Current drug metabolism最新文献

{"title":"A Cross-sectional Comparative Analysis of Eleven Population Pharmacokinetic Models for Docetaxel in Chinese Breast Cancer Patients.","authors":"Genzhu Wang, Qiang Sun, Xiaojing Li, Shenghui Mei, Shihui Li, Zhongdong Li","doi":"10.2174/0113892002322494240816032948","DOIUrl":"10.2174/0113892002322494240816032948","url":null,"abstract":"<p><strong>Objective: </strong>Various population pharmacokinetic (PPK) models have been established to help determine the appropriate dosage of docetaxel, however, no clear consensus on optimal dosing has been achieved. The purpose of this study is to perform an external evaluation of published models in order to test their predictive performance, and to find an appropriate PPK model for Chinese breast cancer patients.</p><p><strong>Methods: </strong>A systematic literature search of docetaxel PPK models was performed using PubMed, Web of Science, China National Knowledge Infrastructure, and WanFang databases. The predictive performance of eleven identified models was evaluated using prediction-based and simulation-based diagnostics on an independent dataset (112 docetaxel concentrations from 56 breast cancer patients). The -2×log (likelihood) and Akaike information criterion were also calculated to evaluate model fit.</p><p><strong>Results: </strong>The median prediction error of eight of the eleven models was less than 10%. The model fitting results showed that the three-compartment model of Bruno et al. had the best prediction performance and that the three compartment model of Wang et al. had the best simulation effect. Furthermore, although the covariates that significantly affect PK parameters were different between them, seven models demonstrated that docetaxel PK parameters were influenced by liver function.</p><p><strong>Conclusions: </strong>Three compartment PPK models may be predictive of optimal docetaxel dosage for Chinese breast cancer patients. However, for patients with impaired liver function, the choice of which model to use to predict the blood concentration of docetaxel still requires great care.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"479-488"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11826906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of High Altitude Environment on Pharmacokinetic and Pharmacodynamic of Warfarin in Rats.","authors":"Xiaojing Zhang, Hongfang Mu, Yan Zhong, Rong Wang, Wenbin Li","doi":"10.2174/0113892002277930240201101256","DOIUrl":"10.2174/0113892002277930240201101256","url":null,"abstract":"<p><strong>Background: </strong>High altitude environment affects the pharmacokinetic (PK) parameters of drugs and the PK parameters are an important theoretical basis for guiding the rational clinical use of drugs. Warfarin is an oral anticoagulant of the coumarin class commonly used in clinical practice, but it has a narrow therapeutic window and wide individual variation. However, the effect of high altitude environment on PK and pharmacodynamic (PD) of warfarin is unclear.</p><p><strong>Objective: </strong>The objective of this study is to investigate the effect of a high altitude environment on PK and PD of warfarin in rats.</p><p><strong>Method: </strong>Rats were randomly divided into plain group and high altitude group and blood samples were collected through the orbital venous plexus after administration of 2 mg/kg warfarin. Warfarin concentrations in plasma samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and PK parameters were calculated by the non-compartment model using WinNonlin 8.1 software. Meanwhile, the expression of PXR, P-gp and CYP2C9 in liver tissues was also determined by western blotting. The effect of high altitude environment on PD of warfarin was explored by measuring activated partial thromboplastin time (APTT) and prothrombin time (PT) values and then calculated international normalized ratio (INR) values based on PT.</p><p><strong>Results: </strong>Significant changes in PK behaviors and PD of warfarin in high altitude-rats were observed. Compared with the plain-rats, the peak concentration (C_max) and the area under the plasma concentration-time curve (AUC) increased significantly by 50.9% and 107.46%, respectively. At the same time, high altitude environment significantly inhibited the expression of PXR, P-gp and CYP2C9 in liver tissues. The results of the PD study showed that high altitude environments significantly prolonged PT, APTT and INR values.</p><p><strong>Conclusion: </strong>High altitude environment inhibited the metabolism and increased the absorption of warfarin in rats and increased the effect of anticoagulant effect, suggesting that the optimal dose of warfarin for patients at high altitude should be reassessed.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"54-62"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971186","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}

{"title":"A Combination of Magnoflorine and Spinosin Improves the Antidepressant effects on CUMS Mouse Model.","authors":"Fenghe Bi, Zhihui Wang, Yijing Guo, Menglin Xia, Xuehui Zhu, Wei Qiao","doi":"10.2174/0113892002284230240213064248","DOIUrl":"10.2174/0113892002284230240213064248","url":null,"abstract":"<p><strong>Background: </strong>Depression is a common neuropsychiatric disease. As a famous traditional Chinese medicine with significant anti-depressive and sleep-promoting effects, <i>Ziziphi Spinosae</i> Semen (ZSS) has attracted the attention of many researchers. Although it is well known that Magnoflorine (MAG) and Spinosin (SPI) were the main active components isolated from ZSS, there is a lack of research on the combined treatment of depression with these two ingredients.</p><p><strong>Methods: </strong>The shaking bottle method was used to simulate the human environment for detecting the changes in oil-water partition coefficient before and after the drug combination. Cell viability was evaluated by the MTT assay. To establish a mouse model of depression and insomnia by CUMS method, and then to explore the effect of combined administration of MAG and SPI on depression in CUMS model by observing behavior and analyzing pharmacokinetics.</p><p><strong>Results: </strong>The change in LogP values affected the lipid solubility of MAG and increased the water solubility of SPI, allowing them to penetrate more easily through the blood-brain barrier into the brain. Compared with the model group, MAG-SPI with a concentration of 60 μM significantly increased cell survival rate. In both the TST and FST experiments, the mice showed a decrease in immobilization time. Pharmacokinetic results showed that the pharmacokinetic parameters, C_max and AUC of MAG and SPI, were increased in the case of combination, which resulted in enhancement of their relative bioavailability and improvement of <i>in vivo</i> effects.</p><p><strong>Conclusions: </strong>The present study demonstrated that a combination of MAG and SPI had a synergistic antidepressant effect in CUMS mouse model.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"71-80"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982538","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}

{"title":"Safety Issues of Herb-Warfarin Interactions.","authors":"Subhajit Hazra, Preet Amol Singh, Neha Bajwa","doi":"10.2174/0113892002290846240228061506","DOIUrl":"10.2174/0113892002290846240228061506","url":null,"abstract":"<p><p>Warfarin is a popular anticoagulant with high global demand. However, studies have underlined serious safety issues when warfarin is consumed concomitantly with herbs or its formulations. This review aimed to highlight the mechanisms behind herb-warfarin interactions while laying special emphasis on its PKPD interactions and evidence on Herb-Warfarin Interaction (HWI) with regards to three different scenarios, such as when warfarin is consumed with herbs, taken as foods or prescribed as medicine, or when used in special situations. A targeted literature methodology involving different scientific databases was adopted for acquiring information on the subject of HWIs. Results of the present study revealed some of the fatal consequences of HWI, including post-operative bleeding, thrombosis, subarachnoid hemorrhage, and subdural hematomas occurring as a result of interactions between warfarin and herbs or commonly associated food products from <i>Hypericum perforatum, Zingiber officinale, Vaccinium oxycoccos, Citrus paradisi</i>, and <i>Punica granatum</i>. In terms of PK-PD parameters, herbs, such as <i>Coptis chinensis</i> Franch. and <i>Phellodendron amurense</i> Rupr., were found to compete with warfarin for binding with plasma proteins, leading to an increase in free warfarin levels in the bloodstream, resulting in its augmented antithrombic effect. Besides, HWIs were also found to decrease International Normalised Ratio (INR) levels following the consumption of Persea americana or avocado. Therefore, there is an urgent need for an up-to-date interaction database to educate patients and healthcare providers on these interactions, besides promoting the adoption of novel technologies, such as natural language processing, by healthcare professionals to guide them in making informed decisions to avoid HWIs.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"13-27"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140093542","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}

{"title":"Role of P-glycoprotein in Regulating the Efficacy, Toxicity and Pharmacokinetics of Yunaconitine.","authors":"Xiaocui Li, Qi Liang, Caiyan Wang, Huawei Qiu, Tingting Lin, Wentao Li, Rong Zhang, Zhongqiu Liu, Lijun Zhu","doi":"10.2174/0113892002302427240801072910","DOIUrl":"10.2174/0113892002302427240801072910","url":null,"abstract":"<p><strong>Background: </strong>Yunaconitine (YAC) is a hidden toxin that greatly threatens the life safety of patients who are prescribed herbal medicines containing <i>Aconitum</i> species; however, its underlying mechanism remains unclear.</p><p><strong>Objective: </strong>The objective of this study is to elucidate the functions of P-glycoprotein (P-gp) in regulating the efficacy, toxicity, and pharmacokinetics of YAC.</p><p><strong>Methods: </strong>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 <i>via</i> male Mdr1a gene knocked-out mice and wild-type FVB mice.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"317-329"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897017","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}

{"title":"Effect of Salbutamol on the Disposition Kinetics of Levofloxacin in the Plasma and Lung of Rats.","authors":"Murat Ali Cicekler, Halis Oguz, Orhan Corum","doi":"10.2174/0113892002314136240816094609","DOIUrl":"10.2174/0113892002314136240816094609","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>The purpose of this study was to investigate the influence of SLB on the plasma and lung pharmacokinetics of LVX in rats.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>The area under the curve from 0 to 16 h (AUC_0-16), 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 AUC_0-16 lung/AUC_{0-16 plasma} ratios of LVX were 1.60 and 1.39 after administration alone and co-administration with SLB, respectively.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"425-430"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016605","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}

{"title":"Fluoropyrimidine Toxicity: the Hidden Secrets of DPYD.","authors":"Vangelis G Manolopoulos, Georgia Ragia","doi":"10.2174/0113892002296707240311105527","DOIUrl":"10.2174/0113892002296707240311105527","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Results: </strong>While seminal <i>in vitro</i> 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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"91-95"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174063","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}

{"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}

{"title":"Metabolic Pathway of Osilodrostat in Equine Urine Established through High-resolution Mass Spectrometric Characterization for Doping Control.","authors":"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","doi":"10.2174/0113892002325954240903062440","DOIUrl":"10.2174/0113892002325954240903062440","url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"489-504"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139559","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}

{"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}