Article
Pharmacology & Pharmacy
Hanna Cheropkina, Gianluca Catucci, Arianna Marucco, Ivana Fenoglio, Gianfranco Gilardi, Sheila J. Sadeghi
Summary: Out of the five isoforms of human flavin-containing monooxygenase, FMO1 and FMO3 are the most relevant to Phase I drug metabolism. FMO1 was found to form a highly stable C4ahydroperoxyflavin intermediate upon reduction by NADPH and in the presence of O-2, which is more stable compared to FMO3. Additionally, uncoupling reactions of FMO1 show minimal uncoupling in the presence of substrate.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Stefania Bortolussi, Gianluca Catucci, Gianfranco Gilardi, Sheila J. Sadeghi
Summary: Human FMO3 enzyme is highly polymorphic, with variants demonstrating differences in substrate turnover rates. Studies on engineered proteins of common polymorphic variants show that the truncated, more soluble enzymes are better catalysts than full-length proteins. This suggests potential use of soluble enzyme forms for in vitro drug assays and biotechnological applications in high throughput systems.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2021)
Article
Pharmacology & Pharmacy
Yasuhiro Uno, Makiko Shimizu, Yurie Ogawa, Miaki Makiguchi, Hiroaki Kawaguchi, Osamu Yamato, Mayumi Ishizuka, Hiroshi Yamazaki
Summary: In this study, orthologous FMO cDNAs were isolated and characterized from pig, dog, and cat livers. These FMOs shared high sequence identities with human FMOs and exhibited similar catalytic functions. Dog and cat FMO3 were found to be molecularly and functionally similar to human FMO3, suggesting their importance in drug metabolism.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Su Min Choi, Van Cong Pham, Sangkyu Lee, Jeong Ah Kim
Summary: Cinnamomum cassia L. is known worldwide as a spice, flavoring agent, and traditional medicine. Diterpenoids found in C. cassia have various pharmacological effects, but there is limited research on their metabolism. This study investigated the metabolism of seven diterpenoids from C. cassia in human liver microsomes, with most compounds showing high metabolic stability except for AHC, which was rapidly metabolized and involved the CYP3A4 isoform in the metabolic pathway.
Article
Veterinary Sciences
Jianlou Song, Xuefeng Shi, Xianyu Li, Qianni Liang, Lingsen Zeng, Guangqi Li, Yiyuan Yan, Guiyun Xu, Jiangxia Zheng
Summary: This study evaluated the effects of the T329S mutation in FMO3 on atherosclerosis, fatty liver syndrome, and adiposity in older laying hens. The results showed that the T329S mutation reduced the development of atherosclerosis lesions, the incidence of fatty liver syndrome, and fat deposition. Additionally, it improved the laying performance of older layers.
FRONTIERS IN VETERINARY SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Shintaro Inoue, Rihito Morita, Yoshiko Minami
Summary: The study cloned PtFMO from Polygonum tinctorium, revealing its capability to induce indigo production and its collaborative effect with PtIGS in producing indican.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Agriculture, Multidisciplinary
Lianshan Li, Haiyan Shi, Xiude Hua, Minghua Wang, Hongjie Wang
Summary: The study revealed different stereoselective metabolism behaviors of fosthiazate in rats and cocks. The main metabolism pathways of fosthiazate were oxidation and hydrolysis, with five common metabolites identified. This study provides accurate data for risk assessment of chiral fosthiazate.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Lukas Kahlert, Darlon Bernardi, Maurice Hauser, Laura P. Ioca, Roberto G. S. Berlinck, Elizabeth J. Skellam, Russell J. Cox
Summary: This study reveals that two FMO enzymes, TerC and TerD, catalyze the oxidative decarboxylation of 6-hydroxymellein to form a highly oxygenated aromatic compound in the biosynthesis of the mycotoxin terrein. The research also suggests that early dehydration of the side chain is an essential step in the synthesis of terrein and related congeners.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Environmental Sciences
Lingling Kong, Pingping Liu, Moli Li, Huizhen Wang, Jiaoxia Shi, Jingjie Hu, Yueru Li, Xiaoli Hu
Summary: Flavin-containing monooxygenase (FMO) plays a detoxification role in bivalves, especially in dealing with toxin-producing algae. Different subfamilies of FMO genes in scallops show distinct expression patterns in larvae and adult organs.
FRONTIERS IN MARINE SCIENCE
(2021)
Article
Biotechnology & Applied Microbiology
Ziyi Yang, Ryan S. Wang, Billy Y. Cheng, Vincent Ruan, Piju Yang, Chen-Hsien Liang, Claire R. Shen
Summary: This study identified two critical residues, M185 and V402, of the flavin-containing monooxygenase from Corynebacterium glutamicum (CgFMO) and generated variants with enhanced indole hydroxylation activity. The best performing mutant M185L/V402A exhibited nearly 10 fold higher catalytic efficiency and greater improvement in the kcat level compared to wild type CgFMO. The study provides insight into the CgFMO active site and aids in the future design of FMO biocatalysts.
BIOCHEMICAL ENGINEERING JOURNAL
(2023)
Article
Cell Biology
Janna C. Nawroth, Debora B. Petropolis, Dimitris Manatakis, Tengku Ibrahim Maulana, Gabriel Burchett, Katharina Schlunder, Anke Witt, Abhishek Shukla, Konstantia Kodella, Janey Ronxhi, Gauri Kulkarni, Geraldine Hamilton, Ekihiro Seki, Shelly Lu, Katia C. Karalis
Summary: This study utilized a human Liver-Chip to model ALD, successfully recapitulating relevant markers of alcohol-induced liver injury and supporting research on secondary insults. Remodeling of the bile canalicular network provided an in vitro quantitative readout of alcoholic liver toxicity.
Article
Agriculture, Multidisciplinary
Zhen Wang, Rui Li, Qiqi Wu, Jinsheng Duan, Yuting Tan, Xiaofang Sun, Rou Chen, Haiyan Shi, Minghua Wang
Summary: This study investigated the enantioselective metabolism and potential mechanisms of PYD in mammals using in vitro and in silico methods. The results showed that S-PYD metabolized faster than R-PYD in rat liver microsomes, and CYP3A1 and carboxylesterase 1 were identified as major enzymes involved in the metabolism of PYD. Computational results further revealed that S-PYD bound more tightly to CYP3A1 and carboxylesterase 1 with lower binding free energy compared to R-PYD, explaining the mechanism of enantioselective metabolism. Nine phase I metabolites of PYD were identified, and the metabolic pathways of PYD were speculated.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2022)
Article
Chemistry, Analytical
Yiling Tang, Linhao Xu, Junbo Zhao, Ping Xiang, Hui Yan
Summary: This study investigated the metabolism of dipentylone in zebrafish and human liver microsomes (HLMs) using liquid chromatography-high resolution mass spectrometry (LC-HRMS). The study identified 14 dipentylone metabolites and found that the monohydroxylated metabolite (M2) can be used as a marker for dipentylone metabolism.
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
(2023)
Article
Biochemistry & Molecular Biology
Yimeng Li, Rui Li, Yuji Sawada, Surina Boerzhijin, Ayuko Kuwahara, Muneo Sato, Masami Yokota Hirai
Summary: Side-chain modification plays a crucial role in the structural diversity of aliphatic glucosinolates. Glucose treatment in Arabidopsis induces FMOGS-OX2 and FMOGS-OX4 expression through the ABA signaling pathway, leading to reduced accumulation of 4MT GSL.
Article
Biochemistry & Molecular Biology
Qian Du, Mengmeng Teng, Luting Yang, Chao Meng, Yulan Qiu, Chuhui Wang, Jiaojiao Chen, Taotao Wang, Siying Chen, Yu Luo, Jinyao Sun, Yalin Dong
Summary: This study investigates the metabolic characteristics and potential mechanisms of Voriconazole (VOR) - induced liver injury. Plasma metabolic profiles were analyzed in a rat model of VOR - induced liver injury, and significant changes were observed in lipid metabolites and cholesterol and bile acids metabolites. Decreased fatty acids oxidation and bile acid excretion might be the potential mechanisms of VOR - induced liver injury.
CHEMICO-BIOLOGICAL INTERACTIONS
(2023)
Article
Pharmacology & Pharmacy
Nele Steenackers, Tim Vanuytsel, Patrick Augustijns, Ellen Deleus, Wies Deckers, Christophe M. Deroose, Gwen Falony, Matthias Lannoo, Ann Mertens, Raf Mols, Roman Vangoitsenhoven, Lucas Wauters, Bart Van der Schueren, Christophe Matthys
Summary: This study investigated the effects of sleeve gastrectomy and Roux-en-Y gastric bypass on gastrointestinal motility, pH, and bile acid concentration. The findings showed that both surgeries increased pouch emptying and gastric emptying, and also led to higher pH levels and bile acid concentrations in the intestines. These results highlight the significant impact of these surgeries on gastrointestinal physiology.
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
(2023)
Article
Medicine, Research & Experimental
Albin Parrow, Per Larsson, Patrick Augustijns, Christel A. S. Bergstrom
Summary: In this study, coarse-grained molecular dynamics simulations were used to investigate the colloidal attributes and drug solubility in human intestinal fluids. The results showed the importance of glycerides in the formation of colloidal structures in the intestinal fluid. Additionally, the study revealed different types of colloidal structures and the impact of digestion and absorption on them. The simulation results were consistent with experimental solubilization data, highlighting the potential of coarse-grained molecular dynamics simulation in studying intestinal fluids.
MOLECULAR PHARMACEUTICS
(2023)
Review
Pharmacology & Pharmacy
Cleo Demeester, Donnia Robins, Angela Elma Edwina, Jos Tournoy, Patrick Augustijns, Ibrahim Ince, Andreas Lehmann, Maria Vertzoni, Jan Frederik Schlender
Summary: The elderly population, as the fastest-growing demographic and major consumers of pharmaceutical products, present challenges in predicting drug safety and efficacy due to interindividual variability in the dose-exposure-response relationship. Current physiologically based pharmacokinetic (PBPK) models inadequately account for age-related changes in absorption. This review aims to summarize the physiological changes influencing oral absorption in older adults, discuss the capabilities of PBPK models in describing this population, and explore the impact of drug-drug interactions from polypharmacy on model development. Addressing identified gaps and integrating in vitro and in vivo data can enhance decision-making for formulation adequacy and pharmacotherapy in older adults.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Christer Tannergren, Harshad Jadhav, Emma Eckernas, Jonas Fagerberg, Patrick Augustijns, Erik Sjogren
Summary: This study evaluates the ability to predict regional differences in absorption and colon absorption in humans using mechanistic physiologically based biopharmaceutics modeling. The prediction performance is good for high permeability drugs but poor for low permeability drugs. The models need to be improved for more accurate predictions.
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
(2023)
Article
Pharmacology & Pharmacy
Tom de Waal, Joachim Brouwers, Maissa Rayyan, Cordula Stillhart, Liliya Vinarova, Zahari Vinarov, Patrick Augustijns
Summary: This study assessed the solubility of five poorly water-soluble, lipophilic drugs in intestinal fluid pools from 19 infant enterostomy patients. The solubilizing capacity of infant intestinal fluids was similar to that of adults, but the lipid phase of infant intestinal fluids played a significant role in drug solubilization. The huge variability in composition of infant intestinal fluid pools resulted in a highly variable solubilizing capacity.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2023)
Article
Pharmacology & Pharmacy
Tom de Waal, Joachim Brouwers, Raf Mols, Ilse Hoffman, Maissa Rayyan, Patrick Augustijns
Summary: The composition of gastrointestinal fluids plays a crucial role in the absorption of orally administered drugs, and changes in fluid composition due to disease or age can affect drug pharmacokinetics. However, limited studies have been conducted on neonates and infants due to practical and ethical challenges. This study analyzed enterostomy fluids from neonates and infants, finding significant differences in fluid characteristics compared to adult intestinal fluids, which could impact drug absorption.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2023)
Article
Pharmacology & Pharmacy
Zahari Vinarov, James Butler, Filippos Kesisoglou, Mirko Koziolek, Patrick Augustijns
Summary: Food-drug interactions pose challenges to oral drug development due to various factors. Bio-pharmaceutical assessment tools lack standardized settings and protocols. This article provides an overview of the approach and methodology used in food effect assessment and prediction, including in vitro dissolution-based predictions and physiologically based pharmacokinetic models. Animal models, particularly beagle dogs, also provide good predictions. Advanced formulation approaches can improve fasted state pharmacokinetics to decrease the difference in oral bioavailability between fasted and fed states. Regulatory approval of labeling instructions requires combining knowledge from various studies.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2023)
Article
Pharmacology & Pharmacy
Tom de Waal, Joachim Brouwers, Philippe Berben, Talia Flanagan, Jan Tack, Wim Vandenberghe, Tim Vanuytsel, Patrick Augustijns
Summary: Parkinson's disease may not only impact the motor system but also the physiology of the gastrointestinal tract. The composition of intestinal fluids in PD patients is generally similar to healthy controls, with only minor differences. These differences may be attributed to slower gastric emptying and altered intestinal bacterial metabolism.
Letter
Gastroenterology & Hepatology
Mette Julsgaard, Uma Mahadevan, Thea Vestergaard, Raf Mols, Marc Ferrante, Patrick Augustijns
LANCET GASTROENTEROLOGY & HEPATOLOGY
(2023)
Review
Pharmacology & Pharmacy
Cordula Stillhart, Adam Asteriadis, Ekaterina Bocharova, Gabriel Eksteen, Fritz Harder, Jonas Kusch, Theodora Tzakri, Patrick Augustijns, Christophe Matthys, Maria Vertzoni, Werner Weitschies, Christos Reppas
Summary: The purpose of this review is to summarize the current knowledge on three physiological determinants of oral drug absorption in the advanced age population, namely gastric emptying, luminal fluid volume and composition, and intestinal permeability, in order to identify potential knowledge gaps and directions for further research efforts.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Medicine, Research & Experimental
Harshad Jadhav, Patrick Augustijns, Christer Tannergren
Summary: The rate and extent of colon absorption are important for the in vivo performance of extended-release (ER) drug products. This study evaluated different prediction approaches for ER drug product variants with different in vitro release profiles. The results showed that using the slowest ER variant improved prediction performance, regardless of colon absorption limitation.
MOLECULAR PHARMACEUTICS
(2023)
Review
Pharmacology & Pharmacy
Mirko Koziolek, Patrick Augustijns, Constantin Berger, Rodrigo Cristofoletti, David Dahlgren, Janneke Keemink, Paer Matsson, Fiona McCartney, Marco Metzger, Mario Mezler, Janis Niessen, James E. Polli, Maria Vertzoni, Werner Weitschies, Jennifer Dressman
Summary: This review discusses various methodologies used to determine drug permeability in the human gastrointestinal tract, including in vitro, in silico, and in vivo approaches. It highlights advancements in novel techniques such as computational approaches and gut-on-chip models. The review also explores the impact of permeability estimations on PK predictions and the importance of drug permeability in clinical studies.
Correction
Pharmacology & Pharmacy
Matthias van der Veken, Michael Aertsen, Joachim Brouwers, Cordula Stillhart, Neil Parrott, Patrick Augustijns
Article
Pharmacology & Pharmacy
Matthias van der Veken, Joachim Brouwers, Agustos Cetin Ozbey, Kenichi Umehara, Cordula Stillhart, Noel Knops, Patrick Augustijns, Neil John Parrott
Summary: This study investigates the age dependency of tacrolimus exposure in pediatric patients, focusing on absorption, metabolism, and distribution. A physiologically based pharmacokinetic (PBPK) model was developed based on adult data and extrapolated to the pediatric population using kidney transplant patients' data. Selecting appropriate ontogeny profiles for hepatic and intestinal CYP3A4 was crucial for the model's applicability in children. The study also found that the dissolution profiles of tacrolimus could be adequately represented by diffusion-layer-based dissolution modeling in both adult and pediatric PBPK models. Differences in blood plasma partitioning of tacrolimus may contribute to the variability in exposure in pediatric patients.
Article
Pharmacology & Pharmacy
Kimberly Raines, Payal Agarwal, Patrick Augustijns, Alaadin Alayoubi, Lucas Attia, Annette Bauer-Brandl, Martin Brandl, Parnali Chatterjee, Hansong Chen, Yuly Chiang Yu, Carrie Coutant, Ana Luisa Coutinho, David Curran, Jennifer Dressman, Bryan Ericksen, Leah Falade, Yi Gao, Zongming Gao, Debasis Ghosh, Tapash Ghosh, Anitha Govada, Elizabeth Gray, Ruiqiong Guo, Dana Hammell, Andre Hermans, Rohit Jaini, Hanlin Li, Haritha Mandula, Shuaiqian Men, Johanna Milsmann, Huong Moldthan, Rebecca Moody, Dana E. Moseson, Anette Muellertz, Roshni Patel, Kalpana Paudel, Christos Reppas, Rajesh Savkur, Kerstin Schaefer, Abu Serajuddin, Lynne S. Taylor, Rutu Valapil, Kevin Wei, Werner Weitschies, Shinji Yamashita, James E. Polli
Summary: The in-person workshop Drug Dissolution in Oral Drug Absorption was organized into lectures and breakout sessions, focusing on topics such as amorphous solid dispersions, dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. The discussions highlighted the assessment of dissolved drugs, limitations of current testing methods for poorly water soluble drugs, non-compendial methods and conditions, and the potential benefits of integrating quality control and biopredictive/biorelevant methods.