Xenobiotica最新文献_第8页

Preclinical pharmacokinetic investigation of the bioavailability and skin distribution of HY-072808 ointment, a novel drug candidate for the treatment of atopic dermatitis, in minipigs by a newly LC-MS/MS method. 采用新的 LC-MS/MS 方法对治疗特应性皮炎的新型候选药物 HY-072808 软膏在小型猪体内的生物利用度和皮肤分布进行临床前药代动力学研究。

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-03-01 Epub Date: 2024-04-02 DOI: 10.1080/00498254.2024.2333007

Li Shao, Jiajia Mo, Qinlong Xu, Guangwei He, Chunyu Xing, Zhaoxing Chu

{"title":"Preclinical pharmacokinetic investigation of the bioavailability and skin distribution of HY-072808 ointment, a novel drug candidate for the treatment of atopic dermatitis, in minipigs by a newly LC-MS/MS method.","authors":"Li Shao, Jiajia Mo, Qinlong Xu, Guangwei He, Chunyu Xing, Zhaoxing Chu","doi":"10.1080/00498254.2024.2333007","DOIUrl":"10.1080/00498254.2024.2333007","url":null,"abstract":"HY-072808 is a novel phosphodiesterase 4 inhibitor clinically used for topical atopic dermatitis treatment. Cytochrome P450 enzymes are involved in transforming it into major metabolite ZZ-24. An efficient UPLC-MS/MS method was established to detect HY-072808 and ZZ-24 in plasma and skin tissues of minipigs.One-step protein precipitation was performed with acetonitrile. Subsequently, elution was served with a methanol and water gradient containing 0.1% formic acid for 3.5 min. The plasma and skin tissue concentrations of HY-072808 and ZZ-24 showed good linearity from 0.200 to 200 ng/mL.The experimental minipigs exhibited low systemic exposure and bioavailability of 3.1-7.6% after transdermal application of 1-4% HY-072808 ointment. Multiple topical administrations over seven consecutive days showed a minor accumulation in systemic exposure, with accumulation factors of 2.3 and 4.0 for HY-072808 and ZZ-24, respectively.The distribution of HY-072808 ointment among different cortical layers in minipigs was studied for the first time. Following transdermal application of 2% HY-072808 ointment, the concentration in plasma and skin tissues in the order of epidermis > dermis > subcutaneous tissue ≈ subcutaneous muscle ≈ plasma; at 48 h after the administration, the epidermis and dermis still had a high concentration of the drug.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"138-149"},"PeriodicalIF":1.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159142","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

Effects of pharmacogenetics on pharmacokinetics and toxicity of doxorubicin in Egyptian breast cancer patients. 药物遗传学对埃及乳腺癌患者多柔比星药代动力学和毒性的影响

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-03-01 Epub Date: 2024-04-02 DOI: 10.1080/00498254.2024.2330493

N F Ebaid, K S Abdelkawy, M A Shehata, H F Salem, G Magdy, R R S Hussein, F Elbarbry

{"title":"Effects of pharmacogenetics on pharmacokinetics and toxicity of doxorubicin in Egyptian breast cancer patients.","authors":"N F Ebaid, K S Abdelkawy, M A Shehata, H F Salem, G Magdy, R R S Hussein, F Elbarbry","doi":"10.1080/00498254.2024.2330493","DOIUrl":"10.1080/00498254.2024.2330493","url":null,"abstract":"This study investigates the impact of single nucleotide polymorphisms in genes (SLC22A16 and CBR1) involved in the pharmacokinetics and toxicity of doxorubicin (DOX) in Egyptian female patients with breast cancer.Patients administered DOX (60 mg/m2) for 4 cycles every 3 weeks. The peak DOX plasma concentration was measured using a validated chromatographic method. The genotyping for the selected SNPs, SLC22A16 T > C (rs714368), and CBR1 C > T (rs20572), was performed by RT-PCR. Patients were monitored for hematological and cardiac toxicities.The variant carriers of CBR1 C > T (rs20572) exhibited significantly higher DOX concentration, but no significant association to DOX-induced hematological toxicity. On the other hand, SLC22A16 T > C (rs714368) had no significant influence on DOX plasma concentration, but was significantly correlated with lower risk of neutropenia (OR 0.31, 95% CI 0.12-0.75, p = 0.01) and leukopoenia (OR 0.18, 95% CI 0.07-0.5, p = 0.001). DOX-related cardiotoxicity was correlated with the cumulative dose of DOX (R = 0.238, p = 0.017), but not with any of the two examined SNPs.Genetic polymorphisms in SLC22A16 and CBR1 may explain the inter-individual variations in DOX pharmacokinetics and toxicity. Using pharmacogenetic testing is important to customise drug therapy for cancer patients treated with anthracyclines.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"160-170"},"PeriodicalIF":1.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140140835","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

Development of a physiologically based pharmacokinetic model for levetiracetam in patients with renal impairment to guide dose adjustment based on steady-state peak/trough concentrations. 针对肾功能受损患者开发基于生理的左乙拉西坦药代动力学模型，以便根据稳态峰/槽浓度指导剂量调整。

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-03-01 Epub Date: 2024-02-21 DOI: 10.1080/00498254.2024.2317888

Rongrong Wang, Tianlin Wang, Xueliang Han, Mengli Chen, Shu Li

{"title":"Development of a physiologically based pharmacokinetic model for levetiracetam in patients with renal impairment to guide dose adjustment based on steady-state peak/trough concentrations.","authors":"Rongrong Wang, Tianlin Wang, Xueliang Han, Mengli Chen, Shu Li","doi":"10.1080/00498254.2024.2317888","DOIUrl":"10.1080/00498254.2024.2317888","url":null,"abstract":"Levetiracetam may cause acute renal failure and myoclonic encephalopathy at high plasma levels, particularly in patients with renal impairment. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict levetiracetam pharmacokinetics in Chinese adults with epilepsy and renal impairment and define appropriate levetiracetam dosing regimen.PBPK models for healthy subjects and epilepsy patients with renal impairment were developed, validated, and adapted. Furthermore, we predicted the steady-state trough and peak concentrations of levetiracetam in patients with renal impairment using the final PBPK model, thereby recommending appropriate levetiracetam dosing regimens for different renal function stages. The predicted maximum plasma concentration (Cmax), time to maximum concentration (Tmax), area under the plasma concentration-time curve (AUC) were in agreement (0.8 ≤ fold error ≤ 1.2) with the observed, and the fold error of the trough concentrations in end-stage renal disease (ESRD) was 0.77 - 1.22. The prediction simulations indicated that the recommended doses of 1000, 750, 500, and 500 mg twice daily for epilepsy patients with mild, moderate, severe renal impairment, and ESRD, respectively, were sufficient to achieve the target plasma concentration of levetiracetam.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"116-123"},"PeriodicalIF":1.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139724209","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 combination effect of quinidine on the pharmacokinetics of tipepidine using a physiologically based pharmacokinetic model. 利用基于生理学的药代动力学模型预测奎尼丁对替普匹定药代动力学的联合影响。

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-03-01 Epub Date: 2024-01-17 DOI: 10.1080/00498254.2024.2304129

Shun Hayashi, Hiroko Kawaguchi, Takao Watanabe, Izuru Miyawaki, Tatsuki Fukami, Miki Nakajima

{"title":"Prediction of combination effect of quinidine on the pharmacokinetics of tipepidine using a physiologically based pharmacokinetic model.","authors":"Shun Hayashi, Hiroko Kawaguchi, Takao Watanabe, Izuru Miyawaki, Tatsuki Fukami, Miki Nakajima","doi":"10.1080/00498254.2024.2304129","DOIUrl":"10.1080/00498254.2024.2304129","url":null,"abstract":"Tipepidine, an antitussive drug, has been reported to have central pharmacological effects and can be expected to be safely repositioned as treatment for psychiatric disorders. Since tipepidine requires three doses per day, development of a once-daily medication would be highly beneficial. Previously, we reported that combination use with quinidine, a CYP2D6 inhibitor, prolongs the half-life of tipepidine in chimeric mice with humanised liver.In this study, to predict this combination effect in humans, a physiologically based pharmacokinetic (PBPK) model was developed, and quantitative simulation was conducted. The simulation results indicated that concomitant administration of tipepidine with quinidine increased the predicted Cmax, AUC, and t1/2 of tipepidine in the Japanese population by 3.4-, 6.6-, and 2.4-fold, respectively.Furthermore, to compare with another approach that aims to prolong the half-life, the PK profile of tipepidine administered in hypothetical extended-release form was simulated. Extended-release form was predicted to be more influenced by CYP2D6 genotype than combination with quinidine, and the predicted plasma exposure was markedly increased in poor metabolizers, potentially leading to adverse effects.In conclusion, quantitative simulation using the PBPK model suggests the feasibility of the safe repositioning of tipepidine as a once-daily medication in combination with quinidine.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"107-115"},"PeriodicalIF":1.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404603","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

Sodium dodecylbenzene sulphonate (SDBS) present in detergents: action on the gills, skin, and blood of D. rerio fish. 洗涤剂中的十二烷基苯磺酸钠（SDBS）：对 D. rerio 鱼鳃、皮肤和血液的作用。

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-03-01 Epub Date: 2024-02-16 DOI: 10.1080/00498254.2024.2316646

Eduardo Libanio Reis Santos, Odaiza Silva, Jeffesson de Oliveira-Lima, Maria Izabel Camargo-Mathias

{"title":"Sodium dodecylbenzene sulphonate (SDBS) present in detergents: action on the gills, skin, and blood of D. rerio fish.","authors":"Eduardo Libanio Reis Santos, Odaiza Silva, Jeffesson de Oliveira-Lima, Maria Izabel Camargo-Mathias","doi":"10.1080/00498254.2024.2316646","DOIUrl":"10.1080/00498254.2024.2316646","url":null,"abstract":"1. Sodium dodecylbenzene sulphonate (SDBS) is one of the surfactants used worldwide in detergents which, due to high residual discharges, has great potential to cause ecotoxicological impacts. Therefore, the sublethal effects of SDBS on the gills and skin of male Danio rerio fish were investigated.2. The fish were distributed into three groups: GC (control), GT1 (0.25 mg/L of SDBS), and GT2 (0.5 mg/L of SDBS) and exposed for 21 days. After the experiment, histopathological analyses of the gills, histochemical analyses (counting of mucous cells), and biochemical analyses (antioxidant defense enzyme analysis, SOD, and CAT) were conducted.3. A significant increase (p < 0.05) in the incidence of circulatory disorders, progressive, and regressive alterations occurred in the GT1 and GT2 groups. Due to these changes, the total histopathological index of the gills was higher in these groups. Mucous cells in the gills and skin increased. There was an increase in SOD activity and a reduction in CAT activity in these groups. Haematology revealed neutrophilia and lymphocytosis in the blood of GT1 and GT2.4. The results clearly demonstrate that a 21-day exposure to SDBS causes severe morphophysiological damage to the gills, skin, and blood of D. rerio fish.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"150-159"},"PeriodicalIF":1.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139708014","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 metabolism of the orexin-1 selective receptor antagonist nivasorexant. 俄勒欣-1 选择性受体拮抗剂 Nivasorexant 的新陈代谢

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-03-01 DOI: 10.1080/00498254.2024.2319811

Alexander Treiber, Swen Seeland, Belal Haschimi, Aude Weigel, Jodi T Williams, Jerome Gabillet

引用次数: 0

Rehmannioside A inhibits the activity of CYP3A4, 2C9 and 2D6 in vitro 地黄甙 A 在体外可抑制 CYP3A4、2C9 和 2D6 的活性

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-02-22 DOI: 10.1080/00498254.2024.2321969

Congrong Wang, Naixiang Zhou, Mingcui Li, Haixia Chen

引用次数: 0

Indirubin mediates adverse intestinal reactions in guinea pigs by downregulating the expression of AchE through AhR. 靛蓝通过 AhR 下调 AchE 的表达，从而介导豚鼠肠道不良反应。

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-02-01 Epub Date: 2024-01-08 DOI: 10.1080/00498254.2023.2297745

Xiaoting Xu, Reham Taha, Chenghan Chu, Li Xiao, Tao Wang, Xinzhi Wang, Xin Huang, Zhenzhou Jiang, Lixin Sun

{"title":"Indirubin mediates adverse intestinal reactions in guinea pigs by downregulating the expression of AchE through AhR.","authors":"Xiaoting Xu, Reham Taha, Chenghan Chu, Li Xiao, Tao Wang, Xinzhi Wang, Xin Huang, Zhenzhou Jiang, Lixin Sun","doi":"10.1080/00498254.2023.2297745","DOIUrl":"10.1080/00498254.2023.2297745","url":null,"abstract":"Indirubin is the main component of the traditional Chinese medicine Indigo naturalis (IN), a potent agonist of aryl hydrocarbon receptors (AhRs). In China, IN is used to treat psoriasis and ulcerative colitis, and indirubin is used for the treatment of chronic myelogenous leukaemia. However, IN and indirubin have adverse reactions, such as abdominal pain, diarrhoea, and intussusception, and their specific mechanism is unclear.The purpose of our research was to determine the specific mechanism underlying the adverse effects of IN and indirubin. By tracking the modifications in guinea pigs after the intragastric administration of indirubin for 28 days.The results demonstrate that indirubin could accelerate bowel movements and decrease intestinal acetylcholinesterase (AchE) expression. Experiments with NCM460 cells revealed that indirubin significantly reduced the expression of AchE, and the AchE levels were increased after the silencing of AhR and re-exposure to indirubin.This study showed that the inhibition of AchE expression by indirubin plays a key role in the occurrence of adverse reactions to indirubin and that the underlying mechanism is related to AhR-mediated AchE downregulation.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"83-94"},"PeriodicalIF":1.8,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139075209","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 effects of genetic polymorphism on toxicity and pharmacokinetics of methotrexate in Egyptian adult patients with leukaemia or lymphoma. 埃及成人白血病或淋巴瘤患者基因多态性对甲氨蝶呤毒性和药代动力学的影响

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-02-01 Epub Date: 2024-03-05 DOI: 10.1080/00498254.2024.2320778

Khloud Shendy, Khaled Abdelkawy, Ahmed Amin Ali, Fathalla Belal, Mostafa Abdelhakiem, Galal Magdy, Nahla Anber, Fawzy Elbarbry

{"title":"The effects of genetic polymorphism on toxicity and pharmacokinetics of methotrexate in Egyptian adult patients with leukaemia or lymphoma.","authors":"Khloud Shendy, Khaled Abdelkawy, Ahmed Amin Ali, Fathalla Belal, Mostafa Abdelhakiem, Galal Magdy, Nahla Anber, Fawzy Elbarbry","doi":"10.1080/00498254.2024.2320778","DOIUrl":"10.1080/00498254.2024.2320778","url":null,"abstract":"Polymorphisms in genes coding folate-metabolising enzymes might alter the pharmacokinetics and sensitivity for methotrexate \"MTX\".The aim of the study aimed to investigate the influence of MTHFR C677T, DHFR19 Ins/del, GGH -401 C > T, and MTR A2756G polymorphisms on MTX toxicity and pharmacokinetics in Egyptian patients with Acute lymphoblastic leukaemia (ALL) or Non-Hodgkin lymphoma (NHL).Fifty adult Egyptian patients with ALL and NHL, treated with high dose MTX, were prospectively enrolled in the study. Clinical and biochemical data was collected objectively from medical records after each cycle of MTX. Plasma concentrations of MTX were measured after 72 h of initiation of infusion. Genotyping was done with a PCR-ARMS and PCR-RFLP assays.The MTHFR C677T T variants significantly increased the risk of leukopoenia, whereas the genotype MTHFR 677 C > T TT significantly associated with lymphocytopenia, thrombocytopenia, and anaemia. The genotype GGH-401 TT was significantly correlated with anaemia. Plasma MTX level was significantly higher in patients with MTR A2756G G variants.MTHFR polymorphism played the main role in MTX toxicities. The pharmacokinetics of MTX was affected by MTR polymorphism. GGH mutation was mainly concerned with anaemia. Pharmacogenetic testing are recommended to optimise MTX therapy.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"95-105"},"PeriodicalIF":1.8,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913589","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

High-throughput assay to simultaneously evaluate activation of CYP3A and the direct and time-dependent inhibition of CYP3A, CYP2C9, and CYP2D6 using liquid chromatography-tandem mass spectrometry. 利用液相色谱-串联质谱法进行高通量测定，同时评估 CYP3A 的活化以及对 CYP3A、CYP2C9 和 CYP2D6 的直接和时间依赖性抑制。

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-02-01 DOI: 10.1080/00498254.2024.2308818

Yu Yumoto, Takuro Endo, Hiroshi Harada, Kaoru Kobayashi, Takeshi Nakabayashi, Yoshikazu Abe

{"title":"High-throughput assay to simultaneously evaluate activation of CYP3A and the direct and time-dependent inhibition of CYP3A, CYP2C9, and CYP2D6 using liquid chromatography-tandem mass spectrometry.","authors":"Yu Yumoto, Takuro Endo, Hiroshi Harada, Kaoru Kobayashi, Takeshi Nakabayashi, Yoshikazu Abe","doi":"10.1080/00498254.2024.2308818","DOIUrl":"10.1080/00498254.2024.2308818","url":null,"abstract":"In the early stages of drug discovery, adequate evaluation of the potential drug-drug interactions (DDIs) of drug candidates is important. Several CYP3A activators are known to lead to underestimation of DDIs. These compounds affect midazolam 1'-hydroxylation but not midazolam 4-hydroxylation.We used both metabolic reactions of midazolam to evaluate the activation and inhibition of CYP3A activators simultaneously. For our CYP inhibition assay using cocktail probe substrates, simultaneous liquid chromatography-tandem mass spectrometry monitoring of 1'-hydroxymidazolam and 4-hydroxymidazolam for CYP3A was established in addition to monitoring of 4-hydroxydiclofenac and 1'-hydroxybufuralol for CYP2C9 and CYP2D6.The results of our cocktail inhibition assay were well correlated with those of a single inhibition assay, as were the estimated inhibition parameters for typical CYP3A inhibitors. In our assay, a proprietary compound that activated midazolam 1'-hydroxylation and tended to inhibit 4-hydroxylation was evaluated along with known CYP3A activators. All compounds were well characterised by comparison of the results of midazolam 1'- and 4-hydroxylation.In conclusion, our CYP cocktail inhibition assay can detect CYP3A activation and assess the direct and time-dependent inhibition potentials for CYP3A, CYP2C9, and CYP2D6. This method is expected to be very efficient in the early stages of drug discovery.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"45-56"},"PeriodicalIF":1.8,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139543142","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