Drug Metabolism and Disposition最新文献

{"title":"Intestine versus liver? Uncovering the hidden major metabolic organs of silybin in rats.","authors":"Yuanbo Sun, Like Xie, Jing Zhang, Runing Liu, Hanbing Li, Yanquan Yang, Yapeng Wu, Ying Peng, Guangji Wang, Natalie Hughes-Medlicott, Jianguo Sun","doi":"10.1124/dmd.124.001817","DOIUrl":"https://doi.org/10.1124/dmd.124.001817","url":null,"abstract":"<p><p>Silybin, a milk thistle extract, is a flavonolignan compound with hepatoprotective effect. It is commonly used in dietary supplements, functional foods, and nutraceuticals. However, the metabolism of silybin has not been systematically characterized in organisms to date. Therefore, we established a novel high-performance liquid chromatography quadrupole time-of-flight mass spectrometry method to analyze and identify the prototype and metabolites of silybin in rats. In total, 29 (of 32) new metabolic pathways and 56 (of 59) unreported metabolite products were detected. Moreover, we found that the liver had a high first-pass effect of 63.30% ± 13.01% for silybin, and only 1 metabolite was detected. Moreover, the metabolites identified in gastrointestinal tract possessed 88% of all unreported metabolite products (52 of 59). At the same time, the high concentration of silybin in the liver also indicated that large amounts of silybin may be accumulated in the liver instead of being metabolized. These results indicated that the primary metabolizing organ of silybin in rats was intestine rather than liver, which offers a solid chemical foundation for exploring more pharmacological effects of silybin. SIGNIFICANCE STATEMENT: This study confirmed that the primary location of metabolism of silybin in rats after intragastric administration was the gastrointestinal tract instead of the liver and that intestinal microbes were closely involved. In total, 29 (of 32) metabolism pathways and 56 (of 59) metabolites were identified for the first time in rats, to the authors' knowledge. To further study the liver disposition of silybin, its hepatic first-pass effect was determined for the first time. This work is capable of furnishing a robust material foundation for the forthcoming pharmacological investigations regarding silybin.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100005"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064363","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":"Utilization of a human Liver Tissue Chip for drug-metabolizing enzyme induction studies of perpetrator and victim drugs.","authors":"Shivam Ohri, Paarth Parekh, Lauren Nichols, Shiny Amala Priya Rajan, Murat Cirit","doi":"10.1124/dmd.124.001497","DOIUrl":"https://doi.org/10.1124/dmd.124.001497","url":null,"abstract":"<p><p>Polypharmacy-related drug-drug interactions (DDIs) are a significant and growing healthcare concern. An increasing number of therapeutic drugs on the market underscores the necessity to accurately assess new drug combinations during preclinical evaluation for DDIs. In vitro primary human hepatocytes (PHH) models are only applicable for short-term induction studies because of their rapid loss of metabolic function. Though coculturing nonhuman stromal cells with PHH has been shown to stabilize metabolic activity long-term, there are concerns about human specificity for accurate clinical assessment. In this study, we demonstrated a PHH-only liver microphysiological system in the Liver Tissue Chip is capable of maintaining long-term functional and metabolic activity of PHH from 3 individual donors and thus a suitable platform for long-term DDI induction studies. The responses to rifampicin induction of 3 PHH donors were assessed using cytochrome P450 activity and mRNA changes. Additionally, victim pharmacokinetic studies were conducted with midazolam (high clearance) and alprazolam (low clearance) following perpetrator drug treatment, rifampicin-mediated induction, which resulted in a 2-fold and a 2.6-fold increase in midazolam and alprazolam intrinsic clearance values, respectively, compared with the untreated liver microphysiological system. We also investigated the induction effects of different dosing regimens of the perpetrator drug (rifampicin) on cytochrome P450 activity levels, showing minimal variation in the intrinsic clearance of the victim drug (midazolam). This study illustrates the utility of the Liver Tissue Chip for in vitro liver-specific DDI induction studies, providing a translational experimental system to predict clinical clearance values of both perpetrator and victim drugs. SIGNIFICANCE STATEMENT: This study demonstrated the utility of the Liver Tissue Chip with a primary human hepatocyte-only liver microphysiological system for drug-drug interaction induction studies. This unique in vitro system with continuous recirculation maintains long-term functionality and metabolic activity for up to 4 weeks, enabling the study of perpetrator and victim drug pharmacokinetics, quantification of drug-induced cytochrome P450 mRNA and activity levels, investigation of patient variability, and ultimately clinical predictions.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100004"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064463","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":"Characterization of human alcohol dehydrogenase 4 and aldehyde dehydrogenase 2 as enzymes involved in the formation of 5-carboxylpirfenidone, a major metabolite of pirfenidone.","authors":"Rei Sato, Tatsuki Fukami, Kazuya Shimomura, Yongjie Zhang, Masataka Nakano, Miki Nakajima","doi":"10.1124/dmd.124.001917","DOIUrl":"https://doi.org/10.1124/dmd.124.001917","url":null,"abstract":"<p><p>Pirfenidone (PIR) is used in the treatment of idiopathic pulmonary fibrosis. After oral administration, it is metabolized by cytochrome P450 1A2 to 5-hydroxylpirfenidone (5-OH PIR) and further oxidized to 5-carboxylpirfenidone (5-COOH PIR), a major metabolite excreted in the urine (90% of the dose). This study aimed to identify enzymes that catalyze the formation of 5-COOH PIR from 5-OH PIR in the human liver. 5-COOH PIR was formed from 5-OH PIR in the presence of NAD⁺ by human liver microsomes (HLMs) more than by human liver cytosol (HLC), with the concomitant formation of the aldehyde form (5-CHO PIR) as an intermediate metabolite. By purifying enzymes from HLMs, alcohol dehydrogenases (ADHs) were identified as candidate enzymes catalyzing 5-CHO PIR formation, although ADHs are localized in the cytoplasm. Among constructed recombinant ADH1-5 expressed in HEK293T cells, only ADH4 efficiently catalyzed 5-CHO PIR formation from 5-OH PIR with a K_m value (29.0 ± 4.9 μM), which was close to that by HLMs (59.1 ± 4.6 μM). In contrast to commercially available HLC, HLC prepared in-house clearly showed substantial 5-CHO PIR formation, and ADH4 protein levels were significantly (rs = 0.772, P < .0001) correlated with 5-CHO PIR formation in 25 HLC samples prepared in-house. Some components of the commercially available HLC may inhibit ADH4 activity. Disulfiram, an inhibitor of aldehyde dehydrogenases (ALDH), decreased 5-COOH PIR formation and increased 5-CHO PIR formation from 5-OH PIR in HLMs. ALDH2 knockdown in HepG2 cells by siRNA decreased 5-COOH PIR formation by 61%. SIGNIFICANCE STATEMENT: This study clarified that 5-carboxylpirfenidone formation from 5-hydroxylpirfenidone proceeds via a 2-step oxidation reaction catalyzed by ADH4 and disulfiram-sensitive enzymes, including ALDH2. Interindividual differences in the expression levels or functions of these enzymes could cause variations in the pharmacokinetics of pirfenidone.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100010"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064258","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":"https://doi.org/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)₂ vitamin D₃-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}

{"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":"https://doi.org/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}

{"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":"https://doi.org/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}

{"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}

{"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":"https://doi.org/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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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 IC₅₀ (potency) and I_max (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 IC₅₀ 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}

{"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}