Drug Metabolism and Disposition最新文献

{"title":"Investigating the Correlation between Genotypes and Hepatic Protein Expression of <i>CYP2C9, CYP2C19, CYP2D6,</i> and <i>CYP3A5</i> Using Postmortem Tissue from a Danish Population.","authors":"Kata W Pedersen, Jeppe D Andersen, Jakob Hansen, Claus Børsting, Jytte Banner, Jørgen B Hasselstrøm, Jakob R Jornil","doi":"10.1124/dmd.124.001692","DOIUrl":"10.1124/dmd.124.001692","url":null,"abstract":"<p><p>The cytochrome P450 (CYP) family of enzymes plays a central role in the metabolism of many drugs. CYP genes are highly polymorphic, which is known to affect protein levels, but for some low frequent CYP genotypes the correlation between genotype and CYP protein expression is less established. In this study, we determined the <i>CYP2C9, CYP2C19, CYP2D6,</i> and <i>CYP3A5</i> genotypes of 250 Danish individuals included in a postmortem study. For 116 of the individuals, the hepatic CYP protein levels were investigated by a proteomics approach. Overall, we found the postmortem genetic and proteomic data to be in agreement with those of other studies performed on fresh hepatic tissue, showing the usability of postmortem hepatic tissue for this type of investigation. For less investigated genotypes, we could corroborate previously found results: 1) statistically significantly lower levels of hepatic CYP2C9 protein in individuals carrying the <i>CYP2C9</i>*3 variant compared with individuals with two wild type (wt) alleles; 2) comparable levels of CYP2C19 in <i>CYP2C19*2/*17</i> and <i>CYP2C19*1/*2</i> individuals; 3) reduced CYP2D6 protein levels in heterozygous individuals with the <i>CYP2D6*3</i>, <i>CYP2D6</i>*4, and <i>CYP2D6</i>*5 gene deletion variants; and 4) significantly lower levels of CYP3A5 protein in <i>CYP3A5</i>*3 homozygous individuals compared with individuals who were heterozygous for the <i>CYP3A5</i>*3 allele or homozygous individuals for the wt alleles. In conclusion, the use of postmortem tissue significantly increases the access to human specimens for research purposes, and postmortem proteomics can be used to investigate the link between <i>CYP</i> genotypes and hepatic protein expression. SIGNIFICANCE STATEMENT: In tissue samples from a large postmortem cohort (<i>n</i> = 250) we determined the <i>CYP2C9</i>, <i>CYP2C19</i>, <i>CYP2D6</i>, and <i>CYP3A5</i> genotypes. Hepatic CYP protein levels were investigated in 116 individuals using a proteomics approach. For common genotypes, we found results similar to previous knowledge, pointing toward the usability of postmortem tissue. For the less investigated genotypes, we were able to corroborate genotype/protein expression correlations. It is a novel approach to use a large postmortem cohort to investigate genetic/protein expression correlations.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"975-980"},"PeriodicalIF":4.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I Study To Determine the Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of Capivasertib in Healthy Male Participants.","authors":"Claire Miller, Martin Wild, Zhoupeng Zhang, Roberto Sommavilla, Don Shanahan, Christopher Bailey, Malin Gränfors, Ryan A Bragg, Jin Dong, Sharan Sidhu, Marie Cullberg","doi":"10.1124/dmd.124.001636","DOIUrl":"10.1124/dmd.124.001636","url":null,"abstract":"<p><p>An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [¹⁴C]-radiolabeled intravenous microdose of capivasertib (100 <i>μ</i>g). After a 14-day washout, five of the participants proceeded to part 2 and received a single oral dose of [¹⁴C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period [mean recovery: 95.1% (feces, 50.4%; urine, 44.7%)]. Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. SIGNIFICANCE STATEMENT: This study provides characterization of the pharmacokinetics of capivasertib-a potent, selective AKT serine/threonine kinase (AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"939-948"},"PeriodicalIF":4.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of OATP2B1 on Pharmacokinetics of Atorvastatin Investigated in <i>rSlco2b1</i>-Knockout and <i>SLCO2B1</i>-Knockin Rats.","authors":"Jonny Kinzi, Janine Hussner, Isabell Seibert, Mirubagini Vythilingam, Celina Vonwyl, Clarisse Gherardi, Pascal Detampel, Oliver Schwardt, Daniel Ricklin, Henriette E Meyer Zu Schwabedissen","doi":"10.1124/dmd.124.001686","DOIUrl":"10.1124/dmd.124.001686","url":null,"abstract":"<p><p>The organic anion transporting polypeptide (OATP) 2B1 is considered an emerging drug transporter that is found expressed in pharmacokinetically relevant organs such as the liver, small intestine, and kidney. Despite its interaction with various substrate drugs, the understanding of its in vivo relevance is still limited. In this study, we first validated the interaction of atorvastatin with rat OATP2B1 using transiently transfected HeLa cells. Moreover, we characterized our <i>rSlco2b1</i>-knockout and <i>SLCO2B1</i>-knockin rats for mRNA, protein expression, and localization of OATP2B1 in the liver, small intestine, and kidney. The transporter showed the highest expression in the liver followed by the small intestine. In humanized rats, human OATP2B1 is localized on the sinusoidal membrane of hepatocytes. In enterocytes of wild-type and humanized rats, the transporter was detected in the luminal membrane with the vast majority being localized subapical. Subsequently, we assessed atorvastatin pharmacokinetics in male wild-type, <i>rSlco2b1</i>-knockout, and <i>SLCO2B1</i>-knockin rats after a single-dose administration (orally and intravenously). Investigating the contribution of rat OATP2B1 or human OATP2B1 to oral atorvastatin pharmacokinetics revealed no differences in concentration-time profiles or pharmacokinetic parameters. However, when comparing the pharmacokinetics of atorvastatin after intravenous administration in <i>SLCO2B1</i>-humanized rats and knockout animals, notable differences were observed. In particular, the systemic exposure (area under the curve) decreased by approximately 40% in humanized animals, whereas the clearance was 57% higher in animals expressing human OATP2B1. These findings indicate that human OATP2B1 influences pharmacokinetics of atorvastatin after intravenous administration, most likely by contributing to the hepatic uptake. SIGNIFICANCE STATEMENT: Wild-type, <i>rSlco2b1</i>-knockout, and <i>SLCO2B1</i>-humanized Wistar rats were characterized for the expression of rat and human <i>SLCO2B1</i>/OATP2B1. Pharmacokinetic studies of atorvastatin over 24 hours were conducted in male wild-type, <i>rSlco2b1</i>-knockout, and <i>SLCO2B1</i>-humanized rats. After a single-dose intravenous administration, a lower systemic exposure and an increase in clearance were observed in <i>SLCO2B1</i>-humanized rats compared with knockout animals indicating a contribution of OATP2B1 to the hepatic clearance.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"957-965"},"PeriodicalIF":4.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Enteroid Monolayers: A Novel, Functionally-Stable Model for Investigating Oral Drug Disposition.","authors":"Christopher Arian, Eimear O'Mahony, James W MacDonald, Theo K Bammler, Mark Donowitz, Edward J Kelly, Kenneth E Thummel","doi":"10.1124/dmd.124.001551","DOIUrl":"10.1124/dmd.124.001551","url":null,"abstract":"<p><p>To further the development of an in vitro model which faithfully recapitulates drug disposition of orally administered drugs, we investigated the utility of human enteroid monolayers to simultaneously assess intestinal drug absorption and first-pass metabolism processes. We cultured human enteroid monolayers from three donors, derived via biopsies containing duodenal stem cells that were propagated and then differentiated atop permeable Transwell® inserts, and confirmed transformation into a largely enterocyte population via RNA-seq analysis and immunocytochemical (ICC) assays. Proper cell morphology was assessed and confirmed via bright field microscopy and ICC imaging of tight junction proteins and other apically and basolaterally localized proteins. Enteroid monolayer barrier integrity was demonstrated by elevated transepithelial electrical resistance (TEER) that stabilized after 10 days in culture and persisted for 42 days. These results were corroborated by low paracellular transport probe permeability at 7 and 21 days in culture. The activity of a prominent drug metabolizing enzyme, CYP3A, was confirmed at 7, 21, and 42 days culture under basal, 1α,25(OH)2 vitamin D3-induced, and 6',7'-dihydroxybergamottin-inhibited conditions. The duration of these experiments is particularly noteworthy, as this is the first study assessing drug metabolizing enzymes and transporters (DMET) expression/function for enteroids cultured for greater than 12 days. The sum of these results suggests enteroid monolayers are a promising ex vivo model to investigate and quantitatively predict an orally administered drug's intestinal absorption and/or metabolism. <b>Significance Statement</b> This study presents a novel ex vivo model of the human intestine, human intestinal organoid (enteroid) monolayers, that maintain barrier function and metabolic functionality for up to 42-days in culture. The incorporation of both barrier integrity and metabolic function over an extended period within the same model is an advancement over historically used in vitro systems, which either lack one or both of these attributes or have limited viability.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mass Balance, Metabolic Pathways, Absolute Bioavailability, and Pharmacokinetics of Giredestrant in Healthy Subjects.","authors":"Smita Kshirsagar, Ya-Chi Chen, Jiajie Yu, Mary R Gates, Sonoko Kawakatsu, S Cyrus Khojasteh, Shuguang Ma, Luna Musib, Vikram Malhi, Uyi Osaghae, Jing Wang, Sungjoon Cho, Yang Thomas Tang, Donglu Zhang, Weiping Zhao, Tom De Bruyn","doi":"10.1124/dmd.124.001688","DOIUrl":"10.1124/dmd.124.001688","url":null,"abstract":"<p><p>Giredestrant is a potent and selective small-molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination, and metabolite profile of [¹⁴C]giredestrant. In part 1 (mass balance), a single 30.8-mg oral dose of [¹⁴C]giredestrant (105 µCi) was administered to women of nonchildbearing potential (WNCBP; <i>n</i> = 6). The mean recovery of total radioactivity in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized, with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In part 2 (aBA), WNCBP (<i>n</i> = 10) received an oral (30-mg capsule) or intravenous (30-mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. SIGNIFICANCE STATEMENT: This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, a high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"847-857"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Covalent Binding of Reactive Anhydride of Cantharidin to Biological Amines.","authors":"Yaya Fan, Lin Chen, Qiuyi Jing, Xiaoli Li, Hong Pan, Chao Fang, Jianyong Zhang, Fuguo Shi","doi":"10.1124/dmd.123.001637","DOIUrl":"10.1124/dmd.123.001637","url":null,"abstract":"<p><p>Cantharidin is a terpenoid from coleoptera beetles. Cantharidin has been used to treat molluscum contagiosum and some types of tumors. Cantharidin is highly toxic, and cantharidin poisoning and fatal cases have been reported worldwide. The mechanisms underlying cantharidin-induced toxicity remain unclear. Cantharidin contains anhydride, which may react with biologic amines. This study aimed to examine the chemical reactivity of cantharidin toward nucleophiles and characterize adducts of cantharidin with biologic amines in vitro and in mice. Here two types of conjugates were formed in the incubation of cantharidin under physiologic conditions with free amino acids, a mimic peptide, or amine-containing compounds, respectively. Amide-type conjugates were produced by the binding of cantharidin anhydride with the primary amino group of biologic amines. Imide-type conjugates were generated from the dehydration and cyclization of amide-type conjugates. The structure of the conjugates was characterized by using high-resolution mass spectrometry. We introduced the ¹⁴N/¹⁵N and ⁷⁹Br/⁸¹Br isotope signatures to confirm the formation of conjugates using L-(<i>ε</i>)¹⁵N-lysine, L-lysine-¹⁵N₂, and bromine-tagged hydrazine, respectively. The structure of imide conjugate was also confirmed by nuclear magnetic resonance experiments. Furthermore, the amide and imide conjugates of cantharidin with amino acids or <i>N</i>-acetyl-lysine were detected in mouse liver and urine. Cantharidin was found to modify lysine residue proteins in mouse liver. Pan-cytochrome P450 inhibitor 1-aminobenzotriazole significantly increased the urine cantharidin-<i>N</i>-acetyl-lysine conjugates, whereas it decreased cantharidin metabolites. In summary, cantharidin anhydride can covalently bind to biologic amines nonenzymatically, which facilitates a better understanding of the role of nonenzymatic reactivity in cantharidin poisoning. SIGNIFICANCE STATEMENT: Anhydride moiety of cantharidin can covalently bind to the primary amino group of biological amines nonenzymatically. Amide and imide conjugates were generated after the covalent binding of cantharidin anhydride with the primary amino groups of amino acids, a mimic peptide, and protein lysine residues. The structure of conjugates was confirmed by ¹⁴N/¹⁵N and ⁷⁹Br/⁸¹Br isotope signatures using isotope-tagged reagents and nuclear magnetic resonance experiments. This study will facilitate the understanding of the role of nonenzymatic reactivity in cantharidin poisoning.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"775-784"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Analysis of Histone Acetylation Regulated CYP4F12 in Esophageal Cancer Development.","authors":"Yanhong Chen, Li Wang, Yuchen Wang, Yanyan Fang, Wenyang Shen, Yingxue Si, Xiaoli Zheng, Su Zeng","doi":"10.1124/dmd.124.001674","DOIUrl":"10.1124/dmd.124.001674","url":null,"abstract":"<p><p>Current therapeutic strategies for esophageal cancer (EC) patients have yielded limited improvements in survival rates. Recent research has highlighted the influence of drug metabolism enzymes on both drug response and EC development. Our study aims to identify specific drug metabolism enzymes regulated by histone acetylation and to elucidate its molecular and clinical features. CYP4F12 exhibited a notable upregulation subsequent to trichostatin A treatment as evidenced by RNA sequencing analysis conducted on the KYSE-150 cell line. The change in gene expression was associated with increased acetylation level of histone 3 K18 and K27 in the promoter. The regulation was dependent on p300. In silicon analysis of both The Cancer Genome Atlas esophageal carcinoma and GSE53624 dataset suggested a critical role of CYP4F12 in EC development, because CYP4F12 was downregulated in tumor tissues and predicted better disease-free survival. Gene ontology analysis has uncovered a robust correlation between CYP4F12 and processes related to cell migration, as well as its involvement in cytosine-mediated immune activities. Further investigation into the relationship between immune cells and CYP4F12 expression has indicated an increased level of B cell infiltration in samples with high CYP4F12 expression. CYP4F12 was also negatively correlated with the expression of inhibitory checkpoints. An accurate predictive nomogram model was established combining with clinical factors and CYP4F12 expression. In conclusion, CYP4F12 was crucial in EC development, and targeting CYP4F12 may improve the therapeutic efficacy of current treatment in EC patients. SIGNIFICANCE STATEMENT: CYP4F12 expression was downregulated in esophageal cancer (EC) patients and could be induced by trichostatin A. During EC development, CYP4F12 was linked to reduced cell migration and increased infiltration of B cells. CYP4F12 also is a biomarker as prognostic predictors and therapeutic guide in EC patients.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"813-823"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of Angiotensin II-Induced Cellular Hypertrophy by Cannflavin-C: Unveiling the Impact on Cytochrome P450 1B1 and Arachidonic Acid Metabolites.","authors":"Ahmad H Alammari, Fadumo Ahmed Isse, Conor O'Croinin, Neal M Davies, Ayman O S El-Kadi","doi":"10.1124/dmd.124.001705","DOIUrl":"10.1124/dmd.124.001705","url":null,"abstract":"<p><p>This research aimed to clarify the impacts of cannflavin-C on angiotensin II (Ang II)-induced cardiac hypertrophy and their potential role in modulating cytochrome P450 1B1 (CYP1B1) and arachidonic acid (AA) metabolites. Currently there is no evidence to suggest that cannflavin-C, a prenylated flavonoid, has any significant effects on the heart or cardiac hypertrophy. The metabolism of arachidonic acid (AA) into midchain hydroxyeicosatetraenoic acids (HETEs), facilitated by CYP1B1 enzyme, plays a role in the development of cardiac hypertrophy, which is marked by enlarged cardiac cells. Adult human ventricular cardiomyocyte (AC16) cell line was cultured and exposed to cannflavin-C in the presence and absence of Ang II. The assessment of mRNA expression pertaining to cardiac hypertrophic markers and cytochromes P450 (P450s) was conducted via real-time polymerase chain reaction (PCR), whereas the quantification of P450 protein levels was carried out through western blot analysis. Ang II induced hypertrophic markers myosin heavy chain (<i>β</i>/<i>α</i>-MHC), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) and increased cell surface area, whereas cannflavin-C mitigated these effects. Gene and protein expression analysis revealed that cannflavin-C downregulated CYP1B1 gene expression, protein level, and enzyme activity assessed by 7-methoxyresorufin O-deethylase (MROD). Arachidonic acid metabolites analysis, using liquid chromatography-tandem mass spectrometry (LC-MS/MS), demonstrated that Ang II increased midchain (R/S)-HETE concentrations, which were attenuated by cannflavin-C. This study provides novel insights into the potential of cannflavin-C in modulating arachidonic acid metabolites and attenuating Ang II-induced cardiac hypertrophy, highlighting the importance of this compound as potential therapeutic agents for cardiac hypertrophy. SIGNIFICANCE STATEMENT: This study demonstrates that cannflavin-C offers protection against cellular hypertrophy induced by angiotensin II. The significance of this research lies in its novel discovery, which elucidates a mechanistic pathway involving the inhibition of CYP1B1 by cannflavin-C. This discovery opens up new avenues for leveraging this compound in the treatment of heart failure.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"875-885"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Cytochrome P450 2C8*3 Variant (rs11572080) Is Associated with Improved Asthma Symptom Control in Children and Altered Lipid Mediator Production and Inflammatory Response in Human Bronchial Epithelial Cells.","authors":"Marysol Almestica-Roberts, Nam D Nguyen, Lili Sun, Samantha N Serna, Emmanuel Rapp, Katherine L Burrell-Gerbers, Tosifa A Memon, Bryan L Stone, Flory L Nkoy, John G Lamb, Cassandra E Deering-Rice, Joseph E Rower, Christopher A Reilly","doi":"10.1124/dmd.124.001684","DOIUrl":"10.1124/dmd.124.001684","url":null,"abstract":"<p><p>This study investigated an association between the cytochrome P450 (CYP) 2C8*3 polymorphism with asthma symptom control in children and changes in lipid metabolism and pro-inflammatory signaling by human bronchial epithelial cells (HBECs) treated with cigarette smoke condensate (CSC). CYP genes are inherently variable in sequence, and while such variations are known to produce clinically relevant effects on drug pharmacokinetics and pharmacodynamics, the effects on endogenous substrate metabolism and associated physiologic processes are less understood. In this study, CYP2C8*3 was associated with improved asthma symptom control among children: Mean asthma control scores were 3.68 (<i>n</i> = 207) for patients with one or more copies of the CYP2C8*3 allele versus 4.42 (<i>n</i> = 965) for CYP2C8*1/*1 (<i>P</i> = 0.0133). In vitro, CYP2C8*3 was associated with an increase in montelukast 36-hydroxylation and a decrease in linoleic acid metabolism despite lower mRNA and protein expression. Additionally, CYP2C8*3 was associated with reduced mRNA expression of interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL-8) by HBECs in response to CSC, which was replicated using the soluble epoxide hydrolase inhibitor, 12-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]-dodecanoic acid. Interestingly, 9(10)- and 12(13)- dihydroxyoctadecenoic acid, the hydrolyzed metabolites of 9(10)- and 12(13)- epoxyoctadecenoic acid, increased the expression of IL-6 and CXCL-8 mRNA by HBECs. This study reveals previously undocumented effects of the CYP2C8*3 variant on the response of HBECs to exogenous stimuli. SIGNIFICANCE STATEMENT: These findings suggest a role for CYP2C8 in regulating the epoxyoctadecenoic acid:dihydroxyoctadecenoic acid ratio leading to a change in cellular inflammatory responses elicited by environmental stimuli that exacerbate asthma.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"836-846"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpibectir: Early Qualitative and Quantitative Metabolic Profiling from a First-Time-in-Human Study by Combining ¹⁹F-NMR (Nuclear Magnetic Resonance), ¹H-NMR, and High-Resolution Mass Spectrometric Analyses.","authors":"Daniel J Weston, Steve Thomas, Gary W Boyle, Michel Pieren","doi":"10.1124/dmd.124.001562","DOIUrl":"10.1124/dmd.124.001562","url":null,"abstract":"<p><p>Alpibectir (also known as BVL-GSK098 and GSK3729098) is a new chemical entity (NCE) with a novel mechanism for the treatment of tuberculosis. The disposition of alpibectir was determined in subjects from a first-time-in-human trial after a single oral dose of 40 mg and after 7 days repeat dosing at 30 mg. Here we present a combined approach of ¹⁹F-NMR (nuclear magnetic resonance), ¹H-NMR, and high-resolution mass spectrometry (HRMS) to confidently determine the human metabolic fate of alpibectir. Utilizing multiple sites of fluorination in the molecule, it was possible to fractionate human urine and plasma to confidently detect and quantify the metabolite responses using ¹⁹F-NMR. Qualitative detection and structural characterization of F-containing NMR fractions were performed using complementary high-resolution ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) analyses to further add confidence to the metabolite responses in these fractions. Subsequent ¹H-NMR then provided unequivocal standard-free structural confirmation for key metabolites, which would not be possible with conventional radioactivity detection and LC-MS/MS techniques. Alpibectir was shown to undergo extensive hydrolysis of the central amide moiety, where the resultant <i>N</i>-dealkylated amine and trifluorobutyric acid products were detected initially by unbiased ¹⁹F-NMR detection along with major downstream biotransformations to form a carbamoyl glucuronide conjugate and trifluoroacetic acid, respectively. Parallel UHPLC-MS/MS analyses provided confirmatory or additional structural characterization only where relevant. These concerted data allowed for the qualitative metabolic profile and quantitative determination of drug-related material (DRM) in urine and plasma, along with the percentage of dose excreted in urine, to be reported in a comprehensive, efficient, and data-led manner. SIGNIFICANCE STATEMENT: Combining the selectivity of ¹⁹F-NMR (nuclear magnetic resonance) for unfractionated samples as first-intent, data-led sample fractionation prior to ¹⁹F-NMR and structure-rich ¹H-NMR detection, along with the sensitivity of high-resolution ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS), a novel alternative for time-efficient detection and quantification of drug-related material (DRM) in human without use of radiolabeled drug is reported. This allowed more complete data rationalization of human metabolism, permitting early risk assessment and progression of the development of antitubercular agent, alpibectir.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"858-874"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}