Drug Metabolism and Disposition最新文献

{"title":"<b>The ADME characteristics of siRNA therapeutics and the opportunity to predict disposition in pregnant women.</b>","authors":"Ogochukwu Amaeze, Nina Isoherranen, Sara Shum","doi":"10.1124/dmd.123.001383","DOIUrl":"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 LNP-encapsulated siRNA and triGalNAc-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 review, a mechanistic overview of the ADME properties of the five 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 physiological 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 physiological 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 remains limited. Data for precise parameterization of maternal-fetal siRNA PBPK models is lacking presently and underscores 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 possible development of siRNA therapeutics to treat pregnancy related conditions. <b>Significance Statement</b> This review proposes a framework on how siRNA disposition can be predicted in pregnancy based on mechanistic ADME information using physiologically based pharmacokinetic (PBPK) modeling. The mechanistic ADME information and available clinical data in special populations of currently FDA approved siRNA therapeutics are summarized. A detailed discussion on how physiological changes during pregnancy may affect siRNA disposition in pregnant women and on the opportunities to project siRNA disposition in pregnant women using PBPK modeling is provided.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174909","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":"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":"https://doi.org/10.1124/dmd.123.001385","url":null,"abstract":"<p><p>Evidence-based dose selection of drugs in pregnant women has been lacking due to challenges in studying maternal-fetal pharmacokinetics. Hence, many drugs are administered off-label during pregnancy based on data obtained from non-pregnant 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 lab 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 [BCRP, ATP-Binding Cassette (ABC) G2]. Subsequently, they have made significant contributions to the understanding of the role of BCRP and other transporters, particularly P-glycoprotein (P-gp/ABCB1), 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. <b>Significance Statement</b> 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":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174983","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":"HCV Antiviral Drugs Have the Potential to Adversely Perturb the Fetal-Maternal Communication Axis through Inhibition of CYP3A7 DHEA-S Oxidation.","authors":"Hannah M Work, John C Hackett, Jed N Lampe","doi":"10.1124/dmd.123.001434","DOIUrl":"10.1124/dmd.123.001434","url":null,"abstract":"<p><p>The hepatitis C virus (HCV) poses a great risk to pregnant people and their developing fetus, yet no HCV antiviral treatment guidelines have been established. While there has been a substantial increase in the development of HCV antivirals, the effect they have on the developing fetus remains poorly defined. Many of these drugs are metabolized through the cytochrome P450 CYP3A pathway, which is mediated by cytochrome P450 3A7 (CYP3A7) in the fetus and developing infant. In this study, we sought to investigate the effect HCV antivirals have on CYP3A7 metabolism, as this CYP enzyme plays a vital role in proper fetal and neonatal development. Of the 13 HCV antivirals we investigated, 8 (∼62%) inhibited CYP3A7 metabolic activity by 50% or more at a concentration of 20 <i>µ</i>M. Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10 and 20 <i>µ</i>M, which is physiologically relevant in comparison with the K_m of dehydroepiandrosterone-sulfate (DHEA-S) oxidation (reported to be between 5 and 20 <i>µ</i>M). We also discovered that paritaprevir is a time-dependent inhibitor of CYP3A7, which shifts the IC₅₀ ∼twofold from 11 <i>µ</i>M to 5 <i>µ</i>M. Upon further characterization, paritaprevir inactivates DHEA-S metabolism by CYP3A7, with K_I and K_inact values of 4.66 <i>µ</i>M and 0.00954 minute^-1, respectively. Depending on treatment plan and off-label drug use, HCV treatment could adversely affect the fetal-maternal communication axis by blocking fetal CYP3A7 metabolism of important endogenous hormones. SIGNIFICANCE STATEMENT: The prevalence of HCV in pregnant people is estimated at between 1% and 8% of the global population, yet little to no information exists about the risk antiviral treatment poses to the developing fetus. There is a potential risk of drugs adversely affecting mother-fetal communication by inhibiting fetal hepatic CYP3A7, an integral enzyme for estriol production. We discovered that five HCV antivirals inhibited DHEA-S metabolism by CYP3A7, and paritaprevir inactivated the enzyme. Our studies demonstrate the potential threat these drugs pose to proper fetal development.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"516-525"},"PeriodicalIF":4.4,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11114604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Utilizing a Dual Human Transporter MDCKII-MDR1-BCRP Cell Line to Assess Efflux at the Blood Brain Barrier\".","authors":"","doi":"10.1124/dmd.123.001476err","DOIUrl":"https://doi.org/10.1124/dmd.123.001476err","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"52 6","pages":"581"},"PeriodicalIF":3.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955989","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":"Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity.","authors":"Jessica L Beers, Zhu Zhou, Klarissa D Jackson","doi":"10.1124/dmd.123.001435","DOIUrl":"10.1124/dmd.123.001435","url":null,"abstract":"<p><p>Cannabidiol (CBD) is a pharmacologically active metabolite of cannabis that is US Food and Drug Administration approved to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged 1 year and older. During clinical trials, CBD caused dose-dependent hepatocellular toxicity at therapeutic doses. The risk for toxicity was increased in patients taking valproate, another hepatotoxic antiepileptic drug, through an unknown mechanism. With the growing popularity of CBD in the consumer market, an improved understanding of the safety risks associated with CBD is needed to ensure public health. This review details current efforts to describe CBD pharmacokinetics and mechanisms of hepatotoxicity using both pharmacokinetic models and in vitro models of the liver. In addition, current evidence and knowledge gaps related to intracellular mechanisms of CBD-induced hepatotoxicity are described. The authors propose future directions that combine systems-based models with markers of CBD-induced hepatotoxicity to understand how CBD pharmacokinetics may influence the adverse effect profile and risk of liver injury for those taking CBD. SIGNIFICANCE STATEMENT: This review describes current pharmacokinetic modeling approaches to capture the metabolic clearance and safety profile of cannabidiol (CBD). CBD is an increasingly popular natural product and US Food and Drug Administration-approved antiepileptic drug known to cause clinically significant enzyme-mediated drug interactions and hepatotoxicity at therapeutic doses. CBD metabolism, pharmacokinetics, and putative mechanisms of CBD-induced liver injury are summarized from available preclinical data to inform future modeling efforts for understanding CBD toxicity.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"508-515"},"PeriodicalIF":3.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11114601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kinase Inhibitors FDA Approved 2018-2023: Drug Targets, Metabolic Pathways, and Drug-Induced Toxicities.","authors":"Bethany D Latham, Raeanne M Geffert, Klarissa D Jackson","doi":"10.1124/dmd.123.001430","DOIUrl":"10.1124/dmd.123.001430","url":null,"abstract":"<p><p>Small molecule kinase inhibitors are one of the fastest growing classes of drugs, which are approved by the US Food and Drug Administration (FDA) for cancer and noncancer indications. As of September 2023, there were over 70 FDA-approved small molecule kinase inhibitors on the market, 42 of which were approved in the past five years (2018-2023). This minireview discusses recent advances in our understanding of the pharmacology, metabolism, and toxicity profiles of recently approved kinase inhibitors with a central focus on tyrosine kinase inhibitors (TKIs). In this minireview we discuss the most common therapeutic indications and molecular target(s) of kinase inhibitors FDA approved 2018-2023. We also describe unique aspects of the metabolism, bioactivation, and drug-drug interaction (DDI) potential of kinase inhibitors; discuss drug toxicity concerns related to kinase inhibitors, such as drug-induced liver injury; and highlight clinical outcomes and challenges relevant to TKI therapy. Case examples are provided for common TKI targets, metabolism pathways, DDI potential, and risks for serious adverse drug reactions. The minireview concludes with a discussion of perspectives on future research to optimize TKI therapy to maximize efficacy and minimize drug toxicity. SIGNIFICANCE STATEMENT: This minireview highlights important aspects of the clinical pharmacology and toxicology of small molecule kinase inhibitors FDA approved 2018-2023. We describe key advances in the therapeutic indications and molecular targets of TKIs. The major metabolism pathways and toxicity profiles of recently approved TKIs are discussed. Clinically relevant case examples are provided that demonstrate the risk for hepatotoxic drug interactions involving TKIs and coadministered drugs.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"479-492"},"PeriodicalIF":3.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11114602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytochrome P450 Enzymes as Drug Targets in Human Disease.","authors":"F Peter Guengerich","doi":"10.1124/dmd.123.001431","DOIUrl":"10.1124/dmd.123.001431","url":null,"abstract":"<p><p>Although the mention of cytochrome P450 (P450) inhibition usually brings to mind unwanted variability in pharmacokinetics, in several cases P450s are good targets for inhibition. These P450s are essential, but in certain disease states, it is desirable to reduce the concentrations of their products. Most of the attention to date has been with human P450s 5A1, 11A1, 11B1, 11B2, 17A1, 19A1, and 51A1. In some of those cases, there are multiple drugs in use, e.g., exemestane, letrozole, and anastrozole with P450 19A1, the steroid aromatase target in breast cancer. There are also several targets that are less developed, e.g., P450s 2A6, 8B1, 4A11, 24A1, 26A1, and 26B1. SIGNIFICANCE STATEMENT: The selective inhibition of certain cytochrome P450s that have major physiological functions has been shown to be very efficacious in certain human diseases. In several cases, the search for better drugs continues.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"493-497"},"PeriodicalIF":3.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11114603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41114555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Special Section on Cytochrome P450 Enzymes in Toxicology and as Drug Targets-Editorial.","authors":"Xiao-Bo Zhong, Yurong Lai","doi":"10.1124/dmd.124.001763","DOIUrl":"https://doi.org/10.1124/dmd.124.001763","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"52 6","pages":"476-478"},"PeriodicalIF":3.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956080","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":"Correction to \"Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study\".","authors":"","doi":"10.1124/dmd.118.080523err","DOIUrl":"https://doi.org/10.1124/dmd.118.080523err","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"52 6","pages":"580"},"PeriodicalIF":3.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955987","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":"After fifty years of hepatic clearance models, where should we go from here? Improvements and implications for PBPK modeling","authors":"K. Sandy Pang, Weijia Ivy Lu, Gerard J. Mulder","doi":"10.1124/dmd.124.001649","DOIUrl":"https://doi.org/10.1124/dmd.124.001649","url":null,"abstract":"There is overwhelming preference for application of the unphysiologic, well-stirred model (WSM) over the parallel tube (PTM) and dispersion (DM) models to predict hepatic drug clearance, CLH, despite that liver blood flow is dispersive and closer to the DM in nature. The reasoning is the ease in computation relating the hepatic intrinsic clearance (CL_int), hepatic blood flow (Q_H), unbound fraction in blood (fu_b) and the transmembrane clearances (CL_in and CL_ef) to CL_H for the WSM. However, the WSM, being the least efficient liver model, predicts a lower E_H that is associated with the in vitro CL_int (V_max/K_m), therefore requiring scale-up to predict CL_H in vivo. By contrast, the miniPTM, a 3-subcompartment tanks-in-series model of uniform enzymes, closely mimics the DM and yielded similar patterns for CL_int vs. E_H, substrate concentration [S], and K_L/B, the tissue to outflow blood concentration ratio. We placed these liver models nested within PBPK models to describe the kinetics of the flow-limited, phenolic substrate, harmol, using the WSM (single compartment) and the miniPTM and ZLM (zonal liver) models of evenly- and unevenly-distributed glucuronidation and sulfation activities, respectively, to predicted CL_H. For the same, given CL_int (V_max and K_m), the WSM again furnished the lowest extraction ratio (E_H,WSM = 0.5) compared to the miniPTM and ZLM (&gt;0.68). Values of E_H,WSM were elevated to those for E_H,PTM and E_H,ZLM when the V_maxs for sulfation and glucuronidation were raised 5.7 to 1.15-fold. The miniPTM is easily manageable mathematically and should be the new normal for liver/physiological modeling.","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"12 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140927494","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}