Current drug metabolism最新文献

{"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":null,"pages":null},"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":"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":null,"pages":null},"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":null,"pages":null},"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":"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":null,"pages":null},"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":"Worldwide Prevalence of Polypharmacy: A Systematic Review.","authors":"Beatriz Dias Januário,&nbsp;Natália Silva Mafra,&nbsp;Humberto de Souza Silva,&nbsp;Isabella Monteiro Carvalho,&nbsp;Ana Luiza Sobreira Sena,&nbsp;Ana Paula Gomes Soares Pereira,&nbsp;Newton Santos de Faria Júnior,&nbsp;Helton Oliveira Campos","doi":"10.2174/1389200224666230727093010","DOIUrl":"10.2174/1389200224666230727093010","url":null,"abstract":"<p><strong>Introduction: </strong>The present study has compiled the prevalence of polypharmacy worldwide and assessed the prevalence of polypharmacy in different populations, including community-dwelling individuals, hospitalized patients, and institutionalized patients.</p><p><strong>Methods: </strong>This systematic review was conducted and reported according to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. A systematic search of electronic databases, including PubMed, Web of Science, and Scielo, was performed in March 2021 without any date and language restrictions. Combinations of the following keywords were used for the search strategy: polypharmacy OR multiple medications OR multiple medicines OR multiple drug AND prevalence. Based on the search and inclusion criteria, two hundred and eight studies (73,076,167 individuals) were selected for inclusion in the systematic review. It was observed that there is a wide variation in the prevalence of polypharmacy between studies.</p><p><strong>Results: </strong>The prevalence of polypharmacy was found to be 30.2%, 61.7%, and 56.9% for community-dwelling individuals, hospitalized patients, and institutionalized patients, respectively.</p><p><strong>Conclusion: </strong>Based on the analyses, this systematic review has demonstrated a wide variation in the prevalence of polypharmacy between studies and countries and a high prevalence of polypharmacy in institutionalized and hospitalized patients.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9879273","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":"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":null,"pages":null},"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":"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":null,"pages":null},"PeriodicalIF":2.3,"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":null,"pages":null},"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}

{"title":"Covalent Modification of Proteins by Osthole Reactive Metabolites using Proteomic Approaches.","authors":"Yue Zhuo,&nbsp;Huiling Chen,&nbsp;Chenchen Liu,&nbsp;Yida Zhang,&nbsp;Jiansong Fang,&nbsp;Meng Li,&nbsp;Zhendong Wang,&nbsp;Qiyao Jiang,&nbsp;Liangwen Yu,&nbsp;Huafeng Pan,&nbsp;Qi Wang","doi":"10.2174/1389200224666230727123006","DOIUrl":"10.2174/1389200224666230727123006","url":null,"abstract":"<p><strong>Background: </strong>Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,β- unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites.</p><p><strong>Objective: </strong>This study aims to investigate the metabolic profile and the metabolites-protein modification of OST.</p><p><strong>Methods: </strong>The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer.</p><p><strong>Results: </strong>In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST's anti-Alzheimer's disease (AD) and anti-tumor.</p><p><strong>Conclusion: </strong>This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9888751","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":"Molecular Insights into the Mechanism of Modulatory Effects of Proton Pump Inhibitors on P-glycoprotein Mediated Drug Transport of Palbociclib and Ribociclib.","authors":"Mrunal Pradeep Desai,&nbsp;Prajakta Harish Patil,&nbsp;Sai Krishna Anand Vullendula,&nbsp;Sumit Birangal,&nbsp;G Gautham Shenoy,&nbsp;Mahadev Rao,&nbsp;Swapnil Jayant Dengale,&nbsp;Krishnamurthy Bhat,&nbsp;Jagadish Puralae Channabasavaiah","doi":"10.2174/1389200224666230815122312","DOIUrl":"10.2174/1389200224666230815122312","url":null,"abstract":"<p><strong>Background: </strong>Palbociclib and ribociclib are substrates of efflux transporter P-glycoprotein which plays a key role in absorption and transport of these drugs. Proton pump inhibitors, when co-administered with them are known to show inhibitory effect on P-glycoprotein.</p><p><strong>Objective: </strong>Therefore, this study aims to investigate the role of proton pump inhibitors in inhibition of P-glycoprotein mediated efflux of palbociclib and ribociclib.</p><p><strong>Method: </strong>A combined approach of molecular docking and <i>ex vivo</i> everted gut sac model was implemented to predict the potential of proton pump inhibitors <i>i.e.</i>, omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole to inhibit the P-glycoprotein mediated intestinal transport of palbociclib and ribociclib and study the molecular basis of interaction taking place.</p><p><strong>Results: </strong>Molecular docking studies revealed that omeprazole, rabeprazole and pantoprazole bound to the ATP site of nucleotide binding domain with binding energies of -27.53, -29.56 and -38.44 Kcal/mol respectively. In <i>ex vivo</i> studies, rabeprazole and omeprazole, affected the absorptive permeability of palbociclib by 3.04 and 1.26 and ribociclib by 1.76 and 2.54 folds, respectively. Results of molecular docking studies and <i>ex vivo</i> studies highlighted that proton pump inhibitors bound to the ATP binding site to block its hydrolysis thereby inhibiting the P-glycoprotein mediated efflux of palbociclib and ribociclib.</p><p><strong>Conclusion: </strong>The experimental evidence presented highlights the fact that proton pump inhibitors have potential to inhibit P-glycoprotein, giving rise to drug interactions with palbociclib and ribociclib. Hence, monitoring is required while proton pump inhibitors and cyclin-dependent kinase inhibitors are being co-administered to avoid adverse events.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10003078","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}