Drug Metabolism and Disposition最新文献

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Human enteroid monolayers: A novel, functionally stable model for investigating oral drug disposition. 人类肠道单分子层:一种新的,功能稳定的模型,用于研究口服药物处置。
IF 4.4 3区 医学
Drug Metabolism and Disposition Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/dmd.124.001551
Christopher Arian, Eimear O'Mahony, James W MacDonald, Theo K Bammler, Mark Donowitz, Edward J Kelly, Kenneth E Thummel
{"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 that 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 3 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 sequencing analysis and immunocytochemistry (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 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)<sub>2</sub> vitamin D<sub>3</sub>-induced, and 6',7'-dihydroxybergamottin-inhibited conditions. The duration of these experiments is particularly noteworthy, because, to our knowledge, this is the first study to assess drug metabolizing enzymes and transporters 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. SIGNIFICANCE STATEMENT: 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":"53 1","pages":"100002"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064361","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}
引用次数: 0
Isoform-level expression of the constitutive androstane receptor (CAR or NR1I3) transcription factor better predicts the mRNA expression of the cytochrome P450s in human liver samples. 组成型雄甾受体(CAR或NR1I3)转录因子的同型水平表达能更好地预测人肝脏样本中细胞色素p450的mRNA表达。
IF 4.4 3区 医学
Drug Metabolism and Disposition Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/dmd.124.001923
Joseph M Collins, Danxin Wang
{"title":"Isoform-level expression of the constitutive androstane receptor (CAR or NR1I3) transcription factor better predicts the mRNA expression of the cytochrome P450s in human liver samples.","authors":"Joseph M Collins, Danxin Wang","doi":"10.1124/dmd.124.001923","DOIUrl":"10.1124/dmd.124.001923","url":null,"abstract":"<p><p>Many factors cause interperson variability in the activity and expression of the cytochrome P450 (CYP) drug-metabolizing enzymes in the liver, leading to variable drug exposure and treatment outcomes. Several liver-enriched transcription factors are associated with CYP expression, with estrogen receptor α (ESR1) and constitutive androstane receptor (CAR or NR1I3) being the 2 top factors. ESR1 and NR1I3 undergo extensive alternative splicing that results in numerous splice isoforms, but how these splice isoforms associate with CYP expression is unknown. Here, we quantified 18 NR1I3 splice isoforms and the 3 most abundant ESR1 isoforms in 260 liver samples derived from African Americans (n = 125) and European Americans (n = 135). Our results showed variable splice isoform populations in the liver for both NR1I3 and ESR1. Multiple linear regression analyses revealed that compared with gene-level NR1I3, isoform-level NR1I3 expression better predicted the mRNA expression of most CYPs and 3 UDP-glucuronosyltransferases (UGTs), whereas ESR1 isoforms improved predictive models for the UGTs and CYP2D6 but not for most CYPs. Also, different NR1I3 isoforms were associated with different CYPs, and the associations varied depending on sample ancestry. Surprisingly, noncanonical NR1I3 isoforms having retained introns (introns 2 or 6) were abundantly expressed and associated with the expression of most CYPs and UGTs, whereas the reference isoform (NR1I3-205) was only associated with CYP2D6. Moreover, NR1I3 isoform diversity increased during the differentiation of induced pluripotent stem cells to hepatocytes, paralleling increasing CYP expression. These results suggest that isoform-level transcription factor expression may help to explain variation in CYP or UGT expression between individuals. SIGNIFICANCE STATEMENT: We quantified 18 NR1I3 splice isoforms and the 3 most abundant ESR1 splice isoforms in 260 liver samples derived from African American and European American donors and found variable NR1I3 and ESR1 splice isoform expression in the liver. Multiple linear regression analysis showed that, compared with gene-level expression, isoform-level expression of NR1I3 and ESR1 better predicted the mRNA expression of some cytochrome P450s and UDP-glucuronosyltransferases, highlighting the importance of isoform-level analyses to enhance our understanding of gene transcriptional regulatory networks controlling the expression of drug-metabolizing enzymes.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100011"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064374","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}
引用次数: 0
Potential and challenges in application of physiologically based pharmacokinetic modeling in predicting diarrheal disease impact on oral drug pharmacokinetics. 基于生理的药代动力学模型在预测腹泻疾病对口服药物药代动力学影响中的应用潜力和挑战。
IF 4.4 3区 医学
Drug Metabolism and Disposition Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/dmd.122.000964
Cindy X Zhang, Samuel L M Arnold
{"title":"Potential and challenges in application of physiologically based pharmacokinetic modeling in predicting diarrheal disease impact on oral drug pharmacokinetics.","authors":"Cindy X Zhang, Samuel L M Arnold","doi":"10.1124/dmd.122.000964","DOIUrl":"10.1124/dmd.122.000964","url":null,"abstract":"<p><p>Physiologically based pharmacokinetic (PBPK) modeling is a physiologically relevant approach that integrates drug-specific and system parameters to generate pharmacokinetic predictions for target populations. It has gained immense popularity for drug-drug interaction, organ impairment, and special population studies over the past 2 decades. However, an application of PBPK modeling with great potential remains rather overlooked-prediction of diarrheal disease impact on oral drug pharmacokinetics. Oral drug absorption is a complex process involving the interplay between physicochemical characteristics of the drug and physiological conditions in the gastrointestinal tract. Diarrhea, a condition common to numerous diseases impacting many worldwide, is associated with physiological changes in many processes critical to oral drug absorption. In this Minireview, we outline key processes governing oral drug absorption, provide a high-level overview of key parameters for modeling oral drug absorption in PBPK models, examine how diarrheal diseases may impact these processes based on literature findings, illustrate the clinical relevance of diarrheal disease impact on oral drug absorption, and discuss the potential and challenges of applying PBPK modeling in predicting disease impacts. SIGNIFICANCE STATEMENT: Pathophysiological changes resulting from diarrheal diseases can alter important factors governing oral drug absorption, contributing to suboptimal drug exposure and treatment failure. Physiologically based pharmacokinetic (PBPK) modeling is an in silico approach that has been increasingly adopted for drug-drug interaction potential, organ impairment, and special population assessment. This Minireview highlights the potential and challenges of using physiologically based pharmacokinetic modeling as a tool to improve our understanding of how diarrheal diseases impact oral drug pharmacokinetics.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100014"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064317","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}
引用次数: 0
Absolute membrane protein abundance of P-glycoprotein, breast cancer resistance protein, and multidrug resistance proteins in term human placenta tissue and commonly used cell systems: Application in physiologically based pharmacokinetic modeling of placental drug disposition. 人胎盘组织和常用细胞系统中p -糖蛋白、乳腺癌耐药蛋白和多药耐药蛋白的绝对膜蛋白丰度:在胎盘药物处置生理药代动力学模型中的应用
IF 4.4 3区 医学
Drug Metabolism and Disposition Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/dmd.124.001824
Zubida M Al-Majdoub, Jolien J M Freriksen, Angela Colbers, Jeroen van den Heuvel, Jan Koenderink, Khaled Abduljalil, Brahim Achour, Jill Barber, Rick Greupink, Amin Rostami-Hodjegan
{"title":"Absolute membrane protein abundance of P-glycoprotein, breast cancer resistance protein, and multidrug resistance proteins in term human placenta tissue and commonly used cell systems: Application in physiologically based pharmacokinetic modeling of placental drug disposition.","authors":"Zubida M Al-Majdoub, Jolien J M Freriksen, Angela Colbers, Jeroen van den Heuvel, Jan Koenderink, Khaled Abduljalil, Brahim Achour, Jill Barber, Rick Greupink, Amin Rostami-Hodjegan","doi":"10.1124/dmd.124.001824","DOIUrl":"https://doi.org/10.1124/dmd.124.001824","url":null,"abstract":"<p><p>The placenta acts as a barrier, excluding noxious substances while actively transferring nutrients to the fetus, mediated by various transporters. This study quantified the expression of key placental transporters in term human placenta (n = 5) and BeWo, BeWo b30, and JEG-3 placenta cell lines. Combining these results with pregnancy physiologically based pharmacokinetic (PBPK) modeling, we demonstrate the utility of proteomic analysis for predicting placental drug disposition and fetal exposure. Using targeted proteomics with quantification concatemer standards, we found significant expression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, MRP4, and MRP6 in the human placenta (0.05-0.25 pmol/mg membrane protein) with only regional differences observed for P-gp. Unexpectedly, both P-gp and BCRP were below the limit of quantification in the regularly used BeWo cells, indicating that this cell line may not be suitable for the study of placental P-gp and BCRP-mediated transport. In cellular and vesicular overexpression systems, P-gp and BCRP were detectable as expected. Vesicle batches showed consistent P-gp expression correlating with functional activity (N-methyl-quinidine transport). However, BCRP activity (estrone 3-sulfate transport) did not consistently align with expression levels. Incorporating in vitro transporter kinetic data, along with placental transporter abundance, into a PBPK model enabled the evaluation of fetal exposure. Simulation with a hypothetical drug indicated that estimating fetal exposure relies on the intrinsic clearances of relevant transporters. To minimize interlaboratory discrepancies, expression data was generated using consistent proteomic methodologies in the same lab. Integration of this data in pregnancy PBPK modeling offers a promising tool to investigate maternal, placental, and fetal drug exposure. SIGNIFICANCE STATEMENT: This study quantified the expression of key placental transporters in human placenta and various placental cell lines, revealing significant expression variations. By integrating these data with physiologically based pharmacokinetic modeling, the study highlights the importance of transporter abundance data in understanding and predicting placental drug disposition, essential for maternal and fetal health during pregnancy.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100007"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064175","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}
引用次数: 0
Comparative analysis of the physiological and transport functions of various sources of renal proximal tubule cells under static and fluidic conditions in PhysioMimix T12 platform. 在PhysioMimix T12平台上对静态和流体条件下不同来源肾近端小管细胞生理和转运功能的比较分析。
IF 4.4 3区 医学
Drug Metabolism and Disposition Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/dmd.124.001488
Courtney Sakolish, Haley L Moyer, Han-Hsuan D Tsai, Lucie C Ford, Allison N Dickey, Piyush Bajaj, Remi Villenave, Philip Hewitt, Stephen S Ferguson, Jason Stanko, Ivan Rusyn
{"title":"Comparative analysis of the physiological and transport functions of various sources of renal proximal tubule cells under static and fluidic conditions in PhysioMimix T12 platform.","authors":"Courtney Sakolish, Haley L Moyer, Han-Hsuan D Tsai, Lucie C Ford, Allison N Dickey, Piyush Bajaj, Remi Villenave, Philip Hewitt, Stephen S Ferguson, Jason Stanko, Ivan Rusyn","doi":"10.1124/dmd.124.001488","DOIUrl":"10.1124/dmd.124.001488","url":null,"abstract":"<p><p>In vitro models that can faithfully replicate critical aspects of kidney tubule function such as directional drug transport are in high demand in pharmacology and toxicology. Accordingly, development and validation of new models is underway. The objective of this study was to characterize physiologic and transport functions of various sources of human renal proximal tubule epithelial cells (RPTECs). We tested telomerase reverse transcriptase 1 (TERT1)-immortalized RPTECs, including organic anion transporter 1 (OAT1)-, organic cation transporter 2 (OCT2)-, or OAT3-overexpressing variants and primary RPTECs. Cells were cultured on transwell membranes in static (24-well transwells) and fluidic (transwells in PhysioMimix T12 organ-on-chip with 2 μL/s flow) conditions. Barrier formation, transport, and gene expression were evaluated. We show that 2 commercially available primary RPTECs were not suitable for studies of directional transport on transwells because they formed a substandard barrier even though they exhibited higher expression of transporters, especially under flow. TERT1-parent, -OAT1, and -OAT3 cells formed robust barriers but were unaffected by flow. TERT1-OAT1 cells exhibited inhibitable para-aminohippurate transport that was enhanced by flow. However, efficient tenofovir secretion and perfluorooctanoic acid reabsorption by TERT1-OAT1 cells were not modulated by flow. Gene expression showed that TERT1 and TERT1-OAT1 cells were more correlated with human kidney than other cell lines but that flow did not have noticeable effects. Overall, our data show that addition of flow to in vitro studies of the renal proximal tubule may afford benefits in some aspects of modeling kidney function but that careful consideration of the impact such adaptations would have on the cost and throughput of the experiments is needed. SIGNIFICANCE STATEMENT: The topic of reproducibility and robustness of complex microphysiological systems is looming large in the field of biomedical research; therefore, uptake of these new models by the end-users is slow. This study systematically compared various renal proximal tubule epithelial cell sources and experimental conditions, aiming to identify the level of model complexity needed for testing renal tubule transport. We demonstrate that although tissue chips may afford some benefits, their throughput and complexity need careful consideration in each context of use.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100001"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064343","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}
引用次数: 0
CYP P450 and non-CYP P450 Drug Metabolizing Enzyme Families Exhibit Differential Sensitivities towards Proinflammatory Cytokine Modulation. CYP 和非 CYP 药物代谢酶家族对促炎细胞因子调节表现出不同的敏感性。
IF 4.4 3区 医学
Drug Metabolism and Disposition Pub Date : 2024-11-15 DOI: 10.1124/dmd.124.001867
Laura M de Jong, Chandan Harpal, Dirk-Jan van den Berg, Menno Hoekstra, Nienke J Peter, Robert Rissmann, Jesse J Swen, Martijn L Manson
{"title":"CYP P450 and non-CYP P450 Drug Metabolizing Enzyme Families Exhibit Differential Sensitivities towards Proinflammatory Cytokine Modulation.","authors":"Laura M de Jong, Chandan Harpal, Dirk-Jan van den Berg, Menno Hoekstra, Nienke J Peter, Robert Rissmann, Jesse J Swen, Martijn L Manson","doi":"10.1124/dmd.124.001867","DOIUrl":"10.1124/dmd.124.001867","url":null,"abstract":"<p><p>Compromised hepatic drug metabolism in response to proinflammatory cytokine release is primarily attributed to downregulation of cytochrome P450 (CYP) enzymes. However, whether inflammation also affects other phase I and phase II drug metabolizing enzymes (DMEs), such as the flavin monooxygenases (FMOs), carboxylesterases (CESs), and UDP glucuronosyltransferases (UGTs), remains unclear. This study aimed to decipher the impact of physiologically relevant concentrations of proinflammatory cytokines on expression and activity of phase I and phase II enzymes, to establish a hierarchy of their sensitivity as compared with the CYPs. Hereto, HepaRG cells were exposed to interleukin-6 and interleukin-1<i>β</i> to measure alterations in DME gene expression (24 h) and activity (72 h). Sensitivity of DMEs toward proinflammatory cytokines was evaluated by determining IC<sub>50</sub> (potency) and I<sub>max</sub> (maximal inhibition) values from the concentration-response curves. Proinflammatory cytokine treatment led to nearly complete downregulation of <i>CYP3A4</i> (∼98%) but was generally less efficacious at reducing gene expression of the non-CYP DME families. Importantly, FMO, CES, and UGT family members were less sensitive toward interleukin-6 induced inhibition in terms of potency, with IC<sub>50</sub> values that were 4.3- to 7.4-fold higher than <i>CYP3A4.</i> Similarly, 18- to 31-fold more interleukin-1<i>β</i> was required to achieve 50% of the maximal downregulation of <i>FMO3, FMO4, CES1, UGT2B4, and UGT2B7</i> expression. The differential sensitivity persisted at enzyme activity level, highlighting that alterations in DME gene expression during inflammation are predictive for subsequent alterations in enzyme activity. In conclusion, this study has shown that FMOs, CESs, and UGTs enzymes are less impacted by IL-6 and IL-1<i>β</i> treatment as compared with CYP enzymes. SIGNIFICANCE STATEMENT: While the impact of proinflammatory cytokines on CYP expression is well established, their effects on non-CYP phase I and phase II drug metabolism remains underexplored, particularly regarding alterations in drug metabolizing enzyme (DME) activity. This study provides a quantitative understanding of the sensitivity differences to inflammation between DME family members, suggesting that non-CYP DMEs may become more important for the metabolism of drugs during inflammatory conditions due to their lower sensitivity as compared with the CYPs.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"1429-1437"},"PeriodicalIF":4.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343670","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}
引用次数: 0
Quantitative Prediction of Drug-Drug Interactions Caused by CYP3A Induction Using Endogenous Biomarker 4β-Hydroxycholesterol. 利用内源性生物标记物 4β-hydroxycholesterol 定量预测由 CYP3A 诱导引起的药物间相互作用。
IF 4.4 3区 医学
Drug Metabolism and Disposition Pub Date : 2024-11-15 DOI: 10.1124/dmd.124.001876
Hiroaki Takubo, Toshio Taniguchi, Yukihiro Nomura
{"title":"Quantitative Prediction of Drug-Drug Interactions Caused by CYP3A Induction Using Endogenous Biomarker 4<i>β</i>-Hydroxycholesterol.","authors":"Hiroaki Takubo, Toshio Taniguchi, Yukihiro Nomura","doi":"10.1124/dmd.124.001876","DOIUrl":"10.1124/dmd.124.001876","url":null,"abstract":"<p><p>Evaluation of the CYP3A induction risk is important in early drug development stages. This study focused on 4<i>β</i>-hydroxycholesterol (4<i>β</i>-HC) as an endogenous biomarker of drug-drug interactions (DDIs) caused by CYP3A induction. We investigated a new approach using 4<i>β</i>-HC for quantitative prediction of DDIs caused by CYP3A induction based on the mechanistic static pharmacokinetic (MSPK) model. The induction ratio, i.e., the ratio of plasma 4<i>β</i>-HC or 4<i>β</i>-HC/cholesterol (4<i>β</i>-HC/C) with and without a coadministered CYP3A inducer, and the ratio of the area under the plasma concentration-time curve (AUCR), i.e., the ratio of the AUC of plasma CYP3A substrate drugs with and without a coadministered CYP3A inducer, were collected. The scaling factor (<i>d</i>) in the MSPK model was calculated from the induction ratio of 4<i>β</i>-HC or 4<i>β</i>-HC/C based on the systemic term in the MSPK model. The AUCR of 18 CYP3A substrates with and without coadministration of seven CYP3A inducers were then predicted by substituting the calculated <i>d</i> value into the MSPK model. This approach showed that approximately 84% of the predicted AUCR values were within a twofold range of the observed values, showing that this approach can be a good tool to quantitatively predict DDIs caused by CYP3A induction. SIGNIFICANCE STATEMENT: A concise approach to predict drug interactions with adequate accuracy is preferable in the early drug development stage. In this study, a new approach using 4<i>β</i>-hydroxycholesterol for quantitative prediction of drug-drug interactions caused by CYP3A induction was investigated. The predictability was verified using seven CYP3A inducers and 18 substrates.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"1438-1444"},"PeriodicalIF":4.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399710","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}
引用次数: 0
Characterization of Nonclinical Drug Metabolism and Pharmacokinetic Properties of Phosphorodiamidate Morpholino Oligonucleotides, a Novel Drug Class for Duchenne Muscular Dystrophy. 治疗杜氏肌营养不良症的新型药物--磷二酰胺吗啉寡核苷酸的非临床药物代谢和药代动力学特性的表征
IF 4.4 3区 医学
Drug Metabolism and Disposition Pub Date : 2024-11-15 DOI: 10.1124/dmd.124.001819
Andrew K L Goey, Marie Claire Mukashyaka, Yogesh Patel, Louise R Rodino-Klapac, Lilly East
{"title":"Characterization of Nonclinical Drug Metabolism and Pharmacokinetic Properties of Phosphorodiamidate Morpholino Oligonucleotides, a Novel Drug Class for Duchenne Muscular Dystrophy.","authors":"Andrew K L Goey, Marie Claire Mukashyaka, Yogesh Patel, Louise R Rodino-Klapac, Lilly East","doi":"10.1124/dmd.124.001819","DOIUrl":"10.1124/dmd.124.001819","url":null,"abstract":"<p><p>Eteplirsen, golodirsen, and casimersen are phosphorodiamidate morpholino oligomers (PMOs) that are approved in the United States for the treatment of patients with Duchenne muscular dystrophy (DMD) with mutations in the <i>DMD</i> gene that are amenable to exon 51, 53, and 45 skipping, respectively. Here we report a series of in vivo and in vitro studies characterizing the drug metabolism and pharmacokinetic (DMPK) properties of these three PMOs. Following a single intravenous dose, plasma exposure was consistent for all three PMOs in mouse, rat, and nonhuman primate (NHP), and plasma half-lives were similar for eteplirsen (2.0-4.1 h) and golodirsen (2.1-8.7 h) across species and more variable for casimersen (3.2-18.1 h). Plasma protein binding was low (<40%) for all three PMOs in mouse, rat, NHP, and human and was largely concentration independent. In the <i>mdx</i> mouse model of DMD, following a single intravenous injection, extensive biodistribution was observed in the target skeletal muscle tissues and the kidney for all three PMOs; consistent with the latter finding, the predominant route of elimination was renal. In vitro studies using liver microsomes showed no evidence of hepatic metabolism, and none of the PMOs were identified as inhibitors or inducers of the human cytochrome P450 enzymes or membrane drug transporters tested at clinically relevant concentrations. These findings suggest that key DMPK features are consistent for eteplirsen, golodirsen, and casimersen and provide evidence for the concept of a PMO drug class with potential application to novel exon-skipping drug candidates. SIGNIFICANCE STATEMENT: The PMOs eteplirsen, golodirsen, and casimersen share similar absorption, distribution, metabolism, and excretion and DMPK properties, which provides evidence for the concept of a PMO treatment class. A PMO drug class may support a platform approach to enhance understanding of the pharmacokinetic and pharmacodynamic behavior of these molecules. The grouping of novel agent series into platforms could be beneficial in the development of drug candidates for populations in which traditional clinical trials are not feasible.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"1396-1406"},"PeriodicalIF":4.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616568","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}
引用次数: 0
Absorption, Distribution, Metabolism, and Excretion of Icenticaftor (QBW251) in Healthy Male Volunteers at Steady State and In Vitro Phenotyping of Major Metabolites. 健康男性志愿者在稳定状态下对 Icenticaftor(QBW251)的吸收、分布、代谢和排泄以及主要代谢物的体外分型。
IF 4.4 3区 医学
Drug Metabolism and Disposition Pub Date : 2024-11-15 DOI: 10.1124/dmd.124.001751
Ulrike Glaenzel, Felix Huth, Fabian Eggimann, Melissa Hackling, Luc Alexis Leuthold, Axel Meissner, Lidiya Bebrevska
{"title":"Absorption, Distribution, Metabolism, and Excretion of Icenticaftor (QBW251) in Healthy Male Volunteers at Steady State and In Vitro Phenotyping of Major Metabolites.","authors":"Ulrike Glaenzel, Felix Huth, Fabian Eggimann, Melissa Hackling, Luc Alexis Leuthold, Axel Meissner, Lidiya Bebrevska","doi":"10.1124/dmd.124.001751","DOIUrl":"10.1124/dmd.124.001751","url":null,"abstract":"<p><p>Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane conductance regulator protein and is currently in clinical development for the treatment of chronic obstructive pulmonary disease and chronic bronchitis. An absorption, distribution, metabolism, and excretion study was performed at steady state to determine the pharmacokinetics, mass balance, and metabolite profiles of icenticaftor in humans. In this open-label study, six healthy men were treated with unlabeled oral icenticaftor (400 mg b.i.d.) for 4 days. A single oral dose of [<sup>14</sup>C]icenticaftor was administered on Day 5, and unlabeled icenticaftor was administered twice daily from the evening of Day 5 to Day 12. Unchanged icenticaftor accounted for 18.5% of plasma radioactivity. Moderate to rapid absorption of icenticaftor was observed (median time to reach peak or maximum concentration: 4 hours), with 93.4% of the dose absorbed. It exhibited moderate distribution (Vz/F: 335 L) and was extensively metabolized, principally through N-glucuronidation, O-glucuronidation, and/or O-demethylation. The metabolites M8 and M9, formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively, represented the main entities detected in plasma (35.3% and 14.5%, respectively) in addition to unchanged icenticaftor (18.5%). The apparent mean terminal half-life of icenticaftor was 15.4 hours in blood and 20.6 hours in plasma. Icenticaftor was eliminated from the body mainly through metabolism followed by renal excretion, and excretion of radioactivity was complete after 9 days. In vitro phenotyping of icenticaftor showed that cytochrome P450 and uridine diphosphate glucuronosyltransferase were responsible for 31% and 69% of the total icenticaftor metabolism in human liver microsomes, respectively. This study provided invaluable insights into the disposition of icenticaftor. SIGNIFICANCE STATEMENT: The absorption, distribution, metabolism, and excretion of a single radioactive oral dose of icenticaftor was evaluated at steady state to investigate the nonlinear pharmacokinetics observed previously with icenticaftor. [<sup>14</sup>C]Icenticaftor demonstrated good systemic availability after oral administration and was extensively metabolized and moderately distributed to peripheral tissues. The most abundant metabolites, M8 and M9, were formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively. Phenotyping demonstrated that [<sup>14</sup>C]icenticaftor was metabolized predominantly by UGT1A9 with a remarkably low K<sub>m</sub> value.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"1379-1387"},"PeriodicalIF":4.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307297","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}
引用次数: 0
Utility of Common In Vitro Systems for Predicting Circulating Metabolites. 常用体外系统预测循环代谢物的实用性。
IF 4.4 3区 医学
Drug Metabolism and Disposition Pub Date : 2024-11-15 DOI: 10.1124/dmd.124.001732
Elyse C Freiberger, Michael P Thompson, Xiaomei Zhang, Essence B Underwood, Thomas L Lynch, Gary J Jenkins, David S Wagner
{"title":"Utility of Common In Vitro Systems for Predicting Circulating Metabolites.","authors":"Elyse C Freiberger, Michael P Thompson, Xiaomei Zhang, Essence B Underwood, Thomas L Lynch, Gary J Jenkins, David S Wagner","doi":"10.1124/dmd.124.001732","DOIUrl":"10.1124/dmd.124.001732","url":null,"abstract":"&lt;p&gt;&lt;p&gt;In vitro systems such as cultured hepatocytes are used early in drug development as a proxy for in vivo data to predict metabolites in human and the potential preclinical species. These data support preclinical species selection for toxicity studies as well as provide early evidence for potential active and reactive metabolites that can be generated in human. Although in vivo data would be best to select preclinical species for a given compound, only in vitro systems are available when selecting toxicity study species. However, as with any in vitro system, the correlation to actual in vivo results can be variable. Understanding the reliability of predicting in vivo metabolites from the various available in vitro assays and determining which system may be most predictive would help de-risk drug development teams' selection process. In this manuscript, we address these questions: can in vitro systems predict circulating metabolites? If so, is predictivity quantitative or indicative of what levels may be seen circulating? Of the currently available in vitro systems, is one better than the others at generating predictive metabolites? To address the first two issues (general in vitro/in vivo predictivity, and whether any in vitro/in vivo correlations are quantitative), we used historical data from Abbott/AbbVie to compare in vitro metabolite profiles with metabolite profiles from in vivo absorption, distribution, metabolism, excretion, and clinical studies. In this retrospective analysis of historic metabolite profiling data, in vitro systems predicted ∼50% of circulating metabolites present in vivo, across preclinical species and human, with no correlation between apparent concentrations in vitro versus in vivo. To address the final question, we selected 10 commercially available compounds with published metabolism data and incubated them in five common in vitro systems (microsomes, liver S9, suspension hepatocytes, HμREL cocultured hepatocytes, and hepatocyte spheroids); the new in vitro metabolite profiling data were compared against published in vivo data to determine whether any individual system was more accurate in generating known major human circulating metabolites. Suspension hepatocytes and cocultured hepatocytes marginally outperformed the other systems. Current in vitro systems have value early in development when in vivo studies are not feasible and are required for regulatory filings to support preclinical toxicology species selection but should not be treated as wholly representative of a given drug's in vivo metabolism. SIGNIFICANCE STATEMENT: This is a comprehensive assessment of historic metabolism data quantitating the success rate of in vitro to in vivo predictivity. Reliability of in vitro systems for metabolite profiling is important for early drug development, and understanding predictivity will help give appropriate context to the data. New data were also generated to compare common in vitro liver models to determine whe","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"1373-1378"},"PeriodicalIF":4.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460474","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}
引用次数: 0
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