundamental information regarding drug interactions with concomitantly administered drugs. Here, we evaluated the influence of the administration of H12-(ADP)-liposomes, a platelet substitute, on the mRNA and protein expression, and metabolic activity of CYPs, with focus on the CYP1A2, CYP2C11 and CYP3A2, in rat liver.At 24 h after administering saline or H12-(ADP)-liposomes (10 mg of lipids/kg), a quantitative RT-PCR and western blot analysis revealed that the mRNA and proteins expression of all of the target hepatic CYP isoforms were not different between the saline and H12-(ADP)-liposome groups. Furthermore, an ex vivo CYP metabolic activity assay showed that hepatic CYP metabolic activities in the H12-(ADP)-liposome group were comparable to the corresponding saline group. On the other hand, the area under the blood concentration-time curve for substitutes for CYP1A2 and CYP2C11 was higher in H12-(ADP)-liposome group than in saline group, but the degree of elevations was negligible levels.At a minimum, based on these results, we conclude that H12-(ADP)-liposomes have no quantitative and qualitative effect on the hepatic CYP isoforms, indicating that the drug interactions of H12-(ADP)-liposomes with CYP-metabolizing drugs would be negligible.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"624-628"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861103","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

How predictive are isolated perfused liver data of in vivo hepatic clearance? A meta-analysis of isolated perfused rat liver data. 离体灌注肝脏数据对体内肝清除率的预测性如何？离体灌注大鼠肝脏数据的荟萃分析。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-09-23 DOI: 10.1080/00498254.2024.2404170

Julia A Schulz Pauly, J Cory Kalvass

{"title":"How predictive are isolated perfused liver data of in vivo hepatic clearance? A meta-analysis of isolated perfused rat liver data.","authors":"Julia A Schulz Pauly, J Cory Kalvass","doi":"10.1080/00498254.2024.2404170","DOIUrl":"10.1080/00498254.2024.2404170","url":null,"abstract":"Isolated perfused rat liver (IPRL) experiments have been used to answer clearance-related questions, including evaluating the impact of pathological and physiological processes on hepatic clearance (CLH). However, to date, IPRL data has not been evaluated for in vivo CLH prediction accuracy.In addition to a detailed overview of available IPRL literature, we present an in-depth analysis of the performance of IPRL in CLH prediction.While the entire dataset poorly predicted CLH (GAFE = 3.2; 64% within 3-fold), IPRL conducted under optimal experimental conditions, such as in the presence of plasma proteins and with a perfusion rate within 2-fold of physiological liver blood flow and corrected for unbound fraction in the presence of red blood cells, can accurately predict rat CLH (GAFE = 2.0; 78% within 3-fold). Careful consideration of experimental conditions is needed to allow proper data analysis.Further, isolated perfused liver experiments in other species, including human livers, may allow us to address the current in vitro-in vivo disconnects of hepatic metabolic clearance and improve our methodology for CLH predictions.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"658-669"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142296724","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

Teratogenicity is more likely a function of primary and secondary pharmacology than caused by chemically reactive metabolites: a critical evaluation of 40 years of scientific research. 致畸性更可能是原发性和继发性药理作用的结果，而不是化学反应代谢物造成的：对 40 年科学研究的批判性评估。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-07-01 DOI: 10.1080/00498254.2024.2366302

Dennis A Smith

引用次数: 0

Pharmacokinetics, mass balance, tissue distribution, metabolism, and excretion of [¹⁴C]aficamten following single oral dose administration to rats. 大鼠单次口服[14C]Aficamten 的药代动力学、质量平衡、组织分布、代谢和排泄。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-07 DOI: 10.1080/00498254.2024.2381111

Mark P Grillo, Rajaa Sukhun, Mohammad Bashir, Luke Ashcraft, Bradley P Morgan

{"title":"Pharmacokinetics, mass balance, tissue distribution, metabolism, and excretion of [14C]aficamten following single oral dose administration to rats.","authors":"Mark P Grillo, Rajaa Sukhun, Mohammad Bashir, Luke Ashcraft, Bradley P Morgan","doi":"10.1080/00498254.2024.2381111","DOIUrl":"10.1080/00498254.2024.2381111","url":null,"abstract":"The pharmacokinetics, metabolism, excretion, mass balance, and tissue distribution of [14C]aficamten were evaluated following oral administration of an 8 mg/kg dose in Sprague Dawley rats and in a quantitative whole-body autoradiography study in Long Evans rats.[14C]Aficamten accounted for ∼80% and a hydroxylated metabolite (M1) accounted for ∼12% of total radioactivity in plasma over 48-h (AUC0-48). Plasma tmax was 4-h and the t1/2 of total plasma radioactivity was 5.8-h.Tissues showing highest Cmax exposures were myocardium and semitendinosus muscle.Most [14C]aficamten-derived radioactivity was excreted within 48-h post-administration. Mean cumulative recovery in urine and faeces over 168-h was 8.3% and 90.7%, respectively.In urine and bile, unchanged aficamten was detected at <0.1 and <0.2% of dose, respectively; however, based on total radioactivity excreted in urine (8.0%) and bile (51.7%), approximately 60% of dose was absorbed.[14C]Aficamten was metabolised by hydroxylation with subsequent glucuronidation where the most abundant metabolite recovered in bile was M5 (35.2%), the oxygen-linked glucuronide of hydroxylated aficamten (M1a). The major metabolite detected in faeces was a 1,2,4-oxadiazole moiety ring-cleaved metabolite (M18, 35.3%), shown to be formed from the metabolism of M5 in incubations with rat intestinal contents solution.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"670-685"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767605","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

Prediction of human serum concentration-time profiles of therapeutic monoclonal antibodies using common marmosets (Callithrix jacchus): initial assessment with canakinumab, adalimumab, and bevacizumab. 利用普通狨猴（Callithrix jacchus）预测治疗性单克隆抗体的人血清浓度-时间曲线：对卡那单抗、阿达木单抗和贝伐珠单抗的初步评估。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-07-26 DOI: 10.1080/00498254.2024.2371921

Ayaka Tajiri, Shogo Matsumoto, Satoshi Maeda, Takuma Soga, Kensuke Kagiyama, Hiroshi Ikeda, Kazumasa Fukasawa, Atsunori Miyata, Hidetaka Kamimura

{"title":"Prediction of human serum concentration-time profiles of therapeutic monoclonal antibodies using common marmosets (Callithrix jacchus): initial assessment with canakinumab, adalimumab, and bevacizumab.","authors":"Ayaka Tajiri, Shogo Matsumoto, Satoshi Maeda, Takuma Soga, Kensuke Kagiyama, Hiroshi Ikeda, Kazumasa Fukasawa, Atsunori Miyata, Hidetaka Kamimura","doi":"10.1080/00498254.2024.2371921","DOIUrl":"10.1080/00498254.2024.2371921","url":null,"abstract":"Cynomolgus monkeys and human FcRn transgenic mice are generally used for pharmacokinetic predictions of therapeutic monoclonal antibodies (mAbs). In the present study, the application of the common marmoset, a small nonhuman primate, as a potential animal model for prediction was evaluated for the first time.Canakinumab, adalimumab, and bevacizumab, which exhibited linear pharmacokinetics in humans, were selected as the model compounds. Marmoset pharmacokinetic data were reportedly available only for canakinumab, and those for adalimumab and bevacizumab were acquired in-house.Four pharmacokinetic parameters for a two-compartment model (i.e. clearance and volume of distribution in the central and peripheral compartments) in marmosets were extrapolated to the values in humans with allometric scaling using the average exponents of the three mAbs. As a result, the observed human serum concentration-time curves of the three mAbs following intravenous administration and those of canakinumab and adalimumab following subcutaneous injections (with an assumed absorption rate constant and bioavailability) were reasonably predicted.Although further prediction studies using a sufficient number of other mAbs are necessary to evaluate the versatility of this model, the findings indicate that marmosets can be an alternative to preceding animals for human pharmacokinetic predictions of therapeutic mAbs.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"648-657"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559907","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

Meeting report of the 5th European Biotransformation Workshop. 第五届欧洲生物转化研讨会会议报告。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-09-18 DOI: 10.1080/00498254.2024.2400112

M Walles, A Pähler, E M Isin, Marie M Ahlqvist

引用次数: 0

The metabolic activation of and platelet response to vicagrel vary with P-glycoprotein deficiency, rather than P-glycoprotein inhibition, in mice. 在小鼠体内，P-糖蛋白缺乏（而非 P-糖蛋白抑制）会导致维卡格雷的代谢激活和血小板反应发生变化。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-21 DOI: 10.1080/00498254.2024.2390972

Xue-Mei Li, Hao-Dong Li, Yuan-Yuan Shao, Jin-Zi Ji, Ke Tang, Zhao-Dong Zheng, Yu Wu, Pei-Jie Ding, Jin Wang, Li-Ping Jiang, Ting Tai, Qiong-Yu Mi, Min Fu, Hong-Guang Xie

{"title":"The metabolic activation of and platelet response to vicagrel vary with P-glycoprotein deficiency, rather than P-glycoprotein inhibition, in mice.","authors":"Xue-Mei Li, Hao-Dong Li, Yuan-Yuan Shao, Jin-Zi Ji, Ke Tang, Zhao-Dong Zheng, Yu Wu, Pei-Jie Ding, Jin Wang, Li-Ping Jiang, Ting Tai, Qiong-Yu Mi, Min Fu, Hong-Guang Xie","doi":"10.1080/00498254.2024.2390972","DOIUrl":"10.1080/00498254.2024.2390972","url":null,"abstract":"This study aimed to determine changes in the hydrolysis of vicagrel, a substrate drug of arylacetamide deacetylase (Aadac) and carboxylesterase 2 (Ces2), in P-glycoprotein (P-gp)-deficient or P-gp-inhibited mice and to elucidate the mechanisms involved.Male wild-type (WT) and P-gp knock-out (KO) mice were used to investigate the systemic exposure of vicagrel thiol active metabolite H4 and platelet response to vicagrel, and the mRNA and protein expression levels of intestinal Aadac and Ces2. Moreover, WT mice were administered vicagrel alone or in combination with elacridar (a potent P-gp inhibitor) to determine drug-drug interactions.Compared with WT mice, P-gp KO mice exhibited significant increases in the systemic exposure of H4, the protein expression levels of intestinal Aadac and Ces2, and inhibition of ADP-induced platelet aggregation by vicagrel. Further, the H4 exposure was positively correlated with intestinal Aadac protein expression levels but did not vary with short-term inhibition of P-gp efflux activity by elacridar.P-gp-deficient mice, rather than elacridar-treated mice, exhibited significant upregulation of intestinal Aadac and Ces2 and thus, enhanced metabolic activation of and platelet response to vicagrel, suggesting that the metabolic activation of vicagrel may vary with P-gp deficiency, not P-gp inhibition, in mice.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"759-769"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914140","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

Meeting report: DMPK optimisation strategies and quantitative translational PKPD frameworks to predict human PK and efficacious dose of targeted protein degraders. 会议报告：预测靶向蛋白降解剂的人体 PK 和有效剂量的 DMPK 优化策略和定量转化 PKPD 框架。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-07-12 DOI: 10.1080/00498254.2024.2369787

Caroline Rynn, Heide Marika Duevel

引用次数: 0

Improved preclinical drug metabolism and pharmacokinetics of pibothiadine (HEC121210), a novel hepatitis B virus capsid assembly modulator. 新型乙型肝炎病毒囊壳组装调节剂 Pibothiadine (HEC121210) 临床前药物代谢和药代动力学的改进。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-12 DOI: 10.1080/00498254.2024.2381223

Ming Li, Xingguo Yan, Li Zhang, Xinchang Liu, Yayi Liu, Qian Wang, Jing Li

{"title":"Improved preclinical drug metabolism and pharmacokinetics of pibothiadine (HEC121210), a novel hepatitis B virus capsid assembly modulator.","authors":"Ming Li, Xingguo Yan, Li Zhang, Xinchang Liu, Yayi Liu, Qian Wang, Jing Li","doi":"10.1080/00498254.2024.2381223","DOIUrl":"10.1080/00498254.2024.2381223","url":null,"abstract":"Pibothiadine (PBD; HEC121120) is a novel hepatitis B virus capsid assembly modulator based on GLS4 (morphothiadine) and has inhibitory activities against resistant strains.To assess the overall preclinical drug metabolism and pharmacokinetics (DMPK) properties of PBD, in vivo pharmacokinetics studies in rats and dogs have been performed along with a series of in vitro metabolism assays.The oral bioavailability of PBD in rats and dogs might be related to its medium permeability in Caco-2 cells and largely be impacted by the pH-dependent solubility. PBD was highly distributed to the liver where the local exposure was 16.4 fold of the system exposure. PBD showed relatively low metabolic rate in recombinant human cytochrome P450 enzymes, whereas low to moderate in vitro clearance in liver microsomes and low (dog) to moderate (rat) in vivo clearance. Furthermore, β-oxidation and dehydrogenation were proposed as the primary metabolic pathways of PBD in rats.Compared to GLS4, the higher systemic exposure of PBD might be attributed to its improved oral absorption and metabolic stability. In addition, the enhanced liver/plasma exposure ratio could further increase the local exposure around the target. These improved DMPK properties might indicate better development of PBD in the clinical phase.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"701-710"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767604","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

Mechanism-based inactivation of cytochromes P450: implications in drug interactions and pharmacotherapy. 基于机理的细胞色素 P450 失活：药物相互作用和药物治疗的意义》。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-28 DOI: 10.1080/00498254.2024.2395557

Boon Hooi Tan, Nafees Ahemad, Yan Pan, Chin Eng Ong

{"title":"Mechanism-based inactivation of cytochromes P450: implications in drug interactions and pharmacotherapy.","authors":"Boon Hooi Tan, Nafees Ahemad, Yan Pan, Chin Eng Ong","doi":"10.1080/00498254.2024.2395557","DOIUrl":"10.1080/00498254.2024.2395557","url":null,"abstract":"Cytochrome P40 (CYP) enzymes dominate the metabolism of numerous endogenous and xenobiotic substances. While it is commonly believed that CYP-catalysed reactions result in the detoxication of foreign substances, these reactions can also yield reactive intermediates that can bind to cellular macromolecules to cause cytotoxicity or irreversibly inactivate CYPs that create them.Mechanism-based inactivation (MBI) produces either irreversible or quasi-irreversible inactivation and is commonly caused by CYP metabolic bioactivation to an electrophilic reactive intermediate. Many drugs that have been known to cause MBI in CYPs have been discovered as perpetrators in drug-drug interactions throughout the last 20-30 years.This review will highlight the key findings from the recent literature about the mechanisms of CYP enzyme inhibition, with a focus on the broad mechanistic elements of MBI for widely used drugs linked to the phenomenon. There will also be a brief discussion of the clinical or pharmacokinetic consequences of CYP inactivation with regard to drug interaction and toxicity risk.Gaining knowledge about the selective inactivation of CYPs by common therapeutic drugs helps with the assessment of factors that affect the systemic clearance of co-administered drugs and improves comprehension of anticipated interactions with other drugs or xenobiotics.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"575-598"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037076","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