Drug Metabolism and Disposition最新文献

{"title":"Efflux transporters in drug disposition during pregnancy.","authors":"Xin Chen, Chunying Gao, Lyrialle W Han, Sibylle Heidelberger, Michael Z Liao, Naveen K Neradugomma, Zhanglin Ni, Diana L Shuster, Honggang Wang, Yi Zhang, Lin Zhou","doi":"10.1124/dmd.123.001385","DOIUrl":"10.1124/dmd.123.001385","url":null,"abstract":"<p><p>Evidence-based dose selection of drugs in pregnant women has been lacking because of challenges in studying maternal-fetal pharmacokinetics. Hence, many drugs are administered off-label during pregnancy based on data obtained from nonpregnant women. During pregnancy, drug transporters play an important role in drug disposition along with known gestational age-dependent changes in physiology and drug-metabolizing enzymes. In this review, as Dr Qingcheng Mao's former and current laboratory members, we summarize the collective contributions of Dr Mao, who lost his life to cancer, focusing on the role of drug transporters in drug disposition during pregnancy. Dr Mao and his team initiated their research by characterizing the structure of breast cancer resistance protein (ATP-binding cassette G2). Subsequently, they have made significant contributions to the understanding of the role of breast cancer resistance protein and other transporters, particularly P-glycoprotein (ATP-binding cassette B1), in the exposure of pregnant women and their fetuses to various drugs, including nitrofurantoin, glyburide, buprenorphine, bupropion, tetrahydrocannabinol, and their metabolites. This review also highlights the gestation- and pregnancy-dependent transporter expression at the blood-brain and blood-placenta barriers in mice. SIGNIFICANCE STATEMENT: Dr Qingcheng Mao and his team have made significant contributions to the investigation of the role of efflux transporters, especially P-glycoprotein and breast cancer resistance protein, in maternal-fetal exposure to many xenobiotics: nitrofurantoin, glyburide, buprenorphine, bupropion, tetrahydrocannabinol, and their metabolites. Studies of individual compounds and the expression of transporters during gestation and pregnancy have improved the understanding of maternal-fetal pharmacokinetics.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100022"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064356","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":"Uncovering the impact of COVID-19-mediated bidirectional dysregulation of cytochrome P450 3A4 on systemic and pulmonary drug concentrations using physiologically based pharmacokinetic modeling.","authors":"Chukwunonso K Nwabufo","doi":"10.1124/dmd.124.001893","DOIUrl":"https://doi.org/10.1124/dmd.124.001893","url":null,"abstract":"<p><p>Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized patients with COVID-19. However, it is unclear how COVID-19-mediated bidirectional dysregulation of hepatic and pulmonary cytochrome P450 (CYP) 3A4 affects drug concentrations, especially in the lung tissue, which is most affected by the disease. Herein, physiologically based pharmacokinetic modeling was used to demonstrate the differences in systemic and pulmonary concentrations of 4 respiratory infectious disease drugs when CYP3A4 is concurrently downregulated in the liver and upregulated in the lung based on existing clinical data on COVID-19-CYP3A4 interactions at varying severity levels including outpatients, non-intensive care unit (ICU), and ICU patients. The study showed that hepatic metabolism is the primary determinant of both systemic and pulmonary drug concentrations despite the concurrent bidirectional dysregulation of liver and lung CYP3A4. ICU patients had the most systemic and pulmonary drug exposure, with a percentage increase in the area under the concentration-time curve in the plasma compartment of approximately 44%, 56%, 114%, and 196% for clarithromycin, nirmatrelvir, dexamethasone, and itraconazole, respectively, relative to the healthy group. Within the ICU cohort, clarithromycin exhibited its highest exposure in lung tissue mass with a fold change of 1189, whereas nirmatrelvir and dexamethasone showed their highest exposure in the plasma compartment, with fold changes of about 126 and 5, respectively, compared with the maximum therapeutic concentrations for their target pathogens. Itraconazole was significantly underexposed in the lung fluid compartment, potentially explaining its limited efficacy for the treatment of COVID-19. These findings underscore the importance of optimizing dosing regimens in at risk ICU patients to enhance both efficacy and safety profiles. SIGNIFICANCE STATEMENT: This study investigated whether COVID-19-mediated concurrent hepatic downregulation and pulmonary upregulation of cytochrome P450 (CYP) 3A4 leads to differences in the systemic and pulmonary concentrations of 4 respiratory medicines. The study demonstrated that intercompartmental differences in drug concentrations were driven by only hepatic CYP3A4 expression. This work suggests that ICU patients with significant COVID-19-CYP3A4 interactions may be at risk of clinically relevant COVID-19-drug interactions, highlighting the need for optimizing dosing regimens in this patient group to improve safety and efficacy.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100008"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of genetic polymorphisms and drug-drug interactions mediated by carboxylesterase 1 on remimazolam deactivation.","authors":"Zhuo Wang, Zachary McCalla, Li Lin, Dominic Tornichio, Yaw Agyemang, John A Bastulli, Xiaochun Susan Zhang, Hao-Jie Zhu, Xinwen Wang","doi":"10.1124/dmd.124.001916","DOIUrl":"10.1124/dmd.124.001916","url":null,"abstract":"<p><p>Remimazolam (Byfavo, Acacia Pharma), a recent Food and Drug Administration-approved ester-linked benzodiazepine, offers advantages in sedation, such as rapid onset and predictable duration, making it suitable for broad anesthesia applications. Its favorable pharmacological profile is primarily attributed to rapid hydrolysis, the primary metabolism pathway for its deactivation. Thus, understanding remimazolam hydrolysis determinants is essential for optimizing its clinical use. This study aimed to identify the enzyme(s) and tissue(s) responsible for remimazolam hydrolysis and to evaluate the influence of genetic polymorphisms and drug-drug interactions on its hydrolysis in the human liver. An initial incubation study with remimazolam and PBS, human serum, and the S9 fractions of human liver and intestine demonstrated that remimazolam was exclusively hydrolyzed by human liver S9 fractions. Subsequent incubation studies utilizing a carboxylesterase inhibitor (bis(4-nitrophenyl) phosphate), recombinant human carboxylesterase 1 (CES1) and carboxylesterase 2 confirmed that remimazolam is specifically hydrolyzed by CES1 in human liver. Furthermore, in vitro studies with wild-type CES1 and CES1 variants transfected cells revealed that certain genetic polymorphisms significantly impair remimazolam deactivation. Notably, the impact of CES1 G143E was verified using individual human liver samples. Moreover, our evaluation of the drug-drug interactions between remimazolam and several other substrates/inhibitors of CES1-including simvastatin, enalapril, clopidogrel, and sacubitril-found that clopidogrel significantly inhibited remimazolam hydrolysis at clinically relevant concentrations, with CES1 genetic variants potentially influencing the interactions. In summary, CES1 genetic variants and its interacting drugs are crucial factors contributing to interindividual variability in remimazolam hepatic hydrolysis, holding the potential to serve as biomarkers for optimizing remimazolam use. SIGNIFICANCE STATEMENT: This investigation demonstrates that remimazolam is deactivated by carboxylesterase 1 (CES1) in the human liver, with CES1 genetic variants and drug-drug interactions significantly influencing its metabolism. These findings emphasize the need to consider CES1 genetic variability and potential drug-drug interactions in remimazolam use, especially in personalized pharmacotherapy to achieve optimal anesthetic outcomes.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100023"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064362","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":"Real-world application of physiologically based pharmacokinetic models in drug discovery.","authors":"Laura G A Santos, Swati Jaiswal, Kuan-Fu Chen, Hannah M Jones, Ian E Templeton","doi":"10.1124/dmd.122.001036","DOIUrl":"https://doi.org/10.1124/dmd.122.001036","url":null,"abstract":"<p><p>The utility of physiologically based pharmacokinetic (PBPK) models in support of drug development has been well documented. During the discovery stage, PBPK modeling has increasingly been applied for early risk assessment, prediction of human dose, toxicokinetic dose projection, and early formulation assessment. Previous review articles have proposed model-building and application strategies for PBPK-based first-in-human predictions with comprehensive descriptions of the individual components of PBPK models. This includes the generation of decision trees based on literature reviews to guide the application of PBPK models in the discovery setting. The goal of this minireview is to provide additional guidance on the real-world application of PBPK models in support of the discovery stage of drug development, to assist in decision making. We have illustrated our recommended approach through description of case examples where PBPK models have been successfully applied to aid in human pharmacokinetic projection, candidate selection, and prediction of drug interaction liability for parent and metabolite. Through these case studies, we have highlighted fundamental issues, including preverification in preclinical species, the application of empirical scalars in the prediction of in vivo clearance from in vitro systems, in silico prediction of permeability, and the exploration of aqueous and biorelevant solubility data to predict dissolution. In addition, current knowledge gaps have been highlighted and future directions proposed. SIGNIFICANCE STATEMENT: Through description of 3 case studies, this minireview highlights the fundamental principles of physiologically based pharmacokinetic application during drug discovery. These include preverification of the model in preclinical species, application of empirical scalars where necessary in the prediction of clearance, in silico prediction of permeability, and the exploration of aqueous and biorelevant solubility data to predict dissolution. In addition, current knowledge gaps have been highlighted and future directions proposed.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100015"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The absorption, distribution, metabolism and elimination characteristics of small interfering RNA therapeutics and the opportunity to predict disposition in pregnant women.","authors":"Ogochukwu Amaeze, Nina Isoherranen, Sara Shum","doi":"10.1124/dmd.123.001383","DOIUrl":"https://doi.org/10.1124/dmd.123.001383","url":null,"abstract":"<p><p>Small interfering RNA (siRNA) therapeutics represent an emerging class of pharmacotherapy with the potential to address previously hard-to-treat diseases. Currently approved siRNA therapeutics include lipid nanoparticle-encapsulated siRNA and tri-N-acetylated galactosamine-conjugated siRNA. These siRNA therapeutics exhibit distinct pharmacokinetic characteristics and unique absorption, distribution, metabolism, and elimination (ADME) properties. As a new drug modality, limited clinical data are available for siRNA therapeutics in specific populations, including pediatrics, geriatrics, individuals with renal or hepatic impairment, and pregnant women, making dosing challenging. In this Minireview, a mechanistic overview of the ADME properties of the 5 currently approved siRNA therapeutics is presented. A concise overview of the clinical data available for therapeutic siRNAs in special populations, focusing on the potential impact of physiologic changes during pregnancy on siRNA disposition, is provided. The utility of physiologically based pharmacokinetic (PBPK) modeling as a tool to elucidate the characteristics and disposition of siRNA therapeutics in pregnant women is explored. Additionally, opportunities to integrate known physiologic alterations induced by pregnancy into PBPK models that incorporate siRNA ADME mechanisms to predict the effects of pregnancy on siRNA disposition are discussed. Clinical data regarding the use of therapeutic siRNA in special populations remain limited. Data for precise parameterization of maternal-fetal siRNA PBPK models are lacking presently and underscore the need for further research in this area. Addressing this gap in knowledge will not only enhance our understanding of siRNA pharmacokinetics during pregnancy but also advance the possible development of siRNA therapeutics to treat pregnancy-related conditions. SIGNIFICANCE STATEMENT: This Minireview proposes a framework on how small interfering RNA (siRNA) disposition can be predicted in pregnancy based on mechanistic absorption, distribution, metabolism, and elimination (ADME) information using physiologically-based pharmacokinetic (PBPK) modeling. The mechanistic ADME information and available clinical data in special populations of currently Food and Drug Administration-approved siRNA therapeutics are summarized. Additionally, how physiological changes during pregnancy may affect siRNA disposition is reviewed, and the opportunities to use PBPK modeling to predict siRNA disposition in pregnant women is explored.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100018"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064369","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":"Utility of physiologically based pharmacokinetic modeling in predicting and characterizing clinical drug interactions.","authors":"Robert S Foti","doi":"10.1124/dmd.123.001384","DOIUrl":"https://doi.org/10.1124/dmd.123.001384","url":null,"abstract":"<p><p>Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic dynamic modeling approach that can be used to predict or retrospectively describe changes in drug exposure due to drug-drug interactions (DDIs). With advancements in commercially available PBPK software, PBPK DDI modeling has become a mainstream approach from early drug discovery through to late-stage drug development and is often used to support regulatory packages for new drug applications. This Minireview will briefly describe the approaches to predicting DDI using PBPK and static modeling approaches, the basic model structures and features inherent to PBPK DDI models, and key examples where PBPK DDI models have been used to describe complex DDI mechanisms. Future directions aimed at using PBPK models to characterize transporter-mediated DDI, predict DDI in special populations, and assess the DDI potential of protein therapeutics will be discussed. A summary of the 209 PBPK DDI examples published to date in 2023 will be provided. Overall, current data and trends suggest a continued role for PBPK models in the characterization and prediction of DDI for therapeutic molecules. SIGNIFICANCE STATEMENT: Physiologically based pharmacokinetic (PBPK) models have been a key tool in the characterization of various pharmacokinetic phenomena, including drug-drug interactions. This Minireview will highlight recent advancements and publications around physiologically based pharmacokinetic drug-drug interaction modeling, an important area of drug discovery and development research in light of the increasing prevalence of polypharmacology in clinical settings.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100021"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064418","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":"Environmentally persistent free radicals stimulate CYP2E1-mediated generation of reactive oxygen species at the expense of substrate metabolism.","authors":"George F Cawley, J Patrick Connick, Marilyn K Eyer, Wayne L Backes","doi":"10.1124/dmd.124.001939","DOIUrl":"10.1124/dmd.124.001939","url":null,"abstract":"<p><p>Environmentally persistent free radicals (EPFRs) are a recently recognized component of particulate matter that cause respiratory and cardiovascular toxicity. The mechanism of EPFR toxicity appears to be related to their ability to generate reactive oxygen species (ROS), causing oxidative damage. EPFRs were shown to affect cytochrome P450 (P450) function, inducing the expression of some forms through the Ah receptor. However, another characteristic of EPFRs is their ability to inhibit P450 activities. CYP2E1 is one of the P450s that is inhibited by EPFR (MCP230, the laboratory-generated EPFR made by heating silica 5% copper oxide, and silica [<0.2 μm in diameter] and 2-monochlorophenol at ≥230 °C) exposure. Because CYP2E1 is also known to generate ROS, it is important to understand the ability of EPFRs to influence the function of this enzyme and to identify the mechanisms involved. CYP2E1 was shown to be inhibited by EPFRs and to a lesser extent by non-EPFR particles. Because EPFR-mediated inhibition was more robust at subsaturating NADPH-P450 reductase (POR) concentrations, disruption of POR•CYP2E1 complex formation and electron transfer were examined. Surprisingly, neither complex formation nor electron transfer between POR and CYP2E1 was inhibited by EPFRs. Examination of ROS production showed that MCP230 generated a greater amount of ROS than the non-EPFR control particle (CuO-Si). When a POR/CYP2E1-containing reconstituted system was added to the pollutant-particle systems, there was a synergistic stimulation of ROS production. The results indicate that EPFRs cause inhibition of CYP2E1-mediated substrate metabolism, yet do not alter electron transfer and actually stimulate ROS generation. Taken together, the results are consistent with EPFRs affecting CYP2E1 function by inhibiting substrate metabolism and increasing the generation of ROS. SIGNIFICANCE STATEMENT: Environmentally persistent free radicals affect CYP2E1 function by inhibition of monooxygenase activity. This inhibition is not due to disruption of the POR•CYP2E1 complex or inhibition of electron transfer but due to the uncoupling of NADPH and oxygen consumption from substrate metabolism to the generation of reactive oxygen species. These results show that environmentally persistent free radicals block the metabolism of foreign compounds and synergistically stimulate the formation of reactive oxygen species that lead to oxidative damage within the organism.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100012"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064358","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":"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":"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":"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":"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}