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Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-14 Bechtold, B. J., Lynch, K. D., Oyanna, V. O., Call, M. R., White, L. A., Graf, T. N., Oberlies, N. H., Clarke, J. D.
Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1B) transporters encoded by the solute carrier organic anion transporter (SLCO) genes mediate uptake of multiple pharmaceutical compounds. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), decreases OATP1B abundance. This research characterized the pathological and pharmacokinetics
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CYP7A1 gene induction via SHP-dependent or independent mechanisms can increase the risk of drug-induced liver injury independently or in synergy with BSEP inhibition Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-14 Congrong Niu, Xiaodong Xie, Renmeng Liu, Xiaomin Liang, Yiding Hu, Yurong Lai
Drug-induced liver injury (DILI) is a frequent cause of clinical trial failures during drug development. While inhibiting BSEP is a well-documented DILI mechanism, interference with genes related to bile acid (BA) metabolism and transport can further complicate DILI development. Here, the effects of twenty-eight compounds on genes associated with BA metabolism and transport were evaluated, including
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LX-2 stellate cells are a model system for investigating the regulation of hepatic vitamin A metabolism and respond to tumor necrosis factor alpha and interleukin 1 beta Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-14 Lindsay C Czuba, Nina Isoherranen
Hepatic stellate cells (HSC) are the major site of vitamin A (retinol) esterification and subsequent storage as retinyl esters within lipid droplets. However, retinyl esters become depleted in many pathophysiological states, including acute and chronic liver injuries. Recently, using a liver slice culture system as a model of acute liver injury and fibrogenesis, a time-dependent increase and decrease
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Interaction and Transport of Benzalkonium Chlorides by the Organic Cation and Multidrug and Toxin Extrusion Transporters Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-04-01 Letícia Salvador Vieira, Ryan P. Seguin, Libin Xu, Joanne Wang
Humans are chronically exposed to benzalkonium chlorides (BACs) from environmental sources. The U.S. Food and Drug Administration (FDA) has recently called for additional BAC safety data, as these compounds are cytotoxic and have great potential for biochemical interactions. Biodistribution studies revealed that BACs extensively distribute to many tissues and accumulate at high levels, especially in
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Novel Tree Shrew Cytochrome P450 2Ds (CYP2D8a and CYP2D8b) Are Functional Drug-Metabolizing Enzymes that Metabolize Bufuralol and Dextromethorphan Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-04-01 Genki Ushirozako, Norie Murayama, Kyoko Tsukiyama-Kohara, Hiroshi Yamazaki, Yasuhiro Uno
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Use of a Double-Transfected System to Predict hOCT2/hMATE1-Mediated Renal Drug-Drug Interactions Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-13 Vieira, L. S., Wang, J.
Accurate predictions of renal drug–drug interactions (DDIs) mediated by the human organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins (hMATEs) remain challenging. Current DDI evaluation using plasma maximal unbound inhibitor concentrations (Imax,u) and IC50 values determined in single transporter-transfected cells frequently leads to false or overprediction especially for
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Cytosolic 5′-Nucleotidase III and Nucleoside Triphosphate Diphosphohydrolase 1 Dephosphorylate the Pharmacologically Active Metabolites of Gemcitabine and Emtricitabine Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-04-01 Nav Raj Phulara, Chiaki Tsuge Ishida, Peter J. Espenshade, Herana Kamal Seneviratne
Gemcitabine (dFdC) and emtricitabine (FTC) are first-line drugs that are used for the treatment of pancreatic cancer and human immunodeficiency virus, respectively. The above drugs must undergo sequential phosphorylation to become pharmacologically active. Interindividual variability associated with the responses of the above drugs has been reported. The molecular mechanisms underlying the observed
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Gut Microbiome Integration in Drug Discovery and Development of Small Molecules Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-04-01 Patrick Jimonet, Céline Druart, Stéphanie Blanquet-Diot, Lilia Boucinha, Stephanie Kourula, Françoise Le Vacon, Sylvie Maubant, Sylvie Rabot, Tom Van de Wiele, Frank Schuren, Vincent Thomas, Bernard Walther, Michael Zimmermann, on behalf of Medicen Microbiome Drug Metabolism Working Group
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Pharmacogenetic influence on stereoselective steady-state disposition of bupropion Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-11 Kharasch, E. D., Lenze, E. J.
Bupropion is used for treating depression, obesity, seasonal affective disorder, and for smoking cessation. Bupropion is commonly-prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active
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An Integrated Hepatocyte Stability Assay for Simultaneous Metabolic Stability Assessment and Metabolite Profiling Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-04 Christian Leung, Joyce Liu, Katherine Cunico, Kevin Johnson, Zhengyin Yan, Jingwei Cai
The determination of metabolic stability is critical for drug discovery programs, allowing for the optimization of chemical entities and compound prioritization. As such, it is common to perform high-volume in vitro metabolic stability experiments early in the lead optimization process to understand metabolic liabilities. Additional metabolite identification experiments are subsequently performed for
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In Vitro to In Vivo Scalars for Drug Clearance in Non-Alcoholic Fatty Liver and Steatohepatitis Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-29 Teresa Sierra, Brahim Achour
In vitro-in vivo extrapolation (IVIVE) allows prediction of clinical outcomes across populations from in vitro data using specific scalars tailored to the biological characteristics of each population. This study experimentally determined scalars for patients with varying degrees of non-alcoholic fatty liver disease (NAFLD), ranging from fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis
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Enzymatic defluorination of a terminally monofluorinated pentyl moiety: oxidative or hydrolytic mechanism? Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-26 Haschimi, B., Willecke, F., Mundinger, S., Hüttel, W., Jessen, H., Müller, M., Auwärter, V.
Fluorination of organic compounds plays an important role in the chemical and pharmaceutical industry and is often applied in order to improve physicochemical parameters or modify pharmacological properties. While oxidative and reductive defluorination have been shown to be responsible for the metabolic degradation of organofluorine compounds, the involvement of hydrolytic mechanisms catalyzed by human
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Projections of Drug-Drug Interactions Caused by Time-Dependent Inhibitors of Cytochrome P450 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 Using In Vitro Data in Static and Dynamic Models Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-26 Tseng, E., Lin, J., Strelevitz, T. J., DaSilva, E., Goosen, T. C., Obach, R. S.
In vitro time-dependent inhibition (TDI) kinetic parameters for cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6, were determined in pooled human liver microsomes for 19 drugs (and 2 metabolites) for which clinical drug-drug interactions (DDI) are known. In vitro TDI data were incorporated into the projection of the magnitude of DDIs using mechanistic static models and Simcyp®. Results suggest
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Low molecular weight acids and OATP1B mediated hepatic clearance: In vitro and in vivo evaluation using novel hypoxia-inducible factor prolyl hydroxylase inhibitors (Dustats) Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-22 Yi-An Bi, Samantha Jordan, Amanda King-Ahmad, Mark A. West, Emi Yamaguchi, Sangwoo Ryu, Sumathy Mathialagan, David A. Tess, Manthena V. S. Varma
Organic anion transporting polypeptide (OATP1B) plays a key role in the hepatic clearance of a majority of high molecular weight (MW) acids and zwitterions. Here, we evaluated the role of OATP1B-mediated uptake in the clearance of novel hypoxia-inducible factor prolyl hydroxylase inhibitors ("Dustats"), which are typically low MW (300-400 daltons) aliphatic carboxylic acids. Five acid dustats, namely
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Identification and Biosynthesis of an N-Glucuronide Metabolite of Camonsertib Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-20 Robert Papp, Laird Trimble, Adrian J Fretland, Ravi Manohar, Richard Phipps, Lisbet Kvaerno, Alexander L Perryman, Gregory Reynolds, W. Cameron Black
Camonsertib is a novel ATR kinase inhibitor in clinical development for advanced cancers targeting sensitizing mutations. This article describes the identification and biosynthesis of an N-glucuronide metabolite of camonsertib. This metabolite was first observed in human hepatocyte incubations and was subsequently isolated to determine the structure, evaluate its stability as part of bioanalytical
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Assessing trends in cytokine-CYP drug interaction and relevance to drug dosing Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-21 Sawant-Basak, A., Olabode, D., Dai, D., Vishwanathan, K., Phipps, A.
The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied, in vitro and in clinic. Cytokine-mediated suppression of CYPs or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug
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Improving In Vitro-In VivoExtrapolation (IVIVE) of Clearance Using Rat Liver Microsomes for Highly Plasma Protein Bound Molecules Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-15 Markus Trunzer, Joana Teigão, Felix Huth, Birk Poller, Sandrine Desrayaud, Raquel Rodríguez-Pérez, Bernard Faller
It is common practice in drug discovery and development to predict in vivo hepatic clearance from in vitro incubations with liver microsomes or hepatocytes using the well-stirred model (WSM). When applying the WSM to a set of about 3000 Novartis research compounds, 73% of neutral and basic compounds (extended clearance classification system ECCS class 2) were well-predicted within 3-fold. In contrast
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Radiolabel uncovers nonintuitive metabolites of AMPAR potentiator BIIB104: Novel release of [14C]cyanide from 2-cyanothiophene and subsequent formation of [14C]thiocyanate Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-15 Chungang Gu, Jiansheng Huang, Cathy Muste, Jeremy Zhong, Gregory S. Walker, R. Scott Obach, Christopher L Shaffer
BIIB104 (formerly PF-04958242), N-((3S,4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide, is an AMPAR potentiator investigated for the treatment of cognitive impairment associated with schizophrenia. Preliminary in vitro metabolism studies with non-radiolabeled BIIB104 in rat, dog, and human liver microsomes (RLM, DLM, and HLM) showed O-dealkylation in all 3 species
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Roles of the ABCG2 transporter in protoporphyrin IX distribution and toxicity Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-13 Qi, Q., Gu, R., Zhu, J., Anderson, K. E., Ma, X.
ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity.
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Novel Cytochrome P450 2C119 Enzymes in Cynomolgus and Rhesus Macaques Metabolize Progesterone, Diclofenac, and Omeprazole Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-01 Yasuhiro Uno, Norie Murayama, Hiroshi Yamazaki
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Natural Products Inhibition of Cytochrome P450 2B6 Activity and Methadone Metabolism Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-14 Wang, P.-F., Yang, Y., Patel, V., Neiner, A., Kharasch, E. D.
Methadone is cleared predominately by hepatic cytochrome P450 (CYP) 2B6-catalyzed metabolism to inactive metabolites. CYP2B6 also catalyzes the metabolism of several other drugs. Methadone and CYP2B6 are susceptible to pharmacokinetic drug–drug interactions. Use of natural products such as herbals and other botanicals is substantial and growing, and concomitant use of prescription medicines and non-prescription
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Biocatalysis using Thermostable Cytochrome P450 Enzymes in Bacterial Membranes – Comparison of Metabolic Pathways with Human Liver Microsomes and Recombinant Human Enzymes Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-01 Ulrik Jurva, Ann-Sofie Sandinge, Jong Min Baek, Mickaël Avanthay, Raine E. S. Thomson, Stephlina A. D’Cunha, Shalini Andersson, Martin A. Hayes, Elizabeth M. J. Gillam
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Assessing Pleiotropic Effects of a Mixed-Mode Perpetrator Drug, Rifampicin, by Multiple Endogenous Biomarkers in Dogs Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-01 Renmeng Liu, Bin Ma, Marilyn M. Mok, Bernard P. Murray, Raju Subramanian, Yurong Lai
Rifampicin (RIF) is a mixed-mode perpetrator that produces pleiotropic effects on liver cytochrome P450 enzymes and drug transporters. To assess the complex drug-drug interaction liabilities of RIF in vivo, a known probe substrate, midazolam (MDZ), along with multiple endogenous biomarkers were simultaneously monitored in beagle dogs before and after a 7-day treatment period by RIF at 20 mg/kg per
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Correlation of In Vitro Kinetic Stability to Preclinical In Vivo Pharmacokinetics for a Panel of Anti-PD-1 Monoclonal Antibody Interleukin 21 Mutein Immunocytokines Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-01 Kevin D. Cook, Thuy Tran, Veena A. Thomas, Siva Charan Devanaboyina, Dan A. Rock, Josh T. Pearson
The development of therapeutic fusion protein drugs is often impeded by the unintended consequences that occur from fusing together domains from independent naturally occurring proteins, consequences such as altered biodistribution, tissue uptake, or rapid clearance and potential immunogenicity. For therapeutic fusion proteins containing globular domains, we hypothesized that aberrant in vivo behavior
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Identification and Functional Assessment of EightCYP3A4Allelic Variants*39–*46Detected in the Chinese Han Population Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-01 Yuying Qi, Hang Yang, Shuanghu Wang, Lili Zou, Fangling Zhao, Qing Zhang, Yun Hong, Qingfeng Luo, Quan Zhou, Peiwu Geng, Hao Chen, Fusui Ji, Jianping Cai, Dapeng Dai
Cytochrome P450 3A4 (CYP3A4), a key enzyme, is pivotal in metabolizing approximately half of the drugs used clinically. The genetic polymorphism of the CYP3A4 gene significantly influences individual variations in drug metabolism, potentially leading to severe adverse drug reactions (ADRs). In this study, we conducted a genetic analysis on CYP3A4 gene in 1163 Chinese Han individuals to identify the
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Association of Valproic Acid and Its Main Metabolites Plasma Concentrations with Clinical Outcomes among Epilepsy Patients: A 10-Year Retrospective Study Based on Therapeutic Drug Monitoring Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-14 Li, R.-t., Chen, Z.-y., Tang, S.-y., Wen, D.-s., Ren, R.-n., Zhang, X.-x., Liu, S.-z., Zhou, S., Wang, X.-d., Zhou, L.-m., Huang, M.
Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50–100 μg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective
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The Current Status and Use of Microphysiological Systems by the Pharmaceutical Industry: The International Consortium for Innovation and Quality Microphysiological Systems Affiliate Survey and Commentary Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-01 Thomas K. Baker, Terry R. Van Vleet, Prathap Kumar Mahalingaiah, Taraka Sai Pavan Grandhi, Raymond Evers, Jason Ekert, James R. Gosset, Silvi A. Chacko, Anna K. Kopec
Microphysiological systems (MPS) are comprised of one or multiple cell types of human or animal origins that mimic the biochemical/electrical/mechanical responses and blood-tissue barrier properties of the cells observed within a complex organ. The goal of incorporating these in vitro systems is to expedite and advance the drug discovery and development paradigm with improved predictive and translational
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Dihydrotanshinone I–Induced CYP1 Enzyme Inhibition and Alteration of Estradiol Metabolism Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-01 Ying Liu, Yu Chen, Jingyu Zhang, Guangyun Ran, Zihao Cheng, Xin Wang, Yufen Liao, Xu Mao, Ying Peng, Weiwei Li, Jiang Zheng
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Effects of Strong Inhibition of Cytochrome P450 3A and UDP glucuronosyltransferase 1A9 and Strong Induction of Cytochrome P450 3A on the Pharmacokinetics, Safety, and Tolerability of Soticlestat: Two Drug-Drug Interaction Studies in Healthy Volunteers Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-14 Yin, W., Dong, C., Stevenson, A., Lloyd, V., Petrillo, M., Baratta, M., Hui, T., Han, S.
Two open-label, phase 1 studies (NCT05064449, NCT05098041) investigated the effects of cytochrome P450 (CYP) 3A inhibition (via itraconazole), UDP glucuronosyltransferase (UGT) 1A9 inhibition (via mefenamic acid), and CYP3A induction (via rifampin) on the pharmacokinetics of soticlestat and its metabolites M-I and M3. In period 1 of both studies, participants received a single dose of soticlestat 300
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Chronic Exposure to E-Cigarettes Elevates CYP2A5 Activity, Protein Expression, and Cotinine-Induced Production of Reactive Oxygen Species in Mice Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-01 Keiko Kanamori, Syed M. Ahmad, Abdul Hamid, Kabirullah Lutfy
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Leveraging in Vitro Models for Clinically Relevant Rare CYP2D6 Variants in Pharmacogenomics Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-14 Stern, S., Hyland, P. L., Pacanowski, M., Schuck, R. N.
Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of up to 20% of small-molecule drugs and therefore, may impact the safety and efficacy of medicines in broad therapeutic areas. CYP2D6 is highly polymorphic, and the frequency of variants can differ across racial and ethnic populations, significantly affecting enzymatic function and drug metabolism. However, rare variants of CYP2D6 present
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Recommendations on the Use of Multiple Labels in Human Mass Balance Studies Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-03-01 Filip Cuyckens, Mette G. Hvenegaard, Kenneth C. Cassidy, Douglas K. Spracklin, Alexander D. James, Mette L. Pedersen, Graeme Scarfe, David S. Wagner, Katrin Georgi, Simone I. Schulz, Hanno Schieferstein, Inga Bjornsdottir, Andrea A. Romeo, Georges Da Violante, Stefan Blech, Patricia Moliner, Graeme C. Young
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NT5C3 and NTPDase 1 Dephosphorylate the Pharmacologically Active Metabolites of Gemcitabine and Emtricitabine Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-08 Phulara, N. R., Ishida, C. T., Espenshade, P. J., Seneviratne, H. K.
Gemcitabine (dFdC) and emtricitabine (FTC) are first-line drugs that are used for the treatment of pancreatic cancer and HIV, respectively. The above drugs must undergo sequential phosphorylation to become pharmacologically active. Interindividual variability associated with the responses of the above drugs has been reported. The molecular mechanisms underlying the observed variability are yet to be
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Physiologically Based Pharmacokinetic (PBPK) Modeling of small molecules: How Much Progress Have We Made? Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-07 Nina Isoherranen
Physiologically based pharmacokinetic (PBPK) models of small molecules have become mainstream in drug development and academic research. The use of PBPK models is continuously expanding with the majority of work now focusing on predictions of drug-drug interactions, drug-disease interactions, and changes in drug disposition across lifespan. Recently, publications that use PBPK modeling to predict drug
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Use of a Double-Transfected System to Predict hOCT2/hMATE1-mediated Renal Drug-drug Interactions Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-07 Letícia S. Vieira, Joanne Wang
Accurate predictions of renal drug-drug interactions (DDIs) mediated by the human organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins (hMATEs) remain challenging. Current DDI evaluation using plasma maximal unbound inhibitor concentrations (Imax,u) and IC50 values determined in single transporter-transfected cells frequently leads to false or overprediction especially for
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The discovery of gut microbial metabolites as modulators of host susceptibility to acetaminophen-induced hepatotoxicity Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-01 Lee, H., Yang, X., Jin, P.-R., Won, K.-J., Kim, C. H., Jeong, H.
The mammalian gut microbiota plays diverse and essential roles in modulating host physiology. Key mediators determining the outcome of the microbiota-host interactions are the small molecule metabolites produced by the gut microbiota. The liver is the organ massively exposed to gut microbial metabolites, and it serves as the nexus, maintaining healthy interactions between the gut microbiota and host
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Utility of PBPK Modeling in Predicting and Characterizing Clinical Drug Interactions Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-30 Robert S. Foti
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. 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 utilized
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Exogenous Pregnane X Receptor Does Not Undergo Liquid-liquid Phase Separation in Nucleus under Cell-based In Vitro Conditions Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-31 Pengfei Zhao, Yue Gao, Yanying Zhou, Min Huang, Shicheng Fan, Huichang Bi
Pregnane X receptor (PXR) belongs to the nuclear receptor superfamily that plays a crucial role in hepatic physiological and pathological conditions. Phase separation is a process in which biomacromolecules aggregate and condense into a dense phase as liquid condensates and coexist with a dilute phase, contributing to various cellular and biological functions. Till now, whether PXR could undergo phase
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Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-29 Jessica L Beers, Zhu Zhou, Klarissa D. Jackson
Cannabidiol (CBD) is a pharmacologically active metabolite of cannabis that is FDA-approved to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged one 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 (VPA)
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Kinase Inhibitors FDA-Approved 2018-2023: Drug Targets, Metabolic Pathways, and Drug-Induced Toxicities Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-29 Bethany D Latham, Raeanne M Geffert, Klarissa D. Jackson
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 non-cancer 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
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HCV antiviral drugs have the potential to adversely perturb the maternal-fetal communication axis through inhibition of CYP3A7 DHEA-S oxidation Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-24 Hannah M. Work, John C Hackett, Jed N. Lampe
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
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Pharmacometabolomics in Drug Disposition, Toxicity and Precision Medicine Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-16 Trevor, G. R., Lim, Y. J., Urquhart, B. L.
The precision medicine initiative has driven a substantial change in the way scientists and health care practitioners think about diagnosing and treating disease. While it has long been recognized that drug response is determined by the intersection of genetic, environmental and disease factors, improvements in technology have afforded precision medicine guided dosing of drugs to improve efficacy and
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Association of valproic acid and its main metabolites' plasma concentrations with clinical outcomes among epilepsy patients: a 10-year retrospective study based on therapeutic drug monitoring Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-09 Rui-tong Li, Zi-yi Chen, Si-yuan Tang, Ding-sheng Wen, Rui-na Ren, Xiao-xu Zhang, Song-ze Liu, Shan Zhou, Xue-ding Wang, Lie-min Zhou, Min Huang
Background:Valproic acid (VPA) is a first-line anti-epileptic drug with broad efficacy.Due to significant individual differences in drug metabolism, therapeutic drug monitoring (TDM) is commonly used. However, the conventional therapeutic range (50-100 μg/mL) is inadequate for predicting clinical outcomes.Additionally, the relationship between VPA metabolites and patient outcomes remains unclear.MethodsIn
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Novel Independent Trans- and Cis-Genetic Variants Associated with CYP2D6 Expression and Activity in Human Livers Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-01 Dylan Smith, Bing He, Jian Shi, Hao-Jie Zhu, Xinwen Wang
Cytochrome P450 2D6 (CYP2D6) is a critical hepatic drug-metabolizing enzyme in humans, responsible for metabolizing approximately 20%–25% of commonly used medications such as codeine, desipramine, fluvoxamine, paroxetine, and tamoxifen. The CYP2D6 gene is highly polymorphic, resulting in substantial interindividual variability in its catalytic function and the pharmacokinetics and therapeutic outcomes
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Preclinical Characterization of Catabolic Pathways and Metabolism of ABBV-011, a Novel Calicheamicin-Based SEZ6-Targeting Antibody-Drug Conjugate Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-01 Daniel Ladror, Christine Gu, Vince Tong, Alexander Schammel, Julia Gavrilyuk, Anthony Haight, Hetal Sarvaiya
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Comparison of 1Beta- and 5Beta-hydroxylation of Deoxycholate and Glycodeoxycholate as In Vitro Index Reactions for Cytochrome P450 3A Activities Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-09 Wang, C., Cheng, B., Wei, W., Gui, L., Zeng, W., Wang, Y., Wang, Y., Chen, Q., Xu, L., Miao, J., Lan, K.
Cytochrome P450 3A (CYP3A) participates in the metabolism of more than 30% of clinical drugs. The vast intra- and inter-individual variations in CYP3A activity pose great challenges to drug development and personalized medicine. It has been disclosed that human CYP3A4 and CYP3A7 are exclusively responsible for the tertiary oxidations of deoxycholic acid (DCA) and glycodeoxycholic acid (GDCA) regioselectivity
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Association Between Gadoxetic Acid-Enhanced Magnetic Resonance Imaging, Organic Anion Transporters, and Farnesoid X Receptor in Benign Focal Liver Lesions Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-01 Belle V. van Rosmalen, Michele Visentin, Alicia Furumaya, Otto M. van Delden, Geert Kazemier, Thomas M. van Gulik, Joanne Verheij, Bruno Stieger
The organic anion uptake and efflux transporters [organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and multidrug resistance-associated protein (MRP)2 and MRP3] that mediate the transport of the hepatobiliary-specific contrast agent gadoxetate (Gd-EOB-DTPA) are direct or indirect targets of the farnesoid X receptor (FXR), a key regulator of bile acid and lipid homeostasis. In benign liver tumors
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Cytochrome P450 2B6 and UDP-Glucuronosyltransferase Enzyme–Mediated Clearance of Ciprofol (HSK3486) in Humans: The Role of Hepatic and Extrahepatic Metabolism Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-01 Yufan Zhou, Hongjiao Dong, Jiang Fan, Mingshe Zhu, Lu Liu, Yongbin Wang, Pingming Tang, Xiaoyan Chen
Ciprofol (HSK3486) is a novel intravenous agent for general anesthesia. In humans, HSK3486 mainly undergoes glucuronidation to form M4 [fraction of clearance (fCL): 62.6%], followed by the formation of monohydroxylated metabolites that further undergo glucuronidation and sulfation to produce M5-1, M5-2, M5-3, and M3 (summed fCL: 35.2%). However, the complete metabolic pathways of HSK3486 in humans
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Utilizing a Dual Human Transporter MDCKII-MDR1-BCRP Cell Line to Assess Efflux at the Blood Brain Barrier Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-09 Colclough, N., Alluri, R. V., Tucker, J. W., Gozalpour, E., Li, D., Du, H., Li, W., Harlfinger, S., ONeill, D. J., Sproat, G. G., Chen, K., Yan, Y., McGinnity, D. F.
To facilitate the design of drugs readily able to cross the blood brain barrier (BBB), a Madin–Darby canine kidney (MDCK) cell line was established that over expresses both P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), the main human efflux transporters of the BBB. Proteomics analyses indicate BCRP is expressed at a higher level than Pgp in this cell line. This cell line shows good
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Effect of Cimetidine on Metformin Pharmacokinetics and Endogenous Metabolite Levels in Rats Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-01 Anoud Sameer Ailabouni, Vijaya Saradhi Mettu, Aarzoo Thakur, Dilip Kumar Singh, Bhagwat Prasad
Tubular secretion is a primary mechanism along with glomerular filtration for renal elimination of drugs and toxicants into urine. Organic cation transporters (OCTs) and multidrug and toxic extrusion (MATE) transporters facilitate the active secretion of cationic substrates, including drugs such as metformin and endogenous cations. We hypothesized that administration of cimetidine, an Oct/Mate inhibitor
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Vincristine Disposition and Neurotoxicity Are Unchanged in Humanized CYP3A5 Mice Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-01 Yang Li, Yasuhiro Kazuki, Thomas Drabison, Kaoru Kobayashi, Ken-ichi Fujita, Yue Xu, Yan Jin, Eman Ahmed, Junan Li, Eric D. Eisenmann, Sharyn D. Baker, Guido Cavaletti, Alex Sparreboom, Shuiying Hu
Previous studies have suggested that the incidence of vincristine-induced peripheral neuropathy (VIPN) is potentially linked with cytochrome P450 (CYP)3A5, a polymorphic enzyme that metabolizes vincristine in vitro, and with concurrent use of azole antifungals such as ketoconazole. The assumed mechanism for these interactions is through modulation of CYP3A-mediated metabolism, leading to decreased
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Deciphering the Role of Fatty Acid–Metabolizing CYP4F11 in Lung Cancer and Its Potential As a Drug Target Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-02-01 Huiting Jia, Bjoern Brixius, Caleb Bocianoski, Sutapa Ray, David R. Koes, Simone Brixius-Anderko
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Leveraging in Vitro Models for Clinically Relevant RareCYP2D6Variants in Pharmacogenomics Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-02 Sydney Stern, Paula L. Hyland, Michael Pacanowski, Robert Schuck
Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of up to 20% of small molecule drugs, and therefore may impact the safety and efficacy of medicines in broad therapeutic areas. CYP2D6 is highly polymorphic, and the frequency of variants can differ across racial and ethnic populations, significantly affecting enzymatic function and drug metabolism. However, rare variants of CYP2D6 present
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Natural Products Inhibition of CYP2B6 Activity and Methadone Metabolism Drug Metab. Dispos. (IF 3.9) Pub Date : 2023-12-22 Wang, P.-F., Yang, Y., Patel, V., Neiner, A., Kharasch, E. D.
Methadone is cleared predominately by hepatic CYP2B6-catalyzed metabolism to inactive metabolites. CYP2B6 also catalyzes the metabolism of several other drugs. Methadone and CYP2B6 are susceptible to pharmacokinetic drug-drug interactions. Use of natural products such as herbals and other botanicals is substantial and growing, concomitant use of prescription medicines and non-prescription herbals is
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Effects of Strong Inhibition of CYP3A and UGT1A9 and Strong Induction of CYP3A on the Pharmacokinetics, Safety, and Tolerability of Soticlestat: Two Drug-Drug Interaction Studies in Healthy Volunteers Drug Metab. Dispos. (IF 3.9) Pub Date : 2023-12-20 Yin, W., Dong, C., Stevenson, A., Lloyd, V., Petrillo, M., Baratta, M., Hui, T., Han, S.
Two open-label, phase 1 studies (NCT05064449, NCT05098041) investigated the effects of CYP3A inhibition (via itraconazole), UGT1A9 inhibition (via mefenamic acid), and CYP3A induction (via rifampin) on the pharmacokinetics of soticlestat and its metabolites M-I and M3. In period 1 of both studies, participants received a single dose of soticlestat 300 mg. In period 2, participants received itraconazole
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Real-world application of PBPK in drug discovery Drug Metab. Dispos. (IF 3.9) Pub Date : 2023-12-12 Laura G A Santos, Swati Jaiswal, Kuan-Fu Chen, Hannah M. Jones, Ian E. Templeton
The utility of PBPK models in support of drug development has been well documented. During the discovery stage, PBPK 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
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Time-Dependent Inhibition of CYP1A2 by Stiripentol and Structurally Related Methylenedioxyphenyl Compounds via Metabolic Intermediate Complex Formation Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-01 Yasuhiro Masubuchi, Chieko Takahashi, Rina Gendo
Stiripentol (STP), an antiepileptic agent, causes drug–drug interactions by inhibiting cytochrome P450 (P450) enzymes. STP contains a methylenedioxyphenyl (MDP) group, which could form inhibitory metabolic intermediate complexes (MICs) with P450. The present study examined the possible time-dependent inhibition of CYP1A2 via MIC formation by STP and structurally related MDP compounds such as isosafrole
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Construction of HumanizedCYP1A2Rats Using CRISPR/CRISPR-Associated Protein 9 to Promote Drug Metabolism and Pharmacokinetic Research Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-01 Jie Liu, Jian Lu, Bingyi Yao, Yuanjin Zhang, Shengbo Huang, Xi Chen, Yifei Shen, Xin Wang
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Physiologically-Based Pharmacokinetic Modeling for Drugs Cleared by Non-Cytochrome P450 Enzymes: State-of-the-Art and Future Perspectives Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-01 Agustos C. Ozbey, Stephen Fowler, Karen Leys, Pieter Annaert, Kenichi Umehara, Neil Parrott
Physiologically-based pharmacokinetic (PBPK) modeling has become the established method for predicting human pharmacokinetics (PK) and drug-drug interactions (DDI). The number of drugs cleared by non-CYP enzyme metabolism has increased steadily and to date, there is no consolidated overview of PBPK modeling for drugs cleared by non-CYP enzymes. This review aims to describe the state-of-the-art PBPK
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Pharmacokinetic Models Scaled Up from Humanized Liver Mouse Data Can Account for Drug Monitoring Results of Atomoxetine and Its 4-Hydroxylated andN-Demethylated Metabolites in Pediatric Patients Genotyped for CytochromeP450 2D6 Drug Metab. Dispos. (IF 3.9) Pub Date : 2024-01-01 Makiko Shimizu, Shotaro Uehara, Katsuhiro Ohyama, Haruka Nishimura, Yoichi Tanaka, Yoshiro Saito, Hiroshi Suemizu, Sayaka Yoshida, Hiroshi Yamazaki