Bin Ma, UpendraA Argikar, Lionel Cheruzel, Sungjoon Cho, Simon Hauri, KevinM Johnson, Joyce Liu, Simone Schadt, Shuai Wang, S Cyrus Khojasteh
With contributions from colleagues across academia and industry, we have put together the annual reviews of research advances on drug biotransformation and bioactivation since 2016 led by Cyrus Khojasteh. While traditional small molecules and biologics are still predominant in drug discovery, we start to notice a paradigm shift toward new drug modalities (NDMs) including but not limited to peptide and oligonucleotide therapeutics, protein degraders (heterobifunctional degraders and molecule glues), conjugated drugs and covalent inhibitors...
June 19, 2024: Drug Metabolism Reviews
Anam Hammid, Paavo Honkakoski
No abstract text is available yet for this article.
June 18, 2024: Drug Metabolism Reviews
Kunhong Mao, Can Liu, Zhongwen Tang, Zhouzhou Rao, Jie Wen
Osteosarcoma (OS) is a prevalent malignancy among adolescents, commonly manifesting during childhood and adolescence. It exhibits a high degree of malignancy, propensity for metastasis, rapid progression, and poses challenges in clinical management. Chemotherapy represents an efficacious therapeutic modality for OS treatment. However, chemotherapy resistance of OS is a major problem in clinical treatment. In order to treat OS effectively, it is particularly important to explore the mechanism of chemotherapy resistance in OS...
June 13, 2024: Drug Metabolism Reviews
Di Wu, Jiaying Liu, Erickson M Paragas, Jaydeep Yadav, Theresa Aliwarga, Tycho Heimbach, M Sebastian Escotet-Espinoza
pH-mediated drug-drug interactions (DDI) is a prevalent DDI in drug development, especially for weak base compounds with highly pH-dependent solubility. FDA has released a guidance on the evaluation of pH-mediated DDI assessments using in vitro testing and clinical studies. Currently, there is no common practice of ways of testing across the academia and industry. The development of biopredictive method and physiologically-based biopharmaceutics modeling (PBBM) approaches to assess acid-reducing agent (ARA)-DDI have been proven with accurate prediction and could decrease drug development burden, inform clinical design and potentially waive clinical studies...
May 3, 2024: Drug Metabolism Reviews
Sarah Ann Smith, Gia Han Le, Kayla M Teopiz, Angela T H Kwan, Taeho Greg Rhee, Roger C Ho, Jie Wu, Bing Cao, Felicia Ceban, Roger S McIntyre
Due to legal, political, and cultural changes, the use of cannabis has rapidly increased in recent years. Research has demonstrated that the cannabinoids cannabidiol (CBD) and Δ9 -tetrahydrocannabinol (THC) inhibit and induce cytochrome P450 (CYP450) enzymes. The objective of this review is to evaluate the effect of CBD and THC on the activity of CYP450 enzymes and the implications for drug-drug interactions (DDIs) with psychotropic agents that are CYP substrates. A systematic search was conducted using PubMed, Scopus, Scientific Electronic Library Online (SciELO) and PsychINFO...
April 24, 2024: Drug Metabolism Reviews
Alexandra M Wiley, Jade Yang, Rivcka Madhani, Abhinav Nath, Rheem A Totah
Drug withdrawal post-marketing due tocardiotoxicity is a major concern for drug developers, regulatory agencies, and patients. One common mechanism of cardiotoxicity isthroughinhibition of cardiac ion channels, leading to prolongation of the QT intervaland sometimes fatal arrythmias. Recently, oxylipinsignaling compounds have been shown to bind toand alter ion channel function,and disruption in their cardiac levels may contribute to QTprolongation. Cytochrome P450 2J2 (CYP2J2) is the predominant CYP isoform expressed in cardiomyocytes,where it oxidizes arachidonic acid to cardioprotectiveepoxyeicosatrienoic acids (EETs)...
March 13, 2024: Drug Metabolism Reviews
Mir Saleh Hoseininezhad-Namin, Elaheh Rahimpour, Abolghasem Jouyban
Severe acute respiratory syndrome 2 (SARS-CoV-2) caused the emergence of the COVID-19 pandemic all over the world. Several studies have suggested that antiviral drugs such as favipiravir (FAV), remdesivir (RDV), and lopinavir (LPV) may potentially prevent the spread of the virus in the host cells and person-to-person transmission. Simultaneously with the widespread use of these drugs, their stability and action mechanism studies have also attracted the attention of many researchers. This review focuses on the action mechanism, metabolites and degradation products of these antiviral drugs (FAV, RDV and LPV) and demonstrates various methods for their quantification and discrimination in the different biological samples...
March 6, 2024: Drug Metabolism Reviews
Saleh M Khalil, Kevin R MacKenzie, Mirjana Maletic-Savatic, Feng Li
Many drugs that serve as first-line medications for the treatment of depression are associated with severe side effects, including liver injury. Of the 34 antidepressants discussed in this review, four have been withdrawn from the market due to severe hepatotoxicity, and others carry boxed warnings for idiosyncratic liver toxicity. The clinical and economic implications of antidepressant-induced liver injury are substantial, but the underlying mechanisms remain elusive. Drug-induced liver injury may involve the host immune system, the parent drug, or its metabolites, and reactive drug metabolites are one of the most commonly referenced risk factors...
February 4, 2024: Drug Metabolism Reviews
Sara A Helal, Samar H Gerges, Ayman O S El-Kadi
The phenomenon of chirality has been shown to greatly impact drug activities and effects. Different enantiomers may exhibit different effects in a certain biological condition or disease state. Cytochrome P450 (CYP) enzymes metabolize arachidonic acid (AA) into a large variety of metabolites with a wide range of activities. Hydroxylation of AA by CYP hydroxylases produces hydroxyeicosatetraenoic acids (HETEs), which are classified into mid-chain (5, 8, 9, 11, 12, and 15-HETE), subterminal (16-, 17-, 18- and 19-HETE) and terminal (20-HETE) HETEs...
February 2024: Drug Metabolism Reviews
Robert E London
Two aminosalicylate isomers have been found to possess useful pharmacological behavior: p -aminosalicylate (PAS, 4AS) is an anti-tubercular agent that targets M. tuberculosis , and 5-aminosalicylate (5AS, mesalamine, mesalazine) is used in the treatment of ulcerative colitis (UC) and other inflammatory bowel diseases (IBD). PAS, a structural analog of pABA, is biosynthetically incorporated by bacterial dihydropteroate synthase (DHPS), ultimately yielding a dihydrofolate (DHF) analog containing an additional hydroxyl group in the pABA ring: 2'-hydroxy-7,8-dihydrofolate...
January 17, 2024: Drug Metabolism Reviews
Yu-Juan Yi, Hong Tang, Peng-Lai Pi, Han-Wen Zhang, Si-Yu Du, Wei-Ye Ge, Qi Dai, Zi-Yan Zhao, Jia Li, Zheng Sun
Melatonin, historically recognized for its primary role in regulating circadian rhythms, has expanded its influence particularly due to its wide range of biological activities. It has firmly established itself in cancer research. To highlight its versatility, we will delve into how melatonin interacts with key signaling pathways, such as the Wnt/β-Catenin, PI3K, and NF-κB pathways, which play foundational roles in tumor development and progression. Notably, melatonin can intricately modulate these pathways, potentially affecting various cellular functions such as apoptosis, metastasis, and immunity...
January 16, 2024: Drug Metabolism Reviews
Mengxu Zhang, Vivi Rottschäfer, Elizabeth Cm de Lange
Drug metabolism is one of the critical determinants of drug disposition throughout the body. While traditionally associated with the liver, recent research has unveiled the presence and functional significance of drug-metabolizing enzymes (DMEs) within the brain. Specifically, cytochrome P-450 enzymes (CYPs) and UDP-glucuronosyltransferases enzymes (UGTs) have emerged as key players in drug biotransformation within the central nervous system (CNS).This comprehensive review explores the cellular and subcellular distribution of CYPs and UGTs within the CNS, emphasizing regional expression and contrasting profiles between the liver and brain, humans and rats...
December 21, 2023: Drug Metabolism Reviews
Rajeswara Babu Mythri, M R Aishwarya
The brain is a privileged organ, tightly guarded by a network of endothelial cells, pericytes, and glial cells called the blood brain barrier. This barrier facilitates tight regulation of the transport of molecules, ions, and cells from the blood to the brain. While this feature ensures protection to the brain, it also presents a challenge for drug delivery for brain diseases. It is, therefore, crucial to identify molecules and/or vehicles that carry drugs, cross the blood brain barrier, and reach targets within the central nervous system...
November 13, 2023: Drug Metabolism Reviews
Nida Hanif, Ammara Zamir, Imran Imran, Hamid Saeed, Abdul Majeed, Anees Ur Rehman, Waseem Ashraf, Faleh Alqahtani, Muhammad Fawad Rasool
Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included...
November 2023: Drug Metabolism Reviews
S Cyrus Khojasteh, Upendra A Argikar, Lionel Cheruzel, Sungjoon Cho, Rachel D Crouch, Deepika Dhaware, Carley J S Heck, Kevin M Johnson, Amit S Kalgutkar, Lloyd King, Joyce Liu, Bin Ma, Hlaing Maw, Grover P Miller, Herana Kamal Seneviratne, Ryan H Takahashi, Shuai Wang, Cong Wei, Klarissa D Jackson
No abstract text is available yet for this article.
September 22, 2023: Drug Metabolism Reviews
Mahmoud A El-Ghiaty, Sara R El-Mahrouk, Mohammed A Alqahtani, Ayman O S El-Kadi
Arsenic is a hazardous heavy metalloid that imposes threats to human health globally. It is widely spread throughout the environment in various forms. Arsenic-based compounds are either inorganic compounds (iAs) or organoarsenicals (oAs), where the latter are biotically generated from the former. Exposure to arsenic-based compounds results in varying biochemical derangements in living systems, leading eventually to toxic consequences. One important target for arsenic in biosystems is the network of metabolic enzymes, especially the superfamily of cytochrome P450 enzymes (CYPs) because of their prominent role in both endobiotic and xenobiotic metabolism...
September 7, 2023: Drug Metabolism Reviews
Paresh P Chothe, Pallabi Mitra, Masanori Nakakariya, Diane Ramsden, Charles J Rotter, Philip Sandoval, Kimio Tohyama
On behalf of all the authors, I am pleased to share our third annual review on drug transporter science with an emphasis on articles published and deemed influential in signifying drug transporters' role in drug disposition in the year 2022. As the drug transporter field is rapidly evolving several key findings were noted including promising endogenous biomarkers, rhythmic activity, IVIVE approaches in transporter-mediated clearance, new modality interaction and transporter effect on gut microbiome. As identified previously (Chothe et al...
August 30, 2023: Drug Metabolism Reviews
Shuai Wang, Upendra A Argikar, Lionel Cheruzel, Sungjoon Cho, Rachel D Crouch, Deepika Dhaware, Carley J S Heck, Kevin M Johnson, Amit S Kalgutkar, Lloyd King, Joyce Liu, Bin Ma, Hlaing Maw, Grover P Miller, Herana Kamal Seneviratne, Ryan H Takahashi, Cong Wei, S Cyrus Khojasteh
With the 50th year mark since the launch of Drug Metabolism and Disposition journal, the field of drug metabolism and bioactivation has advanced exponentially in the past decades (Guengerich 2023).This has, in a major part, been due to the continued advances across the whole spectrum of applied technologies in hardware, software, machine learning (ML), and artificial intelligence (AI). LC-MS platforms continue to evolve to support key applications in the field, and automation is also improving the accuracy, precision, and throughput of these supporting assays...
August 22, 2023: Drug Metabolism Reviews
Delong Duo, Yabin Duan, Junbo Zhu, Xue Bai, Jianxin Yang, Guiqin Liu, Qian Wang, Xiangyang Li
High-altitude hypoxic environments have critical implications on cardiovascular system function as well as blood pressure regulation. Such environments place patients with hypertension at risk by activating the sympathetic nervous system, which leads to an increase in blood pressure. In addition, the high-altitude hypoxic environment alters the in vivo metabolism and antihypertensive effects of antihypertensive drugs, which changes the activity and expression of drug-metabolizing enzymes and drug transporters...
August 22, 2023: Drug Metabolism Reviews
Huan Lan, Ying Zhang, Minqi Fan, Bingxin Wu, Caiyan Wang
Cholestatic liver injury (CLI) is caused by toxic bile acids (BAs) accumulation in the liver and can lead to inflammation and liver fibrosis. The mechanisms underlying CLI development remain unclear, and this disease has no effective cure. However, regulating BA synthesis and homeostasis represents a promising therapeutic strategy for CLI treatment. Pregnane X receptor (PXR) plays an essential role in the metabolism of endobiotics and xenobiotics via the transcription of metabolic enzymes and transporters, which can ultimately modulate BA homeostasis and exert anti-cholestatic effects...
August 18, 2023: Drug Metabolism Reviews
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