Xenobiotica最新文献_第2页

Pharmacometric analysis of dapagliflozin for triglyceride-lowering effects in Japanese patients with type 2 diabetes mellitus based on long-term real-world data and experimental analysis of dyslipidemia model rats. 基于长期真实数据和血脂异常模型大鼠实验分析达格列净对日本2型糖尿病患者甘油三酯降低作用的药理学分析

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-10-07 DOI: 10.1080/00498254.2026.2745915

Ryosuke Terada, Shinji Kobuchi, Ayaka Anada, Rina Watanabe, Tatsuya Miyoshi, Satoru Tanide, Kiichi Hiroi, Takafumi Nishiwaki, Raiya Kitagawa, Ken-Ichiro Kato, Tetsuo Hayakawa, Toshiyuki Sakaeda

{"title":"Pharmacometric analysis of dapagliflozin for triglyceride-lowering effects in Japanese patients with type 2 diabetes mellitus based on long-term real-world data and experimental analysis of dyslipidemia model rats.","authors":"Ryosuke Terada, Shinji Kobuchi, Ayaka Anada, Rina Watanabe, Tatsuya Miyoshi, Satoru Tanide, Kiichi Hiroi, Takafumi Nishiwaki, Raiya Kitagawa, Ken-Ichiro Kato, Tetsuo Hayakawa, Toshiyuki Sakaeda","doi":"10.1080/00498254.2026.2745915","DOIUrl":"https://doi.org/10.1080/00498254.2026.2745915","url":null,"abstract":"1. Although dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown potential triglyceride-lowering effects, the clinical evidence remains inconsistent. This study aimed to determine whether the triglyceride-lowering effect observed in patients receiving dapagliflozin was associated with dapagliflozin exposure using a pharmacometric approach integrating clinical data and a preclinical model.2. Clinical data were retrieved from 85 Japanese patients with type 2 diabetes mellitus who received dapagliflozin 5 mg/day for 12 months. Serum triglyceride levels and plasma concentrations of dapagliflozin were analyzed using a population pharmacokinetic-pharmacodynamic (PK-PD) model. In addition, dapagliflozin (0.1 or 0.2 mg/kg) was administered to poloxamer-407-induced dyslipidemia model rats to examine exposure-dependent triglyceride-lowering effects.3. Among the 18 patients with elevated serum triglyceride levels (≥150 mg/dL) at baseline, dapagliflozin significantly reduced triglyceride levels, with a mean reduction of 47 mg/dL at 12 months. The population PK-PD model captured 103 triglyceride measurements and revealed an exposure-dependent triglyceride-lowering effect. Consistently, a dose-dependent reduction in triglyceride levels was observed in the dyslipidemia model rats.4. These findings suggest that dapagliflozin exposure is associated with triglyceride-lowering effects, demonstrating an exposure-response relationship supported by pharmacometric analysis of long-term real-world data and a dyslipidemia model.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-32"},"PeriodicalIF":1.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128461","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

Modulatory effects of zinc and cystine on diisononyl phthalate-induced male reproductive injury. 锌和胱氨酸对邻苯二甲酸二异壬酯诱导的雄性生殖损伤的调节作用。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-10-07 DOI: 10.1080/00498254.2026.2740560

Randa Djemil, Alima Messai, Sabrina Lekmine, Samia Ati

{"title":"Modulatory effects of zinc and cystine on diisononyl phthalate-induced male reproductive injury.","authors":"Randa Djemil, Alima Messai, Sabrina Lekmine, Samia Ati","doi":"10.1080/00498254.2026.2740560","DOIUrl":"10.1080/00498254.2026.2740560","url":null,"abstract":"This study investigated the combined effects of zinc and cystine on reproductive damage induced by diisononyl phthalate (DiNP) in male rats.A total of 28 rats were randomly assigned to four groups (n = 7 per group) and treated for 45 days. Group 0 (Control) received physiological saline, Group G1 (positive control) received a zinc- cystine combination at a dose of 5 mg zinc + 50 mg cystine/kg body weight, Group 2 received DiNP alone (15 mg/kg body weight), whereas Group 3 received DiNP in combination with zinc (5 mg/kg body weight) and cystine (50 mg/kg body weight).Hormonal parameters, including luteinizing hormone (LH), Follicle-stimulating hormone (FSH), and testosterone, were measured. Sperm concentration, motility, speed, and vitality were also evaluated, together with testicular oxidative stress markers, including GSH, GSH-Px, MDA, and SOD.The results showed that the zinc-cystine combination significantly alleviated the reproductive and oxidative damage induced by DiNP exposure. Improvements were observed in hormonal status, sperm quality parameters, and antioxidant defence markers compared with the DiNP-treated group.These findings highlight the protective potential of zinc and cystine against environmental toxin-induced reproductive dysfunction and suggest a combined effect that may have therapeutic relevance in reducing the adverse effects associated with phthalate exposure.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-10"},"PeriodicalIF":1.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149064807","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

Astaxanthin nanoemulsion attenuates paraquat-induced Parkinsonism via modulation of oxidative stress, neuroinflammation, and dopaminergic dysfunction in rats. 虾青素纳米乳通过调节大鼠氧化应激、神经炎症和多巴胺能功能障碍来减轻百草枯诱导的帕金森病。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-10-05 DOI: 10.1080/00498254.2026.2732969

Moh Aijaz, Arun Kumar

{"title":"Astaxanthin nanoemulsion attenuates paraquat-induced Parkinsonism via modulation of oxidative stress, neuroinflammation, and dopaminergic dysfunction in rats.","authors":"Moh Aijaz, Arun Kumar","doi":"10.1080/00498254.2026.2732969","DOIUrl":"https://doi.org/10.1080/00498254.2026.2732969","url":null,"abstract":"1. Parkinson's disease (PD) involves dopaminergic dysfunction, oxidative stress, and neuroinflammation. This study evaluated an optimised astaxanthin-loaded nanoemulsion (AXTNE) in paraquat-induced experimental Parkinsonism.2. Male Wistar rats were randomly assigned to nine groups (n = 6). Parkinsonian alterations were induced by paraquat (10 mg/kg, i.p.) twice weekly for 4 weeks. Aqueous astaxanthin (AXT; 30 mg/kg), AXTNE (15 and 30 mg/kg), levodopa + carbidopa (15 + 3.75 mg/kg), and AXTNE-levodopa combinations were administered orally for 28 days. Motor function was assessed using catalepsy, locomotor activity, grip strength, postural instability, and beam-walk tests. Pooled bilateral striatal tissue was analysed for oxidative stress, inflammatory cytokines, monoaminergic neurotransmitters, and dopaminergic protein markers.3. Paraquat induced motor deficits, oxidative imbalance, increased inflammatory cytokines, reduced dopamine and noradrenaline, and altered tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), and α-synuclein levels. AXTNE attenuated these alterations and reduced MDA levels measured by TBARS. AXTNE-levodopa combinations produced additional improvements across several endpoints.4. AXTNE attenuated multiple paraquat-associated Parkinsonian alterations, with generally greater numerical improvements than aqueous AXT. Combination with levodopa showed potential complementary effects. Further histopathological, pharmacokinetic, biodistribution, and mechanistic studies are warranted.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-17"},"PeriodicalIF":1.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115597","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

The influence of human plasma on drug-metabolizing enzymes: an exploratory study. 人血浆对药物代谢酶影响的探索性研究。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-27 DOI: 10.1080/00498254.2026.2734768

Qingchen Zhang, David J Greenblatt, John S Markowitz

{"title":"The influence of human plasma on drug-metabolizing enzymes: an exploratory study.","authors":"Qingchen Zhang, David J Greenblatt, John S Markowitz","doi":"10.1080/00498254.2026.2734768","DOIUrl":"10.1080/00498254.2026.2734768","url":null,"abstract":"1. Endogenous factors can introduce significant interindividual variability in in vitro assessments of drug metabolism and drug-drug interactions.2. The current study evaluated the effects of plasma samples from 12 healthy, non-medicated subjects on the activities of cytochrome P450 (CYP) enzymes.3. The inhibitory effects of pooled plasma across a broader concentration range (3-100%) were assessed on CYP3A activity.4. To further investigate kinetic differences, CYP3A-mediated reactions conducted in plasma were compared with those performed in human serum albumin (HSA) solution.5. Plasma increased the in vitro activities of CYP1A2, CYP2C8, and CYP2C19, while decreasing the activities of CYP3A, and CES1. Interindividual variability was observed for all tested drug metabolic enzymes (DMEs), except CYP3A.6. The inhibitory effect of plasma on CYP3A activity was concentration-dependent, with lower reaction activity observed at higher plasma concentrations.7. Notably, inhibition of CYP3A activity by undiluted plasma and 52 mg/mL HSA buffer was nearly complete. Although both HSA and pooled plasma inhibited in vitro CYP3A4 activity, their effects on kinetic parameters differed.8. These findings identify plasma as a potentially important endogenous modulator of apparent in vitro DME activities and underscore the need for further mechanistic investigation.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-9"},"PeriodicalIF":1.5,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148978147","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

Ergothioneine as a diet-derived xenobiotic: OCTN1-mediated disposition, mitochondrial redox regulation, and emerging implications for cardiovascular disease. 麦角硫因作为饮食来源的外源：octn1介导的处置、线粒体氧化还原调节和心血管疾病的新意义

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-27 DOI: 10.1080/00498254.2026.2732965

Yashvi Pethani, Neha Pethani, Dilip Pethani, Rima Shah, Darshil Shah, Jignesh Shah, Bhumi Shah

{"title":"Ergothioneine as a diet-derived xenobiotic: OCTN1-mediated disposition, mitochondrial redox regulation, and emerging implications for cardiovascular disease.","authors":"Yashvi Pethani, Neha Pethani, Dilip Pethani, Rima Shah, Darshil Shah, Jignesh Shah, Bhumi Shah","doi":"10.1080/00498254.2026.2732965","DOIUrl":"10.1080/00498254.2026.2732965","url":null,"abstract":"Mitochondrial dysfunction is a convergent upstream driver of cardiovascular disease, linking energetic failure, oxidative stress, inflammation, and maladaptive remodelling.The inconsistent results of conventional antioxidant trials are likely to be the result of multiple factors, including compound selection, dose and timing, bioavailability, tissue delivery, patient heterogeneity, endpoint selection, baseline redox status, and interference with physiological redox signalling.Ergothioneine (EGT) is a dietary thiol/thione amino acid transported by OCTN1 and distributed between circulating and intracellular compartments. EGT could potentially impact redox mechanisms in extracellular, cytosolic, and mitochondria-related contexts; however, the precise roles of these contributions are uncertain and direct proof in cardiac mitochondria is lacking.This review evaluates cardiovascular, mechanistic, and translational evidence for EGT, separating direct cardiovascular data from non-cardiac observations and suggested mechanisms that need validation.MPST has emerged as an EGT-responsive enzyme associated with skeletal-muscle bioenergetics, but its mitochondrial, cytosolic, and cardiovascular roles remain unresolved. We also propose a putative neuro-mitochondrial framework in which EGT-mediated redox buffering may provide an adjunct to vagal anti-inflammatory signalling. However, there is no direct evidence for EGT in relation to vagal activity, α7-nAChR signalling or the cholinergic anti-inflammatory response.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-17"},"PeriodicalIF":1.5,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012256","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

Evodiamine alleviates CUMS-induced depressive-like behaviours associated with modulation of uptake-2 transporters. evolodiamine缓解cms诱导的与摄取-2转运体调节相关的抑郁样行为。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-15 DOI: 10.1080/00498254.2026.2732971

Xianmei Song, Ruifeng Liang, Yanyan Zhang, Li Ma, Wenjing Ge, Xiaobo Kou, Mingli Zhang

{"title":"Evodiamine alleviates CUMS-induced depressive-like behaviours associated with modulation of uptake-2 transporters.","authors":"Xianmei Song, Ruifeng Liang, Yanyan Zhang, Li Ma, Wenjing Ge, Xiaobo Kou, Mingli Zhang","doi":"10.1080/00498254.2026.2732971","DOIUrl":"10.1080/00498254.2026.2732971","url":null,"abstract":"1. Evodiamine has been reported to exert antidepressant-like activity, but the underlying mechanisms remain incompletely understood. This study investigated the antidepressant-like effects of evodiamine and explored its regulation of monoamine neurotransmitter reuptake through modulation of uptake-2 transporters.2. A chronic unpredictable mild stress (CUMS) mouse model was used to evaluate depressive-like behaviours. Male C57BL/6J mice were subjected to CUMS and orally administered evodiamine, while tissue levels of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) in prefrontal cortex (PFC) were quantified. Monoamine uptake assays were performed in mouse brain synaptosomes and MDCK cells stably expressing human organic cation transporter 2 (hOCT2), hOCT3, or human plasma membrane monoamine transporter (hPMAT).3. Evodiamine significantly ameliorated CUMS-induced depressive-like behaviours and restored 5-HT, NE, and DA levels in the PFC. In synaptosomes, evodiamine concentration-dependently inhibited monoamine uptake. Additional studies using selective uptake-1 inhibitors indicated that uptake-2 transporters contributed substantially to these effects. Furthermore, evodiamine potently inhibited OCT2-, OCT3-, and PMAT-mediated uptake of monoamine neurotransmitters, with the strongest inhibitory activity observed towards hOCT3-mediated transport.4. These findings suggest that the antidepressant-like effects of evodiamine are associated with enhanced monoaminergic neurotransmission through inhibition of uptake-2 transporters, highlighting its potential as a novel therapeutic candidate for depression.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-12"},"PeriodicalIF":1.5,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956833","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

In vitro assessments for pharmacokinetic drug-drug interaction potential of vornorexant, a novel dual orexin 1/2 receptor antagonist. 新型双食欲素1/2受体拮抗剂vornorexant的体外药动学-药物相互作用潜力评估。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-14 DOI: 10.1080/00498254.2026.2720767

Shunsuke Kamigaso, Yoshihiro Konno, Daiji Kambe, Kenji Hachiuma, Akiko Mizuno-Yasuhira

{"title":"In vitro assessments for pharmacokinetic drug-drug interaction potential of vornorexant, a novel dual orexin 1/2 receptor antagonist.","authors":"Shunsuke Kamigaso, Yoshihiro Konno, Daiji Kambe, Kenji Hachiuma, Akiko Mizuno-Yasuhira","doi":"10.1080/00498254.2026.2720767","DOIUrl":"10.1080/00498254.2026.2720767","url":null,"abstract":"Vornorexant, a novel dual orexin 1/2 receptor antagonist with a short half-life, has been approved in Japan for the treatment of insomnia. We performed in vitro assessments to evaluate the drug-drug interaction (DDI) potential of vornorexant and its metabolite M3 mediated by CYP enzymes and transporters.Human CYP reaction phenotyping studies indicated that vornorexant and M3 are primarily metabolised by CYP3A4, and to a lesser extent by CYP3A5 and CYP2C8.Vornorexant exhibited weak reversible and time-dependent inhibition of CYP3A. Both vornorexant and M3 showed the potential to induce CYP2B6 and CYP3A4. However, these effects were not considered to have any impact on causing DDIs at these unbound systemic concentrations at the clinical doses of vornorexant.Vornorexant was a weak substrate for P-gp but not for BCRP, OATP1B1 or OATP1B3.Vornorexant and M3 exhibited weak or no inhibitory effects against P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1 and MATE2-K.These data suggest that while vornorexant might be an object drug of CYP3A precipitants, vornorexant is unlikely to cause clinically relevant DDIs mediated by either CYP enzymes or transporters involved in the metabolism and disposition of concomitantly administered drugs.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-10"},"PeriodicalIF":1.5,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888643","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

Preclinical pharmacokinetics and biodistribution of the dual adenosine A2A/A2B inhibitor muvadenant (M1069) in rats. 双腺苷A2A/A2B抑制剂muvadenant （M1069）在大鼠体内的临床前药代动力学和生物分布

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-06 DOI: 10.1080/00498254.2026.2720770

Jonny Nachtigall, Christine K Maurer, Marc Lecomte, Kai Schiemann, Rinat Zaynagetdinov, Tanja Reuter, Holger Scheible

{"title":"Preclinical pharmacokinetics and biodistribution of the dual adenosine A2A/A2B inhibitor muvadenant (M1069) in rats.","authors":"Jonny Nachtigall, Christine K Maurer, Marc Lecomte, Kai Schiemann, Rinat Zaynagetdinov, Tanja Reuter, Holger Scheible","doi":"10.1080/00498254.2026.2720770","DOIUrl":"10.1080/00498254.2026.2720770","url":null,"abstract":"Muvadenant is a selective, dual A2A/A2B adenosine receptor antagonist that demonstrated anti-tumour efficacy in preclinical in vitro and in vivo models.In rats,14C-muvadenant related radioactivity was quickly and widely distributed throughout the body with highest exposure observed in metabolic/excretory and melanin containing tissues and the gastrointestinal tract and lowest in the central nervous system.Following single oral administration, 6.27% of the radioactive dose was excreted via urine and 90.3% via faeces with a total recovery of 97.6%. After single intravenous dosing, the amounts of radioactivity excreted via urine and faeces were 13.7% and 80.2%, respectively, with a total recovery of 94.6% within 7 days.Whereas the parent compound accounted for the majority of the circulating radioactivity (>50%), metabolism plays the dominant role in the elimination of muvadenant.Metabolite structures derived from in vivo profiles in rats and in vitro incubations across species revealed extensive phase 1 metabolism of muvadenant with comparable metabolic pathways in human and preclinical species.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-10"},"PeriodicalIF":1.5,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881612","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

Comprehensive metabolic profiling and enzyme kinetics of cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside in normal and hyperlipidemic rats. 顺式-2,3,5,4′-四羟基二苯乙烯-2- o -β- d -葡萄糖苷在正常和高脂血症大鼠体内的综合代谢谱和酶动力学

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-01 Epub Date: 2026-07-23 DOI: 10.1080/00498254.2026.2704708

Jiexin Qiu, Beibei Yao, Qing Yu, Jiajie Wang, Lingling Huang, Jiale Chen, Yufeng Lu, Chunying Wang

{"title":"Comprehensive metabolic profiling and enzyme kinetics of cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside in normal and hyperlipidemic rats.","authors":"Jiexin Qiu, Beibei Yao, Qing Yu, Jiajie Wang, Lingling Huang, Jiale Chen, Yufeng Lu, Chunying Wang","doi":"10.1080/00498254.2026.2704708","DOIUrl":"10.1080/00498254.2026.2704708","url":null,"abstract":"Cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (cis-THSG), a photoisomer of the major bioactive component in Polygoni Multiflori Radix Praeparata (He-Shou-Wu), has enhanced hypolipidemic activity but is associated with idiosyncratic hepatotoxicity. Its metabolic fate under pathological conditions and key clearance enzymes remain unclear.This study aimed to compare metabolite profiles of cis-THSG in normal and hyperlipidemic rats in vivo and in vitro, identify metabolites, and characterise enzyme kinetics in rat liver microsomes (RLMs) and major CYP450 isoforms. Metabolites in plasma, urine, faeces, bile, and intestinal bacteria incubation fluids were analysed by UHPLC-Q-TOF-MS/MS. Enzymatic kinetics and CYP450 isoforms were investigated via chemical inhibition assays.A total of 27 metabolites were characterised; cis-THSG underwent rapid glucoside hydrolysis, and its aglycone underwent phase I and II reactions. Hyperlipidaemia reduced metabolites to 20 and markedly increased plasma cis-THSG and aglycone abundance. Kinetic parameters were Km 32.86 μmol/L, Vmax 0.7285 μmol/(min·mg protein), CLint 0.02217 L/(min·mg protein). Rat liver microsomal CYP isoforms analogous to human CYP3A4 and CYP2C9 mediated cis-THSG oxidative metabolism.This study provides the first comprehensive metabolite map of cis-THSG, identifies its aglycone as a potential bioactive form, and reveals a disease-related metabolic shift. CYP phenotyping offers a mechanistic basis for predicting clinical drug-drug interactions.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"709-721"},"PeriodicalIF":1.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473327","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

An LC-MS/MS method for simultaneous quantification of six components of Angelicae pubescentis radix and systematic evaluation of Angelicae pubescentis radix as a potential inhibitor of multiple cytochrome P450 enzymes. LC-MS/MS法同时定量测定短毛当归6种成分及系统评价短毛当归作为多种细胞色素P450酶抑制剂的作用。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-01 Epub Date: 2026-07-18 DOI: 10.1080/00498254.2026.2704711

Jia Yao, Shunjun Yang, Ying Liu, Rong Ye, Yufen Liao, Yong Guo, Rong Tan, Tiantai Wu, Yang Jin, Gangyan Yu, Chang Lin, Weiwei Li, Shiyu Zhang, Jia Yu

{"title":"An LC-MS/MS method for simultaneous quantification of six components of Angelicae pubescentis radix and systematic evaluation of Angelicae pubescentis radix as a potential inhibitor of multiple cytochrome P450 enzymes.","authors":"Jia Yao, Shunjun Yang, Ying Liu, Rong Ye, Yufen Liao, Yong Guo, Rong Tan, Tiantai Wu, Yang Jin, Gangyan Yu, Chang Lin, Weiwei Li, Shiyu Zhang, Jia Yu","doi":"10.1080/00498254.2026.2704711","DOIUrl":"10.1080/00498254.2026.2704711","url":null,"abstract":"Quantitative analytical method was developed for six coumarin constituents in Angelicae pubescentis radix (APR), and the inhibitory effect of the herb's extract on cytochrome P450 enzymes was investigated.A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of six coumarins (imperatorin, 8-methoxypsoralen, isopimpinellin, isoimperatorin, bergapten, and cnidilin) in APR. Concurrently, the inhibitory effects of its aqueous extract on multiple P450s were evaluated in rat liver microsomes using a 'Pittsburgh cocktail' approach.The method demonstrated excellent linearity (R2 > 0.999), precision, stability, repeatability (RSD < 3.0%), and recovery (95.15-102.36%). The extract exhibited significant time-dependent inhibition of CYP1A2 (residual activity 58.2%), with weaker effects on other P450s.A robust LC-MS/MS method was successfully established. The extract of APR was identified as a potent time-dependent inhibitor of CYP1A2 in rat liver microsomes (RLMs), suggesting a potential risk for metabolism-based drug interactions in rats that warrants further investigation in human systems.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"744-754"},"PeriodicalIF":1.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473268","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