Drug Metabolism and Disposition最新文献

{"title":"Quantitative clinical risk assessment of CYP2C, UDP-glucuronosyltransferase, P-glycoprotein induction, and complex drug-drug interactions using TruVivo human hepatocyte triculture platform.","authors":"Diane Ramsden, Cody L Fullenwider, Cipriano Santos, Edward L LeCluyse","doi":"10.1016/j.dmd.2025.100052","DOIUrl":"https://doi.org/10.1016/j.dmd.2025.100052","url":null,"abstract":"<p><p>Quantitative prediction and clinical risk assessment for induction of drug-metabolizing enzymes and transporters beyond CYP3A has been hindered by low dynamic response in the gold standard hepatocyte monoculture model. A gap in translation of the drug-drug interaction (DDI) potential of a compound is particularly apparent when an inducer also inhibits CYP3A, leading to uncertainty in the potential net clinical outcome for CYP3A substrates. In addition, enzymes such as CYP2C8, CYP2C9, CYP2C19, UGT1A4, and P-glycoprotein, which are coregulated with CYP3A, may result in clinically relevant induction that cannot be derisked by conducting clinical interaction studies with CYP3A substrates. Identification of an in vitro model that demonstrates consistent and well defined induction of enzymes and transporters beyond CYP3A would open the opportunity to avoid unnecessary clinical interaction studies and subsequently have high value in the drug discovery and development toolbox. The TruVivo model is a novel all-human primary cell model, containing hepatocytes plus stromal and epithelial feeder cells. Within these studies, the TruVivo model was validated as a predictive tool for clinical risk assessment for induction of CYP2C8, CYP2C9, CYP2C19, CYP3A4, UGT1A4, and P-glycoprotein using known clinical inducers. Exploration into the utility of TruVivo to delineate complex DDI involving coinducers/inhibitors was also conducted and showed immense opportunity, demonstrating the value of in situ DDI experiments when clinically relevant levels of precipitant and object drugs are used. These data highlight the potential of this in vitro tool to model induction and complex DDI. SIGNIFICANCE STATEMENT: Clinical risk assessment for induction of enzymes and transporters coregulated with CYP3A, including the CYP2C enzymes, UDP-glucuronosyltransferases, and P-gp has been hampered by the low dynamic response of available in vitro models. These studies aimed to validate a novel all-human hepatocyte model, TruVivo, as a predictive tool for induction-based DDI. In addition, the model was evaluated for in situ prediction of complex DDI and shows promise in predicting net clinical outcomes for several inducers/inhibitors against selective and nonselective CYP3A substrates.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 4","pages":"100052"},"PeriodicalIF":4.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709001","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":"Improved clearance predictions for aldehyde oxidase substrates using a novel triculture human hepatocyte model.","authors":"Alexander Byer-Alcorace, Cody Thomas, Mitchell E Taub, Stephanie Piekos","doi":"10.1016/j.dmd.2025.100051","DOIUrl":"https://doi.org/10.1016/j.dmd.2025.100051","url":null,"abstract":"<p><p>Over the last several decades, efforts in medicinal chemistry have aimed to reduce the extent of CYP metabolism of new chemical entities. This approach, however, has led to increased susceptibility to metabolism by non-CYP-mediated pathways, particularly involving other phase I enzymes such as aldehyde oxidase (AO). Commonly used in vitro models, such as suspended or cocultured primary human hepatocytes, have limitations in evaluating the disposition of compounds metabolized by AO due to low or variable levels of enzyme activity. Thus, an in vitro model that exhibits high to moderate levels of AO activity that can better predict the contribution of AO to drug metabolism and its impact on drug clearance is needed. A novel, 2D+ primary human hepatocyte model, TruVivo, was evaluated for its potential utility to improve hepatic clearance (CL_h) predictions and determine the contribution of AO to drug metabolism in humans. TruVivo demonstrated stable levels of AO activity for at least 2 weeks that were higher than levels in other hepatocyte models. CL_h predictions generated using TruVivo for the reference compounds carbazeran, zoniporide, zaleplon, and O6-benzylguanine were within 2-fold of reported in vivo CL values. Furthermore, the estimated fraction metabolized by AO for zaleplon and zoniporide was within 25% of reported in vivo values, whereas that for carbazeran and O6-benzylguanine was similar to those generated in other systems. These findings suggest TruVivo may offer a novel means to assess CL_h of AO substrates more accurately, even over extended incubation times for low clearance compounds. SIGNIFICANCE STATEMENT: The TruVivo in vitro primary human hepatocyte model maintains high levels of aldehyde oxidase (AO) activity for at least 14 days in culture, making the system suitable for evaluating slowly metabolized compounds, particularly those metabolized by AO. This novel system may therefore be useful for improving human clearance predictions for AO substrates.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 4","pages":"100051"},"PeriodicalIF":4.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729314","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":"Quantitative prediction of drug disposition for uridine diphosphate-glucuronosyltransferase substrates using humanized mice.","authors":"Taiji Miyake, Yuito Fujita, Manabu Hirabayashi, Natsuko Komiyama, Keiichi Morita, Tatsuhiko Tachibana, Kimio Terao","doi":"10.1016/j.dmd.2025.100050","DOIUrl":"https://doi.org/10.1016/j.dmd.2025.100050","url":null,"abstract":"<p><p>Drug clearance and drug-drug interactions are essential for pharmacokinetic assessment. However, current in vitro systems and animal scale-up approaches often fail to accurately predict drug disposition mediated by metabolizing enzymes, especially uridine diphosphate-glucuronosyltransferase (UGT). This study demonstrates how UGT-mediated drug disposition in humans can be predicted using hu-PXB mice (cDNA-uPA/severe combined immunodeficiency (SCID) mice transplanted with human-derived hepatocytes). To estimate human hepatic intrinsic clearance (CL_h,int) in vitro, UGT substrates (acetaminophen, entacapone, ketoprofen, lorazepam, oxazepam, posaconazole, and zidovudine) were incubated with cryopreserved human hepatocytes. CL_h,int was calculated based on the rate of substrate disappearance. In vivo human CL_h,int values were calculated based on literature. To evaluate human CL_h,int predictability, the 7 substrates were administered independently and intravenously to hu-PXB and SCID mice. We calculated the CL_h,int in the mice and compared it with that in humans. For predicting UGT-mediated drug-drug interactions, 2 UGT substrates were administered intravenously to hu-PXB mice with or without probenecid (a UGT inhibitor). We compared the changes in clearance with those in humans. The in vitro assay using hepatocytes significantly underpredicted CL_h,int in humans. Hu-PXB mice had a much better correlation with humans in CL_h,int (R² = 0.95) compared with SCID mice (R² = 0.69). Hu-PXB mice predicted the CL_h,int of UGT substrate drugs within 2-fold of the clinical values for every compound we evaluated. The decrease in clearance caused by probenecid in hu-PXB mice reflected that in humans. Our findings demonstrate that human drug disposition mediated by UGT can be predicted based on the in vivo studies using hu-PXB mice. SIGNIFICANCE STATEMENT: Human liver chimeric mice can accurately predict the clearance of uridine diphosphate-glucuronosyltransferase (UGT) substrate drugs and are likely to predict the magnitude of UGT-mediated drug-drug interactions. Findings from in vivo studies in humanized mice enable the selection of better candidates in drug discovery and allow for the more precise physiologically based pharmacokinetic modeling of UGT substrate drugs in clinical practice.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 4","pages":"100050"},"PeriodicalIF":4.4,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575556","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":"Species-specific in vivo exposure assessment and in vivo-in vitro correlation of the carboxylate esters prodrug HD56 targeting FK506 binding proteins: The pivotal role of humanized mice.","authors":"Mengmeng Yang, Shi Yao, Wenpeng Zhang, Taiyun Zhao, Cong Li, Hengxiao Ai, Xia Wu, Junhai Xiao, Xiaomei Zhuang","doi":"10.1016/j.dmd.2025.100049","DOIUrl":"https://doi.org/10.1016/j.dmd.2025.100049","url":null,"abstract":"<p><p>HD561, which was designed to enhance nerve growth, was re-engineered into HD56, a carboxylic acid ester prodrug. The goal of this study was to compare the druggability, species differences, and the correlation between in vitro and in vivo transformation of HD56 to HD561 from a pharmacokinetic (PK) perspective, offering a scientific basis for HD56's clinical research. The bidirectional transmembrane transport of HD56 and HD561 was investigated using Caco-2 cells and LLC-PK1 cells overexpressing MDR1 monolayer cells. Recombinant enzymes and chemical inhibition methods were employed to identify the reaction phenotyping. The conversion of HD56 to HD561 was compared in hepatic and intestinal microsomes, as well as plasma, across different species, including humans, rats, monkeys, and mice with humanized liver. PK studies were conducted in rats, monkeys, and mice with different humanized liver proportions (Hu-URG, Hu-URG-Low, and Hu-URG-High). Finally, an in vivo-in vitro correlation was established between the conversion rate of HD56 to HD561. Results showed that HD56 had better permeability than HD561. HD56 could be hydrolyzed by carboxylesterase 1 to HD561 and be metabolized by cytochrome P450 isoenzymes, while HD561 underwent further metabolism via CYP2C9. Significant species differences existed, and a good in vivo-in vitro correlation was only achieved in humanized mice (r = 0.98). Both in vitro and in vivo PK characteristics of HD56 were remarkably superior to those of HD561, suggesting that HD56 held promise for development. Humanized liver mice serve as a powerful model to address the issue of species differences in ester prodrugs. SIGNIFICANCE STATEMENT: Prodrug HD56 showed superior pharmacokinetic properties compared with the active compound HD561, guiding similar prodrug research. The use of chimeric mice with human hepatocytes, for the first time, to study carboxylesterase (CES) prodrug HD56 provides a model that closely mimics human metabolism. Findings deepen understanding of HD56's behavior and offer a predictive tool for CES prodrugs' metabolic fate, streamlining drug development and improving preclinical accuracy.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 4","pages":"100049"},"PeriodicalIF":4.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613941","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":"Deciphering the cell type-specific and zonal distribution of drug-metabolizing enzymes, transporters, and transcription factors in livers of mice using single-cell transcriptomics.","authors":"Joe Jongpyo Lim, Curtis Dean Klaassen, Julia Yue Cui","doi":"10.1016/j.dmd.2024.100029","DOIUrl":"10.1016/j.dmd.2024.100029","url":null,"abstract":"<p><p>The liver contains multiple cell types, including resident cell types and immune cells. The liver is also categorized into 3 zones: periportal (zone 1), midzonal (zone 2), and centrilobular (zone 3). The goal of this study was to characterize the distribution of drug-processing genes (DPGs) in mouse liver using published single-cell and nuclei transcriptomic datasets, which were subjected to zonal deconvolution. Filtering, normalization, clustering, and differential expression analyses were performed using Seurat V5 in R. Hepatocytes were assigned to 3 zones based on known zonal markers and validated with published spatial transcriptomics data. Among the 195 DPGs profiled, most were expressed highest in hepatocytes (61.3%). Interestingly, certain DPGs were expressed most highly in nonparenchymal cells, such as in cholangiocytes (11.2%, eg, carboxylesterase [Ces] 2e, Ces2g), endothelial cells (7.2%, eg, aldo-keto reductase [Akr] 1c19, Akr1e1), Kupffer cells (5.3%, eg, Akr1a1, Akr1b10), stellate cells (5.1%, eg, retinoic acid receptor [Rar] α, Rarβ), myofibroblasts (2.9%, RAR-related orphan receptor [Rar] α), and a few were expressed in immune cell types. In hepatocytes, 72.4% of phase-I enzymes were enriched in zone 3. Phase-II conjugation enzymes such as UDP-glucuronosyltransferases (75%) were enriched in zone 3, whereas sulfotransferases (40%) were enriched in zone 1. Hepatic xenobiotic transporters were enriched in zone 3. The xenobiotic biotransformation-regulating transcription factors were enriched in zone 3 hepatocytes. The enrichment of DPGs in liver cell types, including non-parenchymal cells and zone 1 hepatocytes, may serve as an additional repertoire for xenobiotic biotransformation. SIGNIFICANCE STATEMENT: Our study is among the first to systematically characterize the baseline mRNA enrichment of important drug-processing genes in different cell types and zones in the liver. This finding will aid in further understanding the mechanisms of chemical-induced liver injury with improved resolution and precision.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100029"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370726","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":"Identification and characterization of a novel ergothioneine conjugate of raloxifene.","authors":"Abhijith Rao, Sivaprasad Putluru, Prasanth Eapen, Hemantha Kumar, Raviraj Landge, Khemraj Bairwa, Srikanth Sridhar, T Thanga Mariappan, Michael Sinz, Prakash Vachaspati","doi":"10.1016/j.dmd.2024.100034","DOIUrl":"10.1016/j.dmd.2024.100034","url":null,"abstract":"<p><p>Raloxifene (RX) in the presence of liver microsomes and glutathione (GSH) has shown oxidative bioactivation to reactive intermediates that are conjugated by GSH. L-Ergothioneine (ET) is a naturally occurring sulfhydryl amino acid, similar to GSH, derived from dietary sources with antioxidant properties and reported to accumulate in high concentrations in animals and humans. We hypothesized that ET may have detoxification/conjugation properties similar to GSH. Using rat and human liver microsomes and mouse, rat, dog, monkey, and human hepatocytes, a novel ergothioneine conjugate of raloxifene (RX-ET) (M1) was identified by mass spectrometry. The RX-ET conjugate was further scaled up in rat liver microsomes, isolated, and characterized by high-resolution mass spectrometry and NMR to confirm the structure. A single RX-ET conjugate was characterized and the site of ET conjugation was identified at the C-17 position of RX. The in vivo relevance of this unique conjugate was also established through metabolism studies in intact and bile duct cannulated rats, both untreated and pretreated with ET. In general, the RX-ET conjugate was found in trace amounts in plasma and urine, but in higher concentrations in bile and feces. The major elimination pathway of RX-ET was through biliary elimination. In rats that were pretreated with ET prior to RX administration, significantly larger quantities of ET and RX-ET conjugate were found in in vivo samples. Lastly, these studies suggest that ET conjugation is an additional pathway for scavenging reactive species arising from xenobiotics and may potentially reduce drug-related toxicities. SIGNIFICANCE STATEMENT: Ergothioneine is well known for its antioxidant and free radical scavenging activity. This study identifies its role in conjugating the reactive species arising from the bioactivation of raloxifene in vitro and in vivo suggesting that ergothioneine may act as an additional conjugation pathway similar to glutathione in the disposition of reactive centers or metabolites of xenobiotics.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100034"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373911","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":"Decreased expression of P-glycoprotein in the placenta of women with autoimmune disease.","authors":"Angela Pollinzi, Kamelia Mirdamadi, Navaz Karimian Pour, Rashi Asthana-Nijjar, Dennis Lee, Ori Nevo, Micheline Piquette-Miller","doi":"10.1016/j.dmd.2024.100031","DOIUrl":"https://doi.org/10.1016/j.dmd.2024.100031","url":null,"abstract":"<p><p>Autoimmune diseases (ADs), such as systemic lupus erythematosus (SLE), require multiple medications to ensure maternal-fetal health during pregnancy. These medications are often substrates for placental transporters that could cross over to the fetal compartment. However, the effects of ADs on placental transporters remain poorly understood. This study aimed to investigate the impact of ADs on placental transporters and key inflammatory cytokines. Human preterm and term placentas from AD-affected women (n = 28) and gestational age-matched controls (n = 38) were collected. The placentas were examined for transporter expression via quantitative real-time PCR and immunodetection. Subgroup analysis and untargeted proteomic analysis of samples from patients with SLE were performed. P-glycoprotein (P-gp/ABCB1) and organic anion transporter 4 (OAT4/SLC22A11) mRNA expression were significantly decreased and expression of T helper 17- associated cytokines were increased in preterm and term AD placenta relative to controls. P-gp protein expression was also downregulated in preterm, but not in term AD placenta. Subgroup analysis of SLE also detected downregulation of P-gp and OAT4 at the mRNA level in preterm samples. Proteomic analysis of SLE and control samples indicated global changes in proteins related to processes like inflammation, oxidative stress, angiogenesis, and hemostasis. These findings elucidate that ADs such as SLE are associated with the downregulation of the ABC transporter P-gp in the placenta as well as global changes to the placenta proteome. Dysregulation of cytokines and associated pathways was also observed and postulated to cause changes in placental transporters. Future studies that validate these mechanisms could offer potential strategies to mitigate inflammation-mediated alterations in placental transporters, ultimately improving fetal and neonatal health. SIGNIFICANCE STATEMENT: Autoimmune diseases have significant effects on the placenta, influencing pregnancy outcomes and the effectiveness of prescribed medications. The study revealed that autoimmune diseases induce inflammatory cytokines in the placenta and were associated with a significant downregulation of P-glycoprotein. Additionally, in patients affected by lupus, proteomics uncovered the enrichment of pathways associated with placental damage and dysfunction. This work will help inform care plans for these patients by identifying clinically relevant proteins that are affected by the disease, improving maternal-fetal outcomes.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100031"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536513","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":"Cannabidiol and Δ9-tetrahydrocannabinol induce drug-metabolizing enzymes, but not transporters, in human hepatocytes: Implications for predicting complex cannabinoid-drug interactions.","authors":"Ankit Balhara, Yik Pui Tsang, Jashvant D Unadkat","doi":"10.1016/j.dmd.2025.100037","DOIUrl":"10.1016/j.dmd.2025.100037","url":null,"abstract":"<p><p>Cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC) can inhibit multiple CYPs and UGTs in vivo and/or in vitro. CBD, but not THC, is also a time-dependent inhibitor of CYP3A, CYP1A2, and CYP2C19. We showed that a single 640 mg oral dose of CBD inhibits oral midazolam plasma clearance by 56%, whereas others found no interaction of chronic CBD with midazolam. These data can be explained if chronic CBD induces CYP3A enzymes. To investigate if CBD or THC induces CYP enzymes or transporters, we treated 4 lots of human hepatocytes for 72 hours with in vivo relevant concentrations of CBD (42 nM, 420 nM) or THC (250 nM, 700 nM). Then, mRNA expression and CYP activity were measured using quantitative polymerase chain reaction and liquid chromatography-tandem mass spectrometry, respectively. CYP3A4 mRNA was significantly induced to 7.3-, 11.1-, and 3.3-fold by CBD (420 nM) and 14.8-, 5.9-, and 3.1-fold by THC (700 nM) in 3 of the 4 lots. CYP3A activity was significantly induced 3.39- and 3.28-fold by low (42 nM) and 2.4- and 2.3-fold by high (420 nM) CBD concentrations, respectively, in 2 lots, and 2.3-fold by THC (700 nM) in 1 lot. Rifampin (10 μM) significantly induced CYP3A mRNA and activity across all lots. CBD (420 nM) significantly induced CYP1A2 and CYP2B6 mRNA (but not activity) in 2 lots. No significant induction of other CYPs, UGTs, or transporters was observed. Incorporation of CBD E_max and EC₅₀ of CYP3A4 mRNA induction (without scaling by rifampin mRNA induction) into a CBD physiologically-based pharmacokinetic model successfully captured the lack of the observed chronic CBD-midazolam drug interaction. SIGNIFICANCE STATEMENT: Time-dependent inhibition and induction of CYP3A enzymes by cannabidiol (CBD) is a plausible explanation for the significant CBD-midazolam pharmacokinetic interaction after single-dose CBD administration and the absence of such an interaction after multiple-dose CBD administration.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100037"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515055","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":"Improvement in static and dynamic projections of drug-drug interactions caused by cytochrome P4503A time-dependent inhibitors through in vitro allosteric modulation by progesterone.","authors":"Pooja Hegde, Brianna Rodriguez, Alec Bell, Stephen D Hall, Luc R A Rougée","doi":"10.1016/j.dmd.2024.100030","DOIUrl":"https://doi.org/10.1016/j.dmd.2024.100030","url":null,"abstract":"<p><p>Current drug discovery screens to assess the drug-drug interaction (DDI) risk caused by time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 are known to overpredict or produce false positives that do not translate in vivo. Recent work identified that inclusion of the allosteric modulator progesterone (PGS), at a concentration of 45 μM to human liver microsomal incubations, generated in vitro TDI values that replicated clinical DDI predictions for 2 well established mechanism-based inhibitors. Further application of this approach across a diverse set of compounds was undertaken in this study, with 56 molecules reported in literature as time-dependent inhibitors in vitro tested in the human liver microsomal TDI kinetic assay in the absence and presence of 45 μM PGS. No TDI signal was observed for 15 molecules under control conditions despite literature reports. For the remaining compounds observed to have a TDI signal under control conditions, presence of PGS modified the inactivation efficiency for 36 compounds and eliminated the TDI signal for 5 compounds that were false positives. In vitro kinetic values were incorporated into mechanistic static and dynamic physiologically based pharmacokinetic models to project DDIs. TDI parameters established in the presence of PGS decreased the magnitude of overprediction while maintaining a high sensitivity (96% and 100%) for the detection of TDI with improved specificity (69% and 89%) when using mechanistic static and dynamic models, respectively. Inclusion of PGS into in vitro TDI assays provides a simple, rapid, and cost-effective solution for identifying true CYP3A4 TDIs and improving TDI-related DDI predictions. SIGNIFICANCE STATEMENT: The impact of the previously determined optimal concentration of the allosteric modulator progesterone (45 μM) was evaluated across a set of 56 compounds reported to be time-dependent inhibitors in vitro. In vitro generated values were incorporated into mechanistic static and physiologically based pharmacokinetic models to predict extent of drug-drug interactions and compared to clinical reports. Inclusion of progesterone into the assay identified in vitro false positives and improved risk predictions.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100030"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536715","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":"Exploring cytochrome P450 under hypoxia: potential pharmacological significance in drug metabolism and protection against high-altitude diseases.","authors":"Qian Wang, Guiqin Liu, Yabin Duan, Delong Duo, Junbo Zhu, Xiangyang Li","doi":"10.1016/j.dmd.2024.100026","DOIUrl":"https://doi.org/10.1016/j.dmd.2024.100026","url":null,"abstract":"<p><p>High-altitude hypoxia affects the human respiratory, central nervous, cardiovascular, and endocrine systems. These outcomes affect the expression of cytochrome P450 (CYP), the most important family of metabolic enzymes in the body that is involved in the metabolism of both exogenous and endogenous substances (such as arachidonic acid, vitamins, and steroids). Hypoxia influences CYP expression and activity, mediating changes in drug and endogenous substance metabolism, with endogenous metabolites playing a significant role in controlling high-altitude diseases. However, the mechanisms regulating CYP changes under hypoxic conditions and the effects of CYP changes on drug and endogenous metabolism remain unclear. We explored how changes in CYP expression and activity during hypoxia affect the metabolism of drugs and endogenous substances, such as arachidonic acid, vitamins, and steroid hormones, and how CYPs are controlled by nuclear receptors, epigenetic modifications, cytokines, and gut microbiota during hypoxia. Special attention will also be given to the complex role of CYP and its metabolites in the pathophysiology of high-altitude diseases to provide valuable insights for plateau medicine research. SIGNIFICANCE STATEMENT: Cytochrome P450 is a class of monooxygenases that metabolize xenobiotics and endogenous substances. Hypoxia affects the expression and activity of cytochrome P450, and this in turn affects the metabolism of drugs and endogenous substances, leading to altered clinical efficacy and the development of hypoxia-associated diseases. A comprehensive understanding of the changes and regulatory mechanisms of cytochrome P450 under hypoxic conditions can improve therapeutic protocols in hypoxic environments and provide new ideas for the targeted treatment of hypoxic diseases.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100026"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536694","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}