ADMET and DMPK最新文献

{"title":"Management of intraocular pressure and inflammation using febuxostat film: <i>in vitro</i> - <i>in vivo</i> correlation.","authors":"Mouli Das, Sk Habibullah, Tanisha Das, Rakesh Swain, Subrata Mallick","doi":"10.5599/admet.2601","DOIUrl":"https://doi.org/10.5599/admet.2601","url":null,"abstract":"<p><strong>Background and purpose: </strong>Urate crystal accumulation may lead to the condition of ocular tophaceous gout, causing ocular inflammation and increased intraocular pressure (IOP) due to the triggering of several inflammatory receptors like NLRP3, A2A, and TLR4. The study has been undertaken to manage intraocular pressure and inflammation using febuxostat (FBX) film formulation for sustained and improved activity, particularly for long-term tophaceous gout patients.</p><p><strong>Experimental approach: </strong>Hydroxypropyl methylcellulose K100 matrix-based hydrogel film of FBX has been fabricated in the presence of plasticizers like triethanolamine, dimethyl-sulphoxide (DMSO), or polyethylene glycol 600 using casting and evaporation technique. Carrageenan was injected into the upper palpebral region to induce ocular inflammation, and a normotensive rabbit eye model was used for monitoring IOP.</p><p><strong>Key results: </strong>Amorphization of the drug was observed from the differential scanning calorimetry and X-ray diffraction results. <i>In vitro</i> release study revealed an improved and diffusion-controlled sustained drug release for more than 5 h (62.69 to 84.76 %). Compared to its absence, decreased IOP was extended up to 5 h using film (with DMSO). Disappearance of ocular inflammation was also observed in the test animals after 2.5 h of film application, whereas acute inflammation was continued in the group without treatment for more than 4 h. Docking study revealed good binding interaction of drug and NLRP3, A2A, and TLR4 receptor.</p><p><strong>Conclusion: </strong>Febuxostat-loaded hydrogel-forming plasticized film could be utilized to better manage and control ocular inflammation and associated IOP, particularly in ocular tophaceous gout patients.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"13 2","pages":"2601"},"PeriodicalIF":3.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microwave coprocessing of modafinil with Gelucire^®: Thermal and compression characteristics.","authors":"Derar Omari, Assayed Sallam, Iyad Rashid, Shereen M Assaf, Faisal Al-Akayleh, Khaldoun A Al-Sou Od","doi":"10.5599/admet.2569","DOIUrl":"10.5599/admet.2569","url":null,"abstract":"<p><strong>Introduction: </strong>Modafinil, a wakefulness-promoting agent, is primarily used to treat excessive daytime sleepiness associated with narcolepsy and fatigue. As a BCS class II drug, modafinil exhibits low solubility and high permeability, with its crystalline structure significantly impacting dissolution, bioavailability, and compressibility. This study explores the use of microwave energy to alter the crystalline structure of modafinil in the presence of Gelucire^® 48/16, aiming to improve its pharmaceutical properties.</p><p><strong>Methods: </strong>Modafinil was treated with microwave energy to form complexes with Gelucire^® 48/16, and the resulting formulations were compared to hot-melt complexes and physical mixtures. The structural and thermal properties of the complexes were characterized using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy. Compressibility and compactibility were evaluated through Kawakita model analysis and response surface methodology). The effect of microwaves on molecular interactions was further investigated using molecular modeling.</p><p><strong>Results: </strong>XRPD analysis revealed distinct crystalline patterns for microwave and hot-melt complexes compared to physical mixtures, with increased amorphousness observed through crystallinity, relative crystallinity, and relative intensity parameters. DSC thermograms indicated a reduction in melting endotherms and heat flow, suggesting structural changes due to complex formation. Compressibility and compactibility studies demonstrated optimal performance at low Gelucire^® content, with microwave-treated complexes exhibiting superior properties to untreated mixtures. Molecular modeling confirmed dipole-dipole interactions between modafinil and the hydrophilic portion of Gelucire^®.</p><p><strong>Conclusions: </strong>The study demonstrates that microwave energy effectively alters the crystalline structure of modafinil in the presence of Gelucire^® 48/16, enhancing its amorphousness, compressibility, and compatibility. These findings highlight the potential of microwave-assisted complexation as a novel approach to improve the pharmaceutical performance of BCS Class II drugs like modafinil.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"13 1","pages":"2569"},"PeriodicalIF":3.4,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of bicarbonate buffer on artificial membrane permeation of drugs.","authors":"Shiori Ishida, Samuel Lee, Balint Sinko, Karl Box, Kiyohiko Sugano","doi":"10.5599/admet.2603","DOIUrl":"10.5599/admet.2603","url":null,"abstract":"<p><strong>Background and purpose: </strong>The pH value of the small intestine is physiologically maintained by bicarbonate buffer (BCB). However, the effect of BCB on the membrane permeation of drugs has not been investigated. The purpose of this study was to investigate the effect of BCB on the passive membrane permeation of drugs.</p><p><strong>Experimental approach: </strong>The μFlux apparatus (pION Inc.) was used for permeability measurements. To avoid a pH change of BCB, a floating lid was newly developed for μFlux. The membrane filter was coated with a 10 % soybean lecithin-decane solution. The flux measurement was performed in an iso-pH condition (pH 6.5, BCB = 10 mM, buffer capacity (<i>β</i>)= 4.4 mM pH^-1). Phosphate buffer (PPB) with the same pH and <i>β</i> was used for comparison (PPB = 8 mM).</p><p><strong>Key results: </strong>The floating lid suppressed the pH increase to less than 0.1 for 120 min. The effective permeability (<i>P</i> _e) values of lipophilic weakly acidic and basic drugs were lower in BCB than in PPB (ketoprofen, naproxen, and propranolol). On the other hand, the <i>P</i> _e values in BCB and PPB were similar for unionizable drugs (caffeine and antipyrine) and hydrophilic weakly basic drugs (metoprolol and procainamide).</p><p><strong>Conclusion: </strong>Passive membrane permeation of lipophilic weakly acidic and basic drugs was slower in BCB than in PPB. This was suggested to be attributed to the slow neutralization rate of BCB, which affects the pH value adjacent to the membrane surface.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"13 1","pages":"2603"},"PeriodicalIF":3.4,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural polymer derivative-based pH-responsive nanoformulations with entrapped diketo-tautomers of 5-fluorouracil for enhanced cancer therapy.","authors":"Anbazhagan Thirumalai, Koyeli Girigoswami, Karthick Harini, Venkatakrishnan Kiran, Pazhani Durgadevi, Agnishwar Girigoswami","doi":"10.5599/admet.2554","DOIUrl":"10.5599/admet.2554","url":null,"abstract":"<p><strong>Background and purpose: </strong>Despite significant advancements in cancer therapies, chemotherapeutics continue to be the mainstay for treating cancer patients, with 5-fluorouracil (5-FU) being commonly used for various cancers. However, its limited ability to penetrate cell membranes and its short half-life, caused by rapid metabolism, necessitate frequent administration of high doses to maintain effective therapeutic levels. This study aimed to synthesize oxidized sodium alginate (OSA) derivatives to create OSA nanoparticles loaded with 5-FU (OSANP@ 5-FU), promoting diketo tautomers, and evaluate their photophysical properties, release profile, and anticancer activity with minimal toxicity.</p><p><strong>Experimental approach: </strong>The investigation encompassed physicochemical characterization, encapsulation efficiency, 5-FU release kinetics at pH 2.2 and 7.4, cell viability assessment via MTT assay in V79 cells, and in vitro anticancer efficacy in the A375 cell line.</p><p><strong>Key results: </strong>Steady-state absorption and emission confirmed the presence of advantageous diketone tautomers of 5-FU, indicating radiative transitions from the second singlet excited state to the ground state (S2→S0) and the drug's encapsulation within the polymeric nanostructure. Dynamic light scattering revealed that OSA nanoparticles, initially 177.8 nm, grew to 226.6 nm after encapsulating 5-FU, retaining high zeta potential for stability. With a 68% encapsulation efficiency, in vitro studies showed 46 to 54 % of 5-FU released across different pH levels within 510 minutes.</p><p><strong>Conclusion: </strong>In acidic conditions, there is a greater release of 5-FU than neutral pH levels, indicating a pH-responsive release profile beneficial for cancer treatment, with the release mechanism of OSANPs following Fickian diffusion as identified by a Korsmeyer-Peppas mathematical model and the formulation showing improved therapeutic efficacy.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"13 1","pages":"2554"},"PeriodicalIF":3.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flavonoids from <i>Clerodendrum</i> genus and their biological activities.","authors":"Meiske Naomi Mamuaja, Tati Herlina, Rymond Jusuf Rumampuk, Iman Permana Maksum, Yaya Rukayadi","doi":"10.5599/admet.2442","DOIUrl":"10.5599/admet.2442","url":null,"abstract":"<p><strong>Background and purpose: </strong>Many studies have been performed to identify new sources, their optimal isolation, and the biological activities of flavonoids due to nutraceutical, pharmaceutical, and cosmeceutical properties.</p><p><strong>Experimental approach: </strong>This review describes the method for flavonoid isolation and characteristic from the <i>Clerodendrum</i> genus and their biological activities with the indication of the most active ones. To perform a comprehensive review, a thorough literature review using Google Scholar, Scopus, and Science Direct was performed with keyword alone or in combination with other words.</p><p><strong>Key results: </strong>The isolation and identification of flavonoids from the Clerodendrum genus have revealed a variety of compounds using various methods. Various studies conducted <i>in vivo</i>, <i>in vitro</i> and <i>in silico</i> also reported bioactivities of these flavonoids.</p><p><strong>Conclusion: </strong>Several factors determine the flavonoid content in the <i>Clerodendrum</i> genus, among others, the different parts of the plant, extraction techniques, and solvent combination used. Isolated flavonoids also show significant biological activities, such as antioxidant, anti-inflammatory, antimicrobials, antidiabetic, anticancer, anti-tyrosinase, and neuroprotective agents.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"12 6","pages":"843-879"},"PeriodicalIF":3.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glyphosate-based herbicide metabolic profiles in human urine samples through proton nuclear magnetic resonance analysis.","authors":"Preechaya Tajai, Giatgong Konguthaithip, Thanyaphisit Chaikhaeng, Churdsak Jaikang","doi":"10.5599/admet.2476","DOIUrl":"10.5599/admet.2476","url":null,"abstract":"<p><strong>Background and purpose: </strong>Glyphosate-based herbicides, extensively utilized worldwide, raise concerns regarding potential human risks due to the detection of glyphosate (GLY) in human body fluids. This study aims to address critical knowledge gaps regarding whether GLY undergoes metabolism in humans, particularly considering the limited information available on human metabolism.</p><p><strong>Experimental approach: </strong>The study investigated GLY and its metabolites in eight amenity horticultural workers using proton nuclear magnetic resonance (¹H-NMR) data analysis. Multiple spot urine samples were collected before and after herbicide applications.</p><p><strong>Key results: </strong>Findings reveal the presence of GLY and its metabolites (AMPA, formaldehyde, sarcosine, glyoxylic acid, and methylamine). Results demonstrate a moderate correlation between median GLY concentration and its metabolites within the studied population.</p><p><strong>Conclusion: </strong>Persuasive evidence suggests the potential metabolism of GLY in humans. ¹H-NMR data analysis might be a promising technique for determining the metabolism of GLY in humans, offering valuable insights into urinary excretion patterns.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"12 6","pages":"957-970"},"PeriodicalIF":3.4,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural serine proteases and their applications in combating amyloid formation.","authors":"Sanjay Kisan Metkar, Saranya Udayakumar, Agnishwar Girigoswami, Koyeli Girigoswami","doi":"10.5599/admet.2551","DOIUrl":"10.5599/admet.2551","url":null,"abstract":"<p><strong>Background and purpose: </strong>Amyloidosis is a group of diseases including diabetes type II and neurological disorders, such as Alzheimer's disease, Parkinson's disease, prion disease, etc., where a common trait is observed; accumulation of misfolded protein at different parts of the body, especially the brain which manifests the typical symptoms like dementia, movement disorders, etc. These misfolded proteins, named amyloids, are protease resistant and thus it becomes difficult to manage these diseases in vivo. Enzymes that catalyse the complete breakdown of proteins are known as proteases. The peptide bonds in proteins are degraded by these serine proteases, which cause amyloid disaggregation.</p><p><strong>Experimental approach: </strong>We have searched for related articles using the search engines Google Scholar, PubMed, and Scopus for the past 10 years, selected the relevant articles, and written the outcomes and benefits of protease using the medical topic \"serine protease\" and the following text phrases -keratinase, lumbrokinase, serratiopeptidase, nattokinase.</p><p><strong>Key results: </strong>Alkaline serine proteases exhibit activity within the neutral to alkaline pH range. They are most capable of degrading host complement proteins, cytokines, and host clotting factors mostly due to their serine centre or metallotype. Because of its potential usage in food, pharmaceutical, and other industrial domains, this category of enzymes has been extensively investigated. Specifically, serine proteases are a group of enzymes that can be consumed orally and are stable in our gastrointestinal tract.</p><p><strong>Conclusion: </strong>In this review, we discussed the role of different serine proteases in amyloid aggregate inhibition and their potential application in treating amyloidosis.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"12 6","pages":"797-820"},"PeriodicalIF":3.4,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined approach of nanoemulgel and microneedle pre-treatment as a topical anticellulite therapy.","authors":"Hiba Imad Hameed, Mohammed Hussain Al-Mayahy","doi":"10.5599/admet.2461","DOIUrl":"10.5599/admet.2461","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cellulite is caused by changes in the metabolism of the fatty tissue beneath the skin. Methylxanthines and retinoids are commonly added to the different anticellulite products. However, their topical permeation into the dermis is limited. Thus, the objective of this research is to formulate a nanoemulgel (NEG) containing a triple therapy of caffeine, aminophylline, and tretinoin as a topical anticellulite product to improve their skin permeation. Furthermore, the influence of microneedles (MNs) as skin pre-treatment on the permeation of the NEG was investigated.</p><p><strong>Experimental approach: </strong>Various nanoemulsion (NE) formulations were prepared using high-energy ultrasonication with different compositions and sonication amplitudes. Several characterisation tests were employed to select the optimum NE formulation. Then, the optimised NE formulation was incorporated with hyaluronic acid to prepare the NEG, which was, in turn, subjected to various evaluations. An <i>ex vivo</i> permeation study using human skin was performed for the NEG compared to a control preparation of plain gel. Additionally, a microneedling pen was applied as a skin pre-treatment at varying lengths prior to NEG application to examine its impact on the NEG's permeation.</p><p><strong>Key results: </strong>The selected NEG has a homogenous and consistent texture with no coarse particles, a droplet size of 175.8 nm and polydispersity index (PDI) of 0.19, an optimum pH value of 5.28, high drug content of caffeine, aminophylline, and tretinoin (99.35, 98.48 and 98.05 %, respectively), high drug release values of approximately 100 % within 6 hours, appropriate viscosity, minimum skin irritation, and adequate short-term stability. The <i>ex vivo</i> permeation study showed that caffeine, aminophylline, and tretinoin permeated more and deposited in the skin with higher percentages from the NEG than plain gel. This skin deposition within the dermis was increased by applying the microneedling pen at varying lengths of 0.5, 1, and 2 mm as a skin pre-treatment.</p><p><strong>Conclusion: </strong>This combined approach of NEG formulation containing a triple therapy of caffeine, aminophylline, and tretinoin, along with MNs application, has the potential to serve as a topical anticellulite product, reducing cellulite formation and improving skin appearance.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"12 6","pages":"903-923"},"PeriodicalIF":3.4,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and metabolism of ketoconazole after single ocular instillation in Sprague-Dawley rats.","authors":"Jiang Pu, Jinsong He, Ru Xue, Ruiqi Gao, Yaoming Yu, Wanyong Feng","doi":"10.5599/admet.2387","DOIUrl":"10.5599/admet.2387","url":null,"abstract":"<p><strong>Background and purpose: </strong>Ketoconazole is limited to its conditioned oral use due to hepatic toxicity. Its ocular eye drop administration may be an option for mycotic keratitis treatment. Therefore, it is necessary to explore its pharmacokinetic and metabolic profile via topical ocular administration.</p><p><strong>Experimental approach: </strong>Nine rats were dosed at 300 μg/rat via topical ocular administration, and sacrificed at 5, 30, and 120 min with 3 rats/timepoint. Plasma, cornea, retina, and vitreous humour samples were collected, processed, and analysed.</p><p><strong>Key results: </strong>Ketoconazole was quantified with a mean peak plasma concentration of 445 ng/mL at 5 min post-dose. In the rat ocular tissue, the mean ketoconazole concentration at 5 min post-dose was 423 μg/g in the cornea, 4.96 μg/g in the retina, and 1.19 μg/g in the vitreous humour, respectively. The mean ketoconazole concentration in each matrix decreased from 5 to 120 min. The mean ketoconazole concentration at 120 min was 38.4 ng/mL in plasma, and 8.36, 0.0944, and 0.116 μg/g in the cornea, retina, and vitreous humour, respectively. Pooled plasma, cornea, retina, and vitreous humour homogenates were used for metabolite identification. Nine metabolites were identified in rat plasma, and O-dealkylated metabolite (M3) and dehydrogenated metabolite (M11) were the top two, accounting for 5.0 and 5.8 % of the relative mass abundance. The metabolic pathways were O-dealkylation, mono-oxygenation, and dehydrogenation. Eleven metabolites were identified in the rat cornea, and two metabolites were identified in the rat retina and vitreous humour, respectively. The O-dealkylated and hydrogenated metabolite (M2) was a dominant metabolite in the cornea, retina, and vitreous humour, while M3 and M11 were the dominant metabolites in plasma.</p><p><strong>Conclusion: </strong>Ketoconazole was a dominant component (≥ 98.5 %) in the cornea, retina, and vitreous humour, having higher concentrations in cornea than in plasma. M2 was identified as a dominant metabolite (1.1-1.2 %) in the cornea, retina, while M3 (5.0 %) and M11 (5.8 %) were identified as dominant metabolites in the plasma.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"12 6","pages":"943-955"},"PeriodicalIF":3.4,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics/pharmacodynamics of glucocorticoids: modeling the glucocorticoid receptor dynamics and dose/response of commonly prescribed glucocorticoids.","authors":"David G Levitt","doi":"10.5599/admet.2414","DOIUrl":"10.5599/admet.2414","url":null,"abstract":"<p><strong>Background and purpose: </strong>The main features of the dynamics of the glucocorticoid receptor (GR) have been known for 50 years: 1) in the absence of glucocorticoid (G), the receptor is localized entirely in the cytoplasm; 2) upon G binding, GR is converted into a tightly bound G form and is rapidly imported into the nucleus where it can bind DNA and modulate transcription; 3) nuclear export of GR is very slow; and 4) the nuclear form of GR can recycle through an unbound form, back to the bound transcription modulating form without leaving the nucleus.</p><p><strong>Experimental approach: </strong>A kinetic model that captures these features is presented, a set of model parameters for dexamethasone is derived, and the clinical implication for the commonly used glucocorticoids is discussed.</p><p><strong>Key results: </strong>At the high concentrations normally used to describe G pharmacodynamics, the model reduces to the standard Michaelis-Menten equation with a <i>K</i> _m that is a function of 4 model parameters. At very low concentrations, it reduces to another Michaelis-Menten equation with about a 1000-fold greater affinity, <i>eg.</i> at the nadir human endogenous cortisol concentration, the full model GR activity is 2.6 times greater than that predicted by extrapolation of the high concentration results.</p><p><strong>Conclusion: </strong>The model is used to relate normal human 24-hour endogenous plasma cortisol levels to transcriptional activity and is applied to the commonly prescribed glucocorticoids (dexamethasone, methylprednisolone, prednisone) in an attempt to provide a pharmacological rationale for the very large therapeutic dosage range that has been traditionally used.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"12 6","pages":"971-989"},"PeriodicalIF":3.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}