Drug metabolism and bioanalysis letters最新文献

{"title":"`3-Hydroxy-6H,7H-chromeno [3,4-c]chromene-6,7-dione as a Substrate for Studying Glucuronidation, Sulfonation and Lactone Hydrolysis.","authors":"Risto O Juvonen, Tuomo Laitinen, Joana David, Margarida Ferreira, Jasmin Etemadi, Oussama Mekhalia, Ina Onatsu, Emma Pätsi, Juhani Huuskonen, Moshe Finel, Hannu Raunio, Veera Lassheikki, Aki T Heikkinen, Seppo Auriola","doi":"10.2174/0118723128351379250312063255","DOIUrl":"10.2174/0118723128351379250312063255","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Glucuronidation and sulfonation enzymes conjugate compounds containing a hydroxyl group, while paraoxonase enzymes hydrolyze lactonecontaining compounds. 3-Hydroxy-6H,7H-chromeno [3,4-c]chromene-6,7-dione (3- hydroxy-V-coumarin) contains both a hydroxyl substituent and two lactone substructures and is strongly fluorescent. This study evaluates glucuronidation, sulfonation and hydrolysis of 3-hydroxy-V-coumarin reactions, which abolish its fluorescence.</p><p><strong>Methods: </strong>Glucuronide, sulfate, and hydrolyzed product formation were confirmed using accurate LC-MS. Fluorescence-based multi-well plate assays were established to determine rates of glucuronidation, sulfonation and hydrolysis of 3-hydroxy-V-coumarin.</p><p><strong>Results: </strong>A decrease in fluorescence correlated with the formation of conjugation or hydrolyzed metabolites of the reactions was observed. 3-Hydroxy-V-coumarin was glucuronidated by human UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A9, 1A10, 2A1, 2B4 and 2B7 and by dog UGT1A1, 1A2 and 1A11, and sulfonated by human SULT1A1, 1A2 and 1E1. The results indicated that paraoxonase 2 hydrolyzed lactone of 3-hydroxy-V-coumarin. 3-Hydroxy-Vcoumarin interacted via a hydrogen bond with serine 221 and via hydrophobic interaction with phenyls 71 and 291 of paraoxonase 2. The hydrolysis rate of 3-hydroxy-V-coumarin was determined in ten rat tissues. In human liver cytosol, the hydrolysis was slower than in rat, mouse, dog, pig, rabbit, and sheep liver cytosol.</p><p><strong>Conclusion: </strong>3-hydroxy-V-coumarin is a new model substrate for studying glucuronidation, sulfonation and lactone hydrolysis reactions.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"18 2","pages":"195-207"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145914149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingolipids in Cancer: Metabolism, Signaling, and Clinical Implications.","authors":"Sharav A Desai, Sandip D Nagare, Vipul P Patel, Nishant B Pagare, Tejas C Jangam","doi":"10.2174/0118723128377799250214075521","DOIUrl":"10.2174/0118723128377799250214075521","url":null,"abstract":"<p><p>Sphingolipids are bioactive lipids that are essential for cellular functions like signaling, apoptosis, and proliferation. They are also important in the biology of cancer. The complex dynamics of sphingolipid metabolism and its consequences for the advancement of cancer are examined in this review. It highlights the regulatory functions of important enzymes such as ceramide kinase (CERK) and sphingosine kinases (SPHKs) in preserving the equilibrium between sphingosine-1-phosphate (S1P), a pro-survival chemical, and ceramides, which encourage cell death. Tumour growth, metastasis, and treatment resistance are all significantly affected by disturbances in this equilibrium. The review emphasizes the potential of sphingolipids as biomarkers for cancer prognosis and stratification, providing information on the course of the disease and the effectiveness of treatment. Their crucial functions in cellular signalling pathways that affect angiogenesis, immunological evasion, and drug resistance, all of which are linked to cancer, are also reviewed. Their role in the tumor microenvironment further highlights sphingolipids' significance as targets for novel therapeutic approaches. Improved clinical results and personalized cancer treatments are made possible by developments in sphingolipid biology and their potential as biomarkers. This thorough synthesis provides the groundwork for further studies that will use sphingolipid metabolism and signalling to create potent cancer treatments. In the fight against cancer, we can improve therapeutic efficacy and diagnostic accuracy by understanding these intricate relationships.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"18 1","pages":"35-53"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantification of Lobeglitazone Sulfate in Bulk and Tablet Dosage Form by a Validated UV Spectroscopy Method: A New Thiazolidinedione Anti-diabetic Drug","authors":"Saradhkumar Mudaliar, Sanjay Sharma","doi":"10.2174/0118723128319462240614111627","DOIUrl":"https://doi.org/10.2174/0118723128319462240614111627","url":null,"abstract":"\u0000\u0000Lobeglitazone sulfate is a novel thiazolidinedione drug used for the therapy of type 2 diabetes. Recent pre-clinical studies show that the drug is also effective in attenuating mucus hypersecretion and airway inflammation caused due to ovalbumin-induced asthma.\u0000\u0000\u0000\u0000This study aimed to develop an accurate, simple, and cost-effective analytical method for the quantification of lobeglitazone sulfate in bulk and pharmaceutical dosage forms by UV spectrophotometric technique.\u0000\u0000\u0000\u0000The drug was identified by FTIR (ATR) instrument and the method development was performed with methanol as the solvent. In compliance with the ICH Q2(R2) guidelines, all the important validation parameters, such as linearity, accuracy, Limit of Detection (LOD), precision, specificity, Limit of Quantification (LOQ), and robustness were deter-mined.\u0000\u0000\u0000\u0000The maximum absorption wavelength of lobeglitazone sulfate was found to be 248 nm. The linearity range was established from 2-14 μg/mL with a linearity equation of y = 0.0361x + 0.0024 and r² = 0.9987. The accuracy of the analytical method was found to be in the range of 99.37-100.41%. The precision studies were performed under three subsets of re-peatability, intra-day, and inter-day, and the results recorded were within the acceptance lim-its, i.e., %RSD (<2%). The developed analytical method's Limit of Detection (LOD) and Limit of Quantification (LOQ) values were 0.07 μg/mL and 0.22 μg/mL, respectively.\u0000\u0000\u0000\u0000The developed analytical method has been found to be valuable in regular qual-ity control analysis of lobeglitazone sulfate in pharmaceutical industries. The adopted ap-proach of the developed method has been found to be facile, accurate, precise, and economi-cal.\u0000","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"114 35","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141668247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid, Simple and Low-Cost Analytical Method Development for Quantification of Eltrombopag Olamine in Tablet dosage by UV Spectroscopy\u0000Method","authors":"Nandan Godani, Sanjay Sharma","doi":"10.2174/0118723128289305240404070703","DOIUrl":"https://doi.org/10.2174/0118723128289305240404070703","url":null,"abstract":"\u0000\u0000Eltrombopag Olamine is a drug used to treat thrombocytopenia, a disorder where blood platelet counts get lower and severe aplastic anemia. It serves as a thrombopoietin receptor agonist, which give rise to platelet production in the bone marrow\u0000\u0000\u0000\u0000The objective of this study is to develop a simple, specific, accurate, precise and\u0000economical Ultraviolet spectroscopy method to estimate the amount of Eltrombopag Olamine in\u0000bulk and tablet dosage form.\u0000\u0000\u0000\u0000The developed method was performed using methanol for identification and physicochemical characterization of the drug. The validation parameters like linearity, precision, accuracy, robustness limits of detection and quantitation, and specificity were assessed as per ICH\u0000Q2 (R2).\u0000\u0000\u0000\u0000The maximum absorbance wavelength (λmax) of the drug was found at 247 nm in\u0000methanol. The linearity was found in the concentration range of 2-14 μg/ml with regression\u0000equation y = 0.0619x - 0.0123 and r² = 0.999. The standard addition method was used to determine the accuracy of the developed method. The result was found in the % recovery range of\u000098-99%. The precision was done on λmax with respect to the parameters such as repeatability,\u0000intraday, and interday. The method was found to be precise as the % RSD value was found to be\u0000<2%. The detection limit value (LOD) and quantitation limit value (LOQ) were 0.0524 µg/ml\u0000and 0.1588 µg/ml, respectively.\u0000\u0000\u0000\u0000The developed method is simple, economical, accurate and selective. The developed method was adaptable for the estimation of Eltrombopag Olamine analysis in pharmaceutical dosage form and routine quality control laboratory.\u0000","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140695088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stability Indicating Method Development and Validation for the\u0000Estimation of Bempedoic Acid by RP-HPLC","authors":"Mansi V. Chaudhari, Ujwala Chaudhari, J. K. Sahu, S. Bagade","doi":"10.2174/0118723128278080240404052506","DOIUrl":"https://doi.org/10.2174/0118723128278080240404052506","url":null,"abstract":"\u0000\u0000Bempedoic acid (BEM) belongs to a category of drugs known as\u0000Adenosine triphosphate-citrate Lyase (ACL) inhibitors. It is a prodrug with intracellular activation that is administered orally. Bempedoic acid is used to treat existing atherosclerotic\u0000cardiovascular diseases, mainly hypercholesterolemia.\u0000\u0000\u0000\u0000For the stability-indicating assay, the HPLC method was employed using a Kromasil 100-5-C8 column (100 mm × 4.6 mm), a UV detector set at 230 nm, and a mobile\u0000phase comprising a 70:30 v/v mixture of acetonitrile and 0.1% Orthophosphoric Acid (OPA)\u0000buffer. The method was operated at an ambient temperature with a flow rate of 1 mL/min.\u0000The method developed has been statistically validated according to ICH guidelines.\u0000\u0000\u0000\u0000The stability-indicating method was executed using a Kromasil 100-5-C8 (100 mm\u0000× 4.6 mm) column at a 1.0 mL/min flow rate. A mixture of acetonitrile and 0.1% Orthophosphoric Acid (OPA) buffer in a 70:30 v/v ratio made up the mobile phase. BEM's retention times were discovered to be 1.88 minutes each. The temperature was kept at room temperature. 234 nm was the ideal wavelength for BEM. According to ICH criteria, the approach developed has undergone statistical validation. BEM's % RSD was discovered to be\u00000.6, respectively. For BEM, the % recovery was determined to be 100.0%. Regression models for bempedoic acid yielded LoD and LoQ values of 3.3 and 10.1 g/mL, respectively. The\u0000method showed good reproducibility and recovery with a % RSD less than 2. Studies on\u0000forced degradation confirmed the method's capacity to indicate stability in the presence of\u0000stress conditions, such as acid, basic, peroxide, UV, heat, and humidity. Both the retention\u0000times and the run time were shortened.\u0000\u0000\u0000\u0000In accordance with ICH Q2 (R1) guidelines, this method was successfully tested with HPLC to confirm the chemical structures of newly produced degradation products of\u0000bempedoic acid.\u0000","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"7 17","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140696218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantum Computing Assays: Advancing Drug Metabolism Studies and Drug Delivery Design.","authors":"Dilpreet Singh","doi":"10.2174/0118723128358210250219103853","DOIUrl":"10.2174/0118723128358210250219103853","url":null,"abstract":"<p><p>Quantum computing is poised to advance drug metabolism studies and drug delivery system design by providing unparalleled precision in simulating molecular interactions and optimizing therapeutic strategies. In drug metabolism, quantum algorithms allow for the accurate modeling of complex enzyme dynamics, such as those involving cytochrome P450 enzymes, which play a pivotal role in drug biotransformation. These simulations offer insights into metabolic pathways, helping predict drug efficacy, potential toxicities, and interactions with other compounds. Additionally, quantum computing is transforming drug delivery system design by enhancing the development of nanocarriers, optimizing their targeting and release profiles, and minimizing off-target effects. Quantum models enable more efficient design of nanoparticles, liposomes, and other carriers by simulating their interactions with biological environments at the atomic level. Together, these innovations enable faster, more personalized drug development, reducing the need for extensive testing and offering a path toward safer, more effective treatments for complex diseases.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"17 3","pages":"99-103"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP1A2*F Polymorphism Contributes at Least Partially to the Variability of Plasma Levels of Dehydroaripiprazole, an Active Metabolite of Aripiprazole, in Schizophrenic Patients.","authors":"Takeshi Suzuki, Goyo Nagai, Kazuo Mihara, Yoko Tomori, Shoko Kagawa, Akifumi Nakamura, Kenji Nemoto, Tsuyoshi Kondo","doi":"10.2174/0118723128246698230921095141","DOIUrl":"10.2174/0118723128246698230921095141","url":null,"abstract":"<p><strong>Aim: </strong>The relationship between CYP1A2 polymorphisms and the steady-state plasma levels of aripiprazole and its active metabolite, dehydroaripiprazole, were investigated in Japanese schizophrenic patients.</p><p><strong>Background: </strong>It has been implied that cytochrome P450 (CYP) 1A2 may play a role in the metabo-lism of aripiprazole. Genetic variations in the <i>CYP1A2</i> gene have been reported.</p><p><strong>Objective: </strong>The authors investigated the relationship between 2 <i>CYP1A2</i> polymorphisms, <i>CYP1A2*C (-3860G>A) and CYP1A2*F (-163C>A)</i>, and the steady-state plasma levels/dose (C/D) ratios of aripiprazole and dehydroaripiprazole in Japanese schizophrenic patients.</p><p><strong>Methods: </strong>All 89 subjects (46 males and 43 females) had been receiving 2 fixed daily doses of aripiprazole (24 mg; n=56 and 12 mg: n=33) for more than 2 weeks. No other drugs were used except flunitrazepam and biperiden. The plasma drug levels were determined by LC/MS/MS. These CYP1A2 polymorphisms were detected using polymerase chain reaction analysis.</p><p><strong>Results: </strong>The mean C/D ratios of dehydroaripiprazole were significantly (P < 0.05) lower in patients with the A/A allele of CYP1A2*F than in those without the allele. No differences were found in the values of aripiprazole and the combination of aripiprazole and dehydroaripiprazole among the <i>CYP1A2</i>*F genotype. There were no differences in the values of aripiprazole, dehydroaripiprazole, or the combination of the 2 compounds among the <i>CYP1A2</i>*C genotype. The absence of the A allele of <i>CYP1A2</i>*F was correlated with the mean C/D ratios of dehydroaripiprazole (standardized partial correlation coefficient = 0.276, P < 0.01) by multiple regression analysis.</p><p><strong>Conclusion: </strong>The findings of this study suggest that the <i>CYP1A2</i>*F polymorphism contributes at least partially to the variability in the steady-state plasma levels of dehydroaripiprazole.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":" ","pages":"7-12"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49685730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimulatory and Inhibitory Effect of Antipsychotic Agents Including Dopaminergic Neuro-depressants on Dopamine Formation from <i>p</i>-tyramine Mediated by Cytochrome P450 2D6.","authors":"Toshiro Niwa, Yuka Yamamoto","doi":"10.2174/2949681016666230914115021","DOIUrl":"10.2174/2949681016666230914115021","url":null,"abstract":"<p><strong>Background and objectives: </strong>The effects of antipsychotic agents, including dopamine D2 receptor blocking agents such as haloperidol, chlorpromazine, and sulpiride, and related compounds such as mirtazapine and sertraline, on dopamine formation from p-tyramine catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared with those of CYP2D6.1.</p><p><strong>Methods: </strong>Dopamine was determined by high-performance liquid chromatography, and Michaelis constants (K_m), maximal velocity (k_cat) values for dopamine formation, and inhibition constants (Ki) of psychotropic agents were estimated.</p><p><strong>Results: </strong>K_m values for all CYP2D6 variants decreased at lower concentrations, and kcat values for CYP2D6 variants except for CYP2D6.10 gradually increased with increasing haloperidol concentrations up to 5 or 10 μM. The k_cat/K_m values for all CYP2D6 variants increased at under 2.5 μM concentrations. Lower sertraline concentrations decreased K_m values for CYP2D6.10. Chlorpromazine at concentrations under 10 μM competitively inhibited the activities catalyzed by all variants; however, the activities for only CYP2D6.10 were increased by chlorpromazine at concentrations over 250 μM. Mirtazapine and sertraline similarly decreased dopamine formation among all variants except for CYP2D6.10. However, CYP2D6.10 inhibition by mirtazapine was weaker than that of the other variants, and sertraline decreased K_m values for CYP2D6.10.</p><p><strong>Conclusion: </strong>Haloperidol and sertraline, but not sulpiride, decreased the Km and/or increased kcat values for CYP2D6. The present findings suggest that Dopamine D₂ receptor-blocking agents and related compounds may polymorphically affect dopamine formation catalyzed by CYP2D6 in the brain.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":" ","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10234830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analyzing Interaction of Rhodacyanine Inhibitor 'MKT-077' with <i>Plasmodium falciparum</i> HSP70s.","authors":"Kumari Chanchal Nainani, Vipul Upadhyay, Bikramjit Singh, Komalpreet Kaur Sandhu, Satinder Kaur, Rachna Hora, Prakash Chandra Mishra","doi":"10.2174/0118723128279697231226044406","DOIUrl":"10.2174/0118723128279697231226044406","url":null,"abstract":"<p><strong>Introduction: </strong>MKT-077 and its derivatives are rhodacyanine inhibitors that hold potential in the treatment of cancer, neurodegenerative diseases and malaria. These allosteric drugs act by inhibiting the ATPase action of heat shock proteins of 70 kDa (HSP70). MKT-077 accumulates in the mitochondria and displays differential activity against HSP70 homologs.</p><p><strong>Methods: </strong>The four <i>Plasmodium falciparum</i> HSP70s (PfHSP70) are present in various subcellular locations to perform distinct functions. In the present study, we have used bioinformatics tools to understand the interaction of MKT-077 at the ADP and HEW (2-amino 4 bromopyridine) binding sites on PfHSP70s. Our molecular docking experiments predict that the mitochondrial and endoplasmic reticulum PfHSP70 homologs are likely to bind MKT-077 with higher affinities at their ADP binding sites.</p><p><strong>Results: </strong>Binding analysis indicates that the nature of the identified interactions is primarily hydrophobic. We have also identified specific residues of PfHSP70s that are involved in interacting with the ligand.</p><p><strong>Conclusion: </strong>Information obtained in this study may form the foundation for the design and development of MKT-077-based drugs against malaria.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":" ","pages":"34-41"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139479701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Species-specific Bioactivation of Morpholines as a Causative of Drug Induced Liver Injury Observed in Monkeys.","authors":"Mithat Gunduz, Upendra A Argikar, Amanda L Cirello, Alan P Brown, Simone Bonazzi, Markus Walles","doi":"10.2174/0118723128260455231104180653","DOIUrl":"10.2174/0118723128260455231104180653","url":null,"abstract":"<p><strong>Background: </strong>Everolimus, an allosteric mechanistic target of rapamycin (mTOR) inhibitor, recently demonstrated the therapeutic value of mTOR inhibitors for Central Nervous System (CNS) indications driven by hyperactivation of mTOR. A newer, potent brain-penetrant analog of everolimus, referred to as (1) in this manuscript [(S)-3-methyl-4-(7-((R)-3-methylmorpholino)-2- (thiazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)morpholine,(1)] catalytically inhibits mTOR function in the brain and increases the lifespan of mice with neuronal mTOR hyperactivation.</p><p><strong>Introduction: </strong>Early evaluation of the safety of 1 was conducted in cynomolgus monkeys in which oral doses were administered to three animals in a rising-dose fashion (from 2 to 30 mg/kg/day). 1 produced severe toxicity including the evidence of hepatic toxicity, along with non-dose proportional increases in drug exposure. Investigations of cross-species hepatic bioactivation of 1 were conducted to assess whether the formation of reactive drug metabolites was associated with the mechanism of liver toxicity.</p><p><strong>Methods: </strong>1 contained two morpholine rings known as structural alerts and can potentially form reactive intermediates through oxidative metabolism. Bioactivation of 1 was investigated in rat, human and monkey liver microsomes fortified with trapping agents such as methoxylamine or potassium cyanide.</p><p><strong>Results: </strong>Our results suggest that bioactivation of the morpholine moieties to reactive intermediates may have been involved in the mechanism of liver toxicity observed with 1. Aldehyde intermediates trappable by methoxylamine were identified in rat and monkey liver microsomal studies. In addition, a total of four cyano conjugates arising from the formation of iminium ion intermediates were observed and identified. These findings may potentially explain the observed monkey toxicity. Interestingly, methoxylamine or cyano adducts of 1 were not observed in human liver microsomes.</p><p><strong>Conclusion: </strong>The bioactivation of 1 appears to be species-specific. Circumstantial evidence for the toxicity derived from 1 point to the formation of iminium ion intermediates trappable by cyanide in monkey liver microsomes. The cyano conjugates were only observed in monkey liver microsomes, potentially pointing to cause at least the hepatotoxicity observed in monkeys. In contrast, methoxylamine conjugates were detected in both rat and monkey liver microsomes, with only a trace amount in human liver microsomes. Cyano conjugates were not observed in human liver microsomes, challenging the team on the drugability and progressivity of 1 through drug development. The mechanisms for drug-induced liver toxicity are multifactorial. These results are highly suggestive that the iminium ion may be an important component in the mechanism of liver toxicity 1 observed in the monkey.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":" ","pages":"13-22"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}