Current drug metabolism最新文献

{"title":"New Psychoactive Substances, New Behaviours, New Drug-drug Interactions: Pharmacology of a Slam Session.","authors":"Benoit Schreck,&nbsp;Marion Istvan,&nbsp;Marylène Guerlais,&nbsp;Edouard-Jules Laforgue,&nbsp;Marie Gérardin,&nbsp;Marie Grall-Bronnec,&nbsp;Aurélie Aquizerate,&nbsp;Caroline Victorri-Vigneau","doi":"10.2174/1389200224666230228103922","DOIUrl":"https://doi.org/10.2174/1389200224666230228103922","url":null,"abstract":"<p><strong>Background: </strong>Slamming has been increasing internationally for ten years, mostly among men who have sex with men. Slamming consists of injecting psychostimulants (including new psychoactive substances-NPS) intravenously to increase sexual performance.</p><p><strong>Objective: </strong>The objective of our work was to analyse drug-drug interactions related to slamming.</p><p><strong>Methods: </strong>Drawing upon a reported case of a slam session describing hour by hour the intake of substances, we performed a drug-interaction analysis using international references and a comprehensive literature review. High doses of sildenafil, GBL and 3-MMC were reported during the 40-hour session described. The specific drug-interaction research was performed using 9 references and 65 of the 209 records identified in the literature review.</p><p><strong>Results: </strong>Pharmacological data regarding nonmedicated substances were scarce. Regarding pharmacodynamics, the risk was high at the cardiovascular level and was related to the vasodilatation effect of sildenafil and the adrenergic and serotoninergic properties of stimulants; this risk may increase with usual treatment (involving other vasodilators or central depressants). Regarding pharmacokinetics, the major interactions concerned metabolism by CYP3A4 and CYP2C9, leading to interactions, particularly with HIV medication.</p><p><strong>Conclusion: </strong>This innovative work provides pharmacological information on drugs that are commonly used in slamming, allowing the development of effective medical-management protocols and the provision of risk-reduction counselling.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"24 2","pages":"80-91"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9921258","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":"Folate Targeting Peptide Conjugates for Inflammatory Response Suppression.","authors":"Elizabeth Ruff,&nbsp;Scott Poh","doi":"10.2174/1389200224666230419090052","DOIUrl":"https://doi.org/10.2174/1389200224666230419090052","url":null,"abstract":"<p><strong>Background and objective: </strong>Protein kinases known as mitogen-activated protein kinases (MAPKs) are responsible for regulating a wide variety of physiological cell responses by generating and release of inflammatory mediators. Suppressing these inflammatory mediators can be utilized to control the propagation of inflammation. During the course of this research, we created folate-targeted MK2 inhibitor conjugates and analyzed the antiinflammatory effects of these compounds.</p><p><strong>Methods: </strong>Using RAW264.7 cells, which are generated from murine macrophages, as an in vitro model. We synthesize and evaluated a folate linked peptide MK2 inhibitor. The cytotoxicity was assessed using the ELISA kits, CCK- 8 test kit, NO concentration and inflammatory factors TNF-, IL-1, and IL-6.</p><p><strong>Results: </strong>The cytotoxicity assay results suggested that the concentration for MK2 inhibitors less than 50.0 μM be non-toxic. The ELISA Kits also demonstrated that MK2 peptide inhibitor treatment significantly decreased the content of NO, TNF-, IL-1, and IL-6 in LPS-stimulated RAW264.7 cells. It was also demonstrated that a folate-targeted MK2 inhibitor was more effective than a non-targeted inhibitor.</p><p><strong>Conclusion: </strong>This experiment demonstrates that LPS-induced macrophages can produce oxidative stress and inflammatory mediators. According to our research, pro-inflammatory mediators can be reduced by targeting folate receptor- positive (FR+) macrophages with an FR-linked anti-inflammatory MK2 peptide inhibitor in vitro, and the uptake was FR-specific.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"24 4","pages":"283-289"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10472891","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":"The Influences and Mechanisms of High-altitude Hypoxia Exposure on Drug Metabolism.","authors":"Anpeng Zhao,&nbsp;Wenbin Li,&nbsp;Rong Wang","doi":"10.2174/1389200224666221228115526","DOIUrl":"https://doi.org/10.2174/1389200224666221228115526","url":null,"abstract":"<p><strong>Background: </strong>The special environment of high-altitude hypoxia not only changes the physiological state of the body but also affects the metabolic process of many drugs, which may affect the safety and efficacy of these drugs. The number of drugs is huge, so it is not wise to blindly repeat the pharmacokinetic studies of all of them on the plateau. Mastering the law of drug metabolism on the plateau is conducive to the comprehensive development of rational drug use on the plateau. Therefore, it is very important to determine the impacts and elucidate the mechanism of drug metabolism in hypobaric hypoxia conditions.</p><p><strong>Methods: </strong>In this review, we searched published studies on changes in drug metabolism in hypoxia conditions to summarize and analyze the mechanisms by which hypoxia alters drug metabolism.</p><p><strong>Results: </strong>Although the reported effects of high-altitude hypoxia on drug metabolism are sometimes controversial, metabolism kinetics for most of the tested drugs are found to be affected. Mechanism studies showed that the major reasons causing metabolism changes are: regulated drug-metabolizing enzymes expression and activity mediated by HIF-1, nuclear receptors and inflammatory cytokines, and change in direct or indirect effects of intestinal microflora on drug metabolism by itself or the host mediated by microflora-derived drug-metabolizing enzymes, metabolites, and immunoregulation.</p><p><strong>Conclusion: </strong>Altered enzyme expression and activity in the liver and altered intestinal microflora are the two major reasons to cause altered drug metabolism in hypoxia conditions.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"24 3","pages":"152-161"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10095164","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":"Application of Nucleic Acid Nanomaterials in the Treatment of Endocrine and Metabolic Diseases.","authors":"Qiang Zhu,&nbsp;Yuping Xie,&nbsp;Ting Fu,&nbsp;Chengji Shi,&nbsp;Long Bai,&nbsp;Lin Liu,&nbsp;Jingang Xiao","doi":"10.2174/1389200224666230410111015","DOIUrl":"10.2174/1389200224666230410111015","url":null,"abstract":"<p><p>Endocrine and metabolic diseases are the most prevalent chronic diseases globally, posing the greatest hazard to human health. Although various medications are applied in treating endocrine and metabolic illnesses, numerous obstacles exist to overcome. Nucleic acid nanomaterials are novel materials synthesized and engineered in the laboratory. In this case, Nucleic acids are employed as non-biological nanomaterials instead of serving as carriers of genetic information in live cells. Because of their high biocompatibility and editability, nucleic acid nanomaterials were frequently employed in disease diagnosis and therapy. In this review, recent developments and new viewpoints on nucleic acid nanomaterials are highlighted in the fields of diabetes mellitus and other endocrine and metabolic diseases.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"385-392"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9273336","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":"Comprehensive Study of <i>In vivo</i> and <i>In vitro</i> Metabolites of Cycloastragenol Based on UHPLC-Q-Exactive Orbitrap Mass Spectrometer.","authors":"Huajian Li,&nbsp;Shaoping Wang,&nbsp;Hong Wang,&nbsp;Haoran Li,&nbsp;Yanan Li,&nbsp;Pingping Dong,&nbsp;Xianming Lan,&nbsp;Jiayu Zhang,&nbsp;Long Dai","doi":"10.2174/1389200224666230202150436","DOIUrl":"https://doi.org/10.2174/1389200224666230202150436","url":null,"abstract":"<p><strong>Background: </strong>Cycloastragenol (CAG) is a sapogenin derived from the main bioactive constituents of Astragali Radix (AR). However, the current research on CAG metabolism in vivo and in vitro is still inadequate, and the metabolite cluster is incomplete due to incomplete analysis strategy.</p><p><strong>Objective: </strong>The objective of this study was to screen and identify the metabolic behavior of CAG in vivo and in vitro.</p><p><strong>Methods: </strong>A simple and rapid analysis strategy based on UHPLC-Q-Exactive Orbitrap mass spectrometry combined with data-mining processing technology was developed and used to screen and identify CAG metabolites in rat body fluids and tissues after oral administration.</p><p><strong>Results: </strong>As a result, a total of 82 metabolites were fully or partially characterized based on their accurate mass, characteristic fragment ions, retention times, corresponding Clog P values, and so on. Among the metabolites, 61 were not been reported in previous reports. These metabolites (6 metabolites in vitro and 91 in vivo) were generated through reactions of hydroxylation, glucuronidation, sulfation, hydrogenation, hydroxylation, demethylation, deisopropylation, dehydroxylation, ring cleavage, and carboxyl substitution and their composite reactions, and the hydroxylation might be the main metabolic reaction of CAG. In addition, the characteristic fragmentation pathways of CAG were summarized for the subsequent metabolite identification.</p><p><strong>Conclusion: </strong>The current study not only clarifies the metabolite cluster-based and metabolic regularity of CAG in vivo and in vitro, but also provides ideas for metabolism of other saponin compounds.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"23 14","pages":"1090-1114"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9422922","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":"Hepatic Effect of 2,3,5,4'-tetrahydroxystilbene-2-O-<i>β</i>-D-glucoside, the Signature Component of Traditional Chinese Medicine Heshouwu: Advances and Prospects.","authors":"Cheng-Yu Wang,&nbsp;Ying-Huan Hu,&nbsp;Zhen-Xiao Sun","doi":"10.2174/1389200224666230223144826","DOIUrl":"https://doi.org/10.2174/1389200224666230223144826","url":null,"abstract":"<p><p>Traditional Chinese medicine Heshouwu, named Polygoni Multiflori Radix in Pharmacopoeia of the People's Republic of China (PPRC, 2020), is derived from the root tuber of Polygonum multiflorum Thunb., Heshouwu or processed Heshouwu is well known for its function in reducing lipids and nourishing the liver. However, increasing cases of Heshouwu-induced hepatotoxicity were reported in recent years. Researchers have begun to study the paradoxical effects of Heshouwu on the liver. 2,3,5,4'-tetrahydroxystilbene-2-<i>O-β-D</i>-glucoside (TSG), an abundant functional component of Heshouwu, shows various biological activities, among which its effect on the liver is worthy of attention. This paper reviews the current studies of TSG on hepatoprotection and hepatotoxicity, and summarizes the doses, experimental models, effects, and mechanisms of action involved in TSG's hepatoprotection and hepatotoxicity, aiming to provide insight for future study of TSG and understanding the effects of Heshouwu on the liver. Emerging evidence suggests that TSG ameliorates both pathological liver injury and chemical-induced liver injury by modulating lipid metabolism, inhibiting the inflammatory response and oxidative stress in the liver. However, with the reports of clinical cases of Heshouwu induced liver injury, it has been found that long-term exposure to a high dose of TSG cause hepatocyte or hepatic tissue damage. Moreover, TSG may cause hepatotoxicity by affecting the transport and metabolism of other possible hepatoxic compounds in Heshouwu. Studies indicate that trans-TSG can be isomerized into <i>cis</i>-TSG under illumination, and <i>cis</i>-TSG had a less detrimental dose to liver function than trans- TSG in LPS-treated rats. In brief, TSG has protective effects on the liver, but liver injury usually occurs under highdose TSG or is idiosyncratic TSG-induced liver injury.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"24 1","pages":"16-27"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9471831","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":"Methods to Improve the Stability of Nucleic Acid-Based Nanomaterials.","authors":"Xueping Xie,&nbsp;Wenjuan Ma,&nbsp;Yuxi Zhan,&nbsp;Qifeng Zhang,&nbsp;Chaowei Wang,&nbsp;Huiyong Zhu","doi":"10.2174/1389200224666230601091346","DOIUrl":"10.2174/1389200224666230601091346","url":null,"abstract":"<p><p>Nucleic acid strands can be synthesized into various nucleic acid-based nanomaterials (NANs) through strict base pairing. The self-assembled NANs are programmable, intelligent, biocompatible, non-immunogenic, and non-cytotoxic. With the rapid development of nanotechnology, the application of NANs in the biomedical fields, such as drug delivery and biological sensing, has attracted wide attention. However, the stability of NANs is often affected by the cation concentrations, enzymatic degradation, and organic solvents. This susceptibility to degradation is one of the most important factors that have restricted the application of NANs. NANs can be denatured or degraded under conditions of low cation concentrations, enzymatic presence, and organic solvents. To deal with this issue, a lot of methods have been attempted to improve the stability of NANs, including artificial nucleic acids, modification with specific groups, encapsulation with protective structures, etc. In this review, we summarized the relevant methods to have a deeper understanding of the stability of NANs.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"315-326"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9553901","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 Comprehensive Study on the Chemical Constituents and Pharmacokinetics of Erzhi Formula and Jiawei Erzhi Formula Based on Targeted and Untargeted LC-MS Analysis.","authors":"Tongtong Zhu,&nbsp;Wanning Chen,&nbsp;Chunyue Han,&nbsp;Zhijie Gao,&nbsp;Erwei Liu,&nbsp;Xiumei Gao,&nbsp;Zhifei Fu,&nbsp;Lifeng Han","doi":"10.2174/1389200224666230130093412","DOIUrl":"https://doi.org/10.2174/1389200224666230130093412","url":null,"abstract":"<p><strong>Background: </strong>Erzhi formula (EZF) is a traditional Chinese medicine prescription, which has been widely used in the treatment of osteoporosis and premature ovarian failure.</p><p><strong>Objective: </strong>To enhance curative effects, the other two herbal medicines, including Spatholobi Caulis (SC) and Achyranthes bidentata Blume (ABB), were added into the original EZF formula to obtain two new Jiawei-EZF (JW-EZF) preparations. To clarify the effect of the compatibility of herbs for original formulas, the chemical constituents and bioactive compounds in vivo were detected.</p><p><strong>Methods: </strong>An efficient and sensitive targeted and untargeted UHPLC/ESI-Q-Orbitrap MS method, together with mass defect filter and precursor ion list, was established firstly for the profiling of different EZF formulas. Furthermore, eleven absorbed compounds (apigenin, luteoloside, luteolin, oleuropein, wedelolactone, acteoside, specnuezhenide, 11-methyloleoside, ecliptasaponin A, formononetin, and β-ecdysone) were simultaneously quantified in rat plasma.</p><p><strong>Results: </strong>A total of 124, 162, and 177 compounds were identified or tentatively identified in EZF, JW-3-EZF (EZF+SC) and JW-4-EZF (EZF+SC+ABB), respectively. 110 compounds were found to be common constituents in the three formulas. Moreover, 66 prototypes were unambiguously identified in the rats' plasma after oral administration of the three formulas using the same strategy. 11 out of the 66 absorbed components were simultaneously quantitated in the pharmacokinetic (PK) study. Compared to the original EZF, the plasma AUC_(0-24h) and AUC_(0-∞) of apigenin, 11-methyloleoside, luteolin, luteoloside, wedelolactone, and acteoside were found to be significantly increased after oral administration of JW-3-EZF, and plasma AUC_(0-24h) and AUC_(0-∞) of apigenin, wedelolactone, and acteoside, were also found to be significantly increased after JW-4-EZF administration.</p><p><strong>Conclusion: </strong>The combined qualitative and quantitative methods were used to provide a potential approach to the characterization and quality control of the Traditional Chinese Medicine (TCM) and its preparations.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"23 14","pages":"1130-1142"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10865016","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":"Crocin Ameliorates Diabetic Nephropathy through Regulating Metabolism, CYP4A11/PPARγ, and TGF-β/Smad Pathways in Mice.","authors":"Wei Chen, Jinhao Su, Yubin Liu, Tianmei Gao, Xiaohui Ji, Hanzhou Li, Huajun Li, Yuansong Wang, Hui Zhang, Shuquan Lv","doi":"10.2174/0113892002257928231031113337","DOIUrl":"10.2174/0113892002257928231031113337","url":null,"abstract":"<p><strong>Introduction: </strong>Crocin is one of the main components of Crocus sativus L. and can alleviate oxidative stress and inflammation in diabetic nephropathy (DN). However, the specific mechanism by which crocin treats DN still needs to be further elucidated.</p><p><strong>Method: </strong>In the present study, a mouse model of DN was first established to investigate the therapeutic effect of crocin on DN mice. Subsequently, non-targeted metabolomics techniques were used to analyze the mechanisms of action of crocin in the treatment of DN. The effects of crocin on CYP4A11/PPARγ and TGF-β/Smad pathway were also investigated.</p><p><strong>Result: </strong>Results showed that crocin exhibited significant therapeutic and anti-inflammatory, and anti-oxidative effects on DN mice. In addition, the non-targeted metabolomics results indicated that crocin treatment affected several metabolites in kidney. These metabolites were mainly associated with biotin metabolism, riboflavin metabolism, and arachidonic acid metabolism. Furthermore, crocin treatment upregulated the decreased levels of CYP4A11 and phosphorylated PPARγ, and reduced the increased levels of TGF-β1 and phosphorylated Smad2/3 in the kidneys of DN mice.</p><p><strong>Conclusion: </strong>In conclusion, our study validated the considerable therapeutic, anti-inflammatory, and antioxidative impacts of crocin on DN mice. The mechanism of crocin treatment may be related to the regulation of biotin riboflavin and arachidonic acid metabolism, the activation of CYP4A11/PPARγ pathway, and the inhibition of TGF-β/Smad pathway in the kidney.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"709-722"},"PeriodicalIF":2.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10825796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71479099","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":"The Effect of Retroconversion Metabolism of <i>N</i>-oxide Metabolites by Intestinal Microflora on Piperaquine Elimination in Mice, as well as in Humans Predicted Using a PBPK Model.","authors":"Hongchang Zhou,&nbsp;Liyuan Zhang,&nbsp;Jianbo Ji,&nbsp;Yuewu Xie,&nbsp;Jie Xing","doi":"10.2174/1389200224666230320112429","DOIUrl":"https://doi.org/10.2174/1389200224666230320112429","url":null,"abstract":"<p><strong>Background: </strong>Piperaquine (PQ) and its pharmacologically active metabolite PQ <i>N</i>-oxide (PM1) can be metabolically interconverted via hepatic cytochrome P450 and FMO enzymes.</p><p><strong>Objectives: </strong>The reductive metabolism of PM1 and its further <i>N</i>-oxidation metabolite (PM2) by intestinal microflora was evaluated, and its role in PQ elimination was also investigated.</p><p><strong>Methods: </strong>The hepatic and microbial reduction metabolism of PM1 and PM2 was studied <i>in vitro</i>. The reaction phenotyping experiments were performed using correlation analysis, selective chemical inhibition, and human recombinant CYP/FMO enzymes. The role of microbial reduction metabolism in PQ elimination was evaluated in mice pretreated with antibiotics. The effect of the reduction metabolism on PQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model.</p><p><strong>Results: </strong>Both hepatic P450/FMOs enzymes and microbial nitroreductases (NTRs) contributed to the reduction metabolism of two PQ <i>N</i>-oxide metabolites. <i>In vitro</i> physiologic and enzyme kinetic studies of both <i>N</i>-oxides showed a comparable intrinsic clearance by the liver and intestinal microflora. Pretreatment with antibiotics did not lead to a significant (P > 0.05) change in PQ pharmacokinetics in mice after an oral dose. The predicted pharmacokinetic profiles of PQ in humans did not show an effect of metabolic recycling.</p><p><strong>Conclusion: </strong>Microbial NTRs and hepatic P450/FMO enzymes contributed to the reduction metabolism of PQ Noxide metabolites. The reduction metabolism by intestinal microflora did not affect PQ clearance, and the medical warning in patients with NTRs-related disease (e.g., hyperlipidemia) will not be clinically meaningful.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"24 2","pages":"131-138"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9551025","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}