keyword
https://read.qxmd.com/read/38327958/herba-epimedii-and-increased-opioid-cravings-while-on-buprenorphine-a-case-report
#21
Heather Burke, Bernard A Sarmiento, Matthew Gunther, Richard Czuma, Cory Klippel, Shixie Jiang
Herba Epimedii, commonly known as yin yang huo, inyokaku, and horny goat weed, is a traditional Chinese herbal medicine utilized for treating osteoporosis and enhancing libido. Studies conducted in vitro have demonstrated that Herba Epimedii interacts with the enzyme cytochrome P450 3A4 (CYP3A4). This interaction poses a potential risk for drug-drug interactions, particularly with medications metabolized by CYP3A4, such as buprenorphine. This paper presents a case of a patient experiencing exacerbated opioid cravings following the initiation of Herba Epimedii...
January 2024: Curēus
https://read.qxmd.com/read/38321419/effects-of-cyp3a4-22-and-por-28-variations-on-the-pharmacokinetics-of-tacrolimus-in-renal-transplant-recipients-a-meta-analysis-of-18-observational-studies
#22
JOURNAL ARTICLE
Ze Li, Xiaozhen Wang, Dandan Li, Sheng Cheng, Zhe Li, Heng Guo, Yiwen Dong, Yingming Zheng, Xingang Li
PURPOSE: This study aimed to investigate the association between cytochrome P450 (CYP) 3A4*22 and cytochrome P450 oxidoreductase (POR)*28 variations and the pharmacokinetics of tacrolimus. METHODS: Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (SCI), MEDLINE, and Embase were systematically searched from inception to August 2022. The outcomes were weight-adjusted daily dose and dose-adjusted trough concentration (C0 /Dose). RESULTS: The study included 2931 renal transplant recipients from 18 publications...
February 6, 2024: BMC Nephrology
https://read.qxmd.com/read/38307724/a-physiologically-based-pharmacokinetic-modeling-approach-to-assess-the-potential-for-drug-interactions-between-trofinetide-and-cyp3a4-metabolized-drugs
#23
JOURNAL ARTICLE
Mona Darwish, James M Youakim, Inger Darling, Viera Lukacova, Joel S Owen, Heather Bradley
PURPOSE: Trofinetide is the first drug to be approved by the US Food and Drug Administration for use in the treatment of patients with Rett syndrome, a multisystem disorder requiring multimodal therapies. Cytochrome P450 (CYP) 3A4 metabolizes >50% of therapeutic drugs and is the CYP isozyme most commonly expressed in the liver and intestines. In vitro studies suggest the concentration of trofinetide producing 50% inhibition (IC50 ) of CYP3A4 is >15 mmol/L; that concentration was much greater than the target clinical concentration associated with the maximal intended therapeutic dose (12 g)...
February 1, 2024: Clinical Therapeutics
https://read.qxmd.com/read/38305718/mechanistic-framework-to-predict-maternal-placental-fetal-pharmacokinetics-of-nifedipine-employing-physiologically-based-pharmacokinetic-modeling-approach
#24
JOURNAL ARTICLE
Marya Antônya Werdan Romão, Leonardo Pinto, Ricardo Carvalho Cavalli, Geraldo Duarte, Natália Valadares de Moraes, Khaled Abduljalil, Fernanda de Lima Moreira
Nifedipine is used for treating mild to severe hypertension and preventing preterm labor in pregnant women. Nevertheless, concerns about nifedipine fetal exposure and safety are always raised. The aim of this study was to develop and validate a maternal-placental-fetal nifedipine physiologically based pharmacokinetic (PBPK) model and apply the model to predict maternal, placental, and fetal exposure to nifedipine at different pregnancy stages. A nifedipine PBPK model was verified with nonpregnant data and extended to the pregnant population after the inclusion of the fetoplacental multicompartment model that accounts for the placental tissue and different fetal organs within the Simcyp Simulator version 22...
February 2, 2024: Journal of Clinical Pharmacology
https://read.qxmd.com/read/38276571/water-exchange-from-the-buried-binding-sites-of-cytochrome-p450-enzymes-1a2-2d6-and-3a4-correlates-with-conformational-fluctuations
#25
JOURNAL ARTICLE
Olgun Guvench
Human cytochrome P450 enzymes (CYPs) are critical for the metabolism of small-molecule pharmaceuticals (drugs). As such, the prediction of drug metabolism by and drug inhibition of CYP activity is an important component of the drug discovery and design process. Relative to the availability of a wide range of experimental atomic-resolution CYP structures, the development of structure-based CYP activity models has been limited. To better characterize the role of CYP conformational fluctuations in CYP activity, we perform multiple microsecond-scale all-atom explicit-solvent molecular dynamics (MD) simulations on three CYP isoforms, 1A2, 2D6, and 3A4, which together account for the majority of CYP-mediated drug metabolism...
January 19, 2024: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/38270613/midostaurin-drug-interaction-profile-a-comprehensive-assessment-of-cyp3a-cyp2b6-and-cyp2c8-drug-substrates-and-oral-contraceptives-in-healthy-participants
#26
JOURNAL ARTICLE
Romain Sechaud, Helen Gu, Gholamreza Rahmanzadeh, Amanda Taylor, Ovidiu Chiparus, Gopal Krishna Sharma, Astrid Breitschaft, Hans D Menssen
PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2...
January 25, 2024: Cancer Chemotherapy and Pharmacology
https://read.qxmd.com/read/38244190/use-of-pharmacokinetic-and-pharmacodynamic-data-to-develop-the-cdk4-6-inhibitor-ribociclib-for-patients-with-advanced-breast-cancer
#27
REVIEW
Yan Ji, Hilmar Schiller, Shu Yang, Michelle Quinlan, Christelle Darstein, Felix Huth, Serge Winter, Abhijit Chakraborty
Ribociclib is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6 inhibition by ribociclib leads to retinoblastoma tumor suppressor protein (Rb) reactivation, thereby restoring Rb-mediated cell cycle arrest. Ribociclib is approved for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced breast cancer (ABC), at the dose of 600 mg once daily (QD) during cycles of 21 days on/7 days off, with optional dose reduction to 400 mg and 200 mg...
January 20, 2024: Clinical Pharmacokinetics
https://read.qxmd.com/read/38236698/evidence-for-cytochrome-p450-3a4-mediated-metabolic-activation-of-sco-267
#28
JOURNAL ARTICLE
Cui Li, Xiaokun Li, Ali Fan, Ning He, Dongmei Wu, Hongyan Yu, Kun Wang, Weijie Jiao, Xu Zhao
SCO-267 is a potent G-protein-coupled receptor 40 agonist that is undergoing clinical development for the treatment of type 2 diabetes mellitus. The current work was undertaken to investigate the bioactivation potential of SCO-267 in vitro and in vivo. Three SCO-267-derived glutathione (GSH) conjugates (M1-M3) were found both in rat and human liver microsomal incubations supplemented with GSH and nicotinamide adenine dinucleotide phosphate. Two GSH conjugates (M1-M2) together with two N-acetyl-cysteine conjugates (M4-M5) were detected in the bile of rats receiving SCO-267 at 10 mg/kg...
January 18, 2024: Biopharmaceutics & Drug Disposition
https://read.qxmd.com/read/38227839/a-multicenter-retrospective-observational-study-analyzing-the-effect-of-polypharmacy-on-oxycodone-tolerability
#29
JOURNAL ARTICLE
Katsuya Makihara, Yoshihiro Yamamoto, Masayuki Miyazaki, Maho Taguchi, Junya Sato, Hisamitsu Takase, Yasuhito Uezono
Polypharmacy is becoming increasingly troublesome in the treatment of cancer. The aim of this study was to explore the effects of concomitant polypharmacy comprising drugs that inhibit CYP3A4 and/or CYP2D6 on the oxycodone tolerability in patients with cancer. We conducted a multicenter retrospective study encompassing 20 hospitals. The data used for the study were obtained during the first 2 wk of oxycodone administration. The incidence of oxycodone discontinuation or dose reductions due to side effects and oxycodone-induced nausea and vomiting (OINV) were compared between patients not treated with either inhibitor and those treated with concomitant CYP3A4 or CYP2D6 inhibitors...
January 16, 2024: Journal of Pain & Palliative Care Pharmacotherapy
https://read.qxmd.com/read/38217901/alkylphenols-disrupt-estrogen-homeostasis-via-diradical-cross-coupling-reactions-a-novel-pathway-of-endocrine-disruption
#30
JOURNAL ARTICLE
Liu Liu, Fangjie Guo, Hongyang Cui, Li Ji, Yi Yang, Ling Jiao, Yixuan Huang, Yi Wan
Estrogen, being an essential class of sex hormone, is an important target of endocrine disruption chemicals. It is well known that environmental disruptors could activate or inhibit estrogen receptors, acting as agonists or antagonists, and thus affect the circulating estrogen concentrations. Here, we report enzyme-mediated diradical cross-coupling reactions between alkylphenols (e.g., 2,4-di-tert-butylphenol [DBP], 4-nonylphenol [4-NP], and 4-tert-octylphenol [4-t-OP]) and estrogens (e.g., estradiol [E2]) that generate coupling metabolites and disrupt estrogen homeostasis...
January 6, 2024: Environment International
https://read.qxmd.com/read/38215156/bruceine-d-and-narclasine-inhibit-the-proliferation-of-breast-cancer-cells-and-the-prediction-of-potential-drug-targets
#31
JOURNAL ARTICLE
Xinhao Chen, Hua Li
BACKGROUND: Breast cancer is one of the most common female malignancies. This study explored the underlying mechanism through which the two plant compounds (Brucaine D and Narclasine) inhibited the proliferation of breast cancer cells. OBJECTIVE: The purpose of this study was to explore the effect of Brucaine D and Narclasine on breast cancer development and their potential drug targets. METHODS: GSE85871 dataset containing 212 samples and the hallmark gene set "h...
2024: PloS One
https://read.qxmd.com/read/38200564/cocaine-regulates-antiretroviral-therapy-cns-access-through-pregnane-x-receptor-mediated-drug-transporter-and-metabolizing-enzyme-modulation-at-the-blood-brain-barrier
#32
JOURNAL ARTICLE
Rodnie Colón Ortiz, Stephen Knerler, Lisa B Fridman, Alicia Mercado, Amira-Storm Price, Jose J Rosado-Franco, Hannah Wilkins, Bianca R Flores, Benjamin C Orsburn, Dionna W Williams
BACKGROUND: Appropriate interactions between antiretroviral therapies (ART) and drug transporters and metabolizing enzymes at the blood brain barrier (BBB) are critical to ensure adequate dosing of the brain to achieve HIV suppression. These proteins are modulated by demographic and lifestyle factors, including substance use. While understudied, illicit substances share drug transport and metabolism pathways with ART, increasing the potential for adverse drug:drug interactions. This is particularly important when considering the brain as it is relatively undertreated compared to peripheral organs and is vulnerable to substance use-mediated damage...
January 10, 2024: Fluids and Barriers of the CNS
https://read.qxmd.com/read/38199567/functional-maturation-of-cytochromes-p4503a4-and-2d6-relies-on-gapdh-and-hsp90-dependent-heme-allocation
#33
JOURNAL ARTICLE
Sidra Islam, Dhanya Thamaraparambil Jayaram, Pranjal Biswas, Dennis J Stuehr
Cytochrome P450 3A4 and 2D6 (EC 1.14.13.97 and 1.14.14; CYP3A4 and 2D6) are heme-containing enzymes that catalyze the oxidation of a wide number of xenobiotic and drug substrates and thus broadly impact human biology and pharmacologic therapies. Although their activities are directly proportional to their heme contents, little is known about the cellular heme delivery and insertion processes that enable their maturation to functional form. We investigated the potential involvement of GAPDH and chaperone Hsp90, based on our previous studies linking these proteins to intracellular heme allocation...
January 8, 2024: Journal of Biological Chemistry
https://read.qxmd.com/read/38195522/identification-and-functional-assessment-of-eight-cyp3a4-allelic-variants-39-46-detected-in-the-chinese-han-population
#34
JOURNAL ARTICLE
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 the severe adverse drug reactions (ADRs). In this study, we conducted a genetic analysis on CYP3A4 gene in 1,163 Chinese Han individuals to identify the genetic variations that might affect their drug metabolism capabilities. For this purpose, a multiplex PCR amplicon sequencing technique was developed, enabling us to perform the genotyping of CYP3A4 gene efficiently and economically on a large scale...
January 9, 2024: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://read.qxmd.com/read/38177893/a-comprehensive-review-of-the-clinical-pharmacokinetics-pharmacodynamics-and-drug-interactions-of-nirmatrelvir-ritonavir
#35
REVIEW
Jacqueline Gerhart, Donna S Cox, Ravi Shankar P Singh, Phylinda L S Chan, Rohit Rao, Richard Allen, Haihong Shi, Joanna C Masters, Bharat Damle
Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that is used as an oral antiviral coronavirus disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above the antiviral in vitro 90% effective concentration value (EC90 ), nirmatrelvir is coadministered with 100 mg of ritonavir, a pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir's cytochrome P450 (CYP) 3A4-mediated metabolism which results in renal elimination becoming the primary route of nirmatrelvir elimination when dosed concomitantly...
January 4, 2024: Clinical Pharmacokinetics
https://read.qxmd.com/read/38176619/the-long-noncoding-rna-hnf1a-as1-with-dual-functions-in-the-regulation-of-cytochrome-p450-3a4
#36
JOURNAL ARTICLE
Yiting Wang, Pei Wang, Qi Wang, Shitong Chen, Xiaofei Wang, Xiaobo Zhong, Wanglai Hu, Rick F Thorne, Shengna Han, Mian Wu, Lirong Zhang
Cytochrome P450 3A4 (CYP3A4) is the most important and abundant drug-metabolizing enzyme in the human liver. Inter-individual differences in the expression and activity of CYP3A4 affect clinical and precision medicine. Increasing evidence indicates that long noncoding RNAs (lncRNAs) play crucial roles in the regulation of CYP3A4 expression. Here, we showed that lncRNA hepatocyte nuclear factor 1 alpha-antisense 1 (HNF1A-AS1) exerted dual functions in regulating CYP3A4 expression in Huh7 and HepG2 cells. Mechanistically, HNF1A-AS1 served as an RNA scaffold to interact with both protein arginine methyltransferase 1 and pregnane X receptor (PXR), thereby facilitating their protein interactions and resulting in the transactivation of PXR and transcriptional alteration of CYP3A4 via histone modifications...
January 2, 2024: Biochemical Pharmacology
https://read.qxmd.com/read/38166553/effect-of-tubeimoside-i-on-the-activity-of-cytochrome-p450-enzymes-in-human-liver-microsomes
#37
JOURNAL ARTICLE
Rui Wang, Kai Zheng, Yunjiao Liu, Shuxia Ji, Yaxin Tang, Jie Wang, Rong Jiang
This study assessed the effect of tubeimoside I on CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 to reveal the potential of tubeimoside I to induce drug-drug interaction.The evaluation of cytochromes P450 enzyme (CYP450) activity was performed in pooled human liver microsomes with probing substrates of CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Typical inhibitors were employed as positive controls and the effect of 0, 2.5, 5, 10, 25, 50, and 100 μM tubeimoside I was investigated.The activity of CYP2D6, 2E1, and 3A4 was significantly inhibited by tubeimoside I with the IC50 values of 10...
January 3, 2024: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/38117809/cyp3a4-1g-polymorphism-is-associated-with-alcohol-drinking-a-5-year-retrospective-single-centered-population-based-study-in-china
#38
JOURNAL ARTICLE
Xiaoqing Jia, Xiaoting Zhang, Tao Zhou, Dalong Sun, Rong Li, Na Yang, Zheng Luo
INTRODUCTION: We investigated the epidemiology of Cytochrome P450 (CYP) 3A4 genotype and the relationship between CYP3A4 genotype and alcohol drinking habits. MATERIALS AND METHODS: A single-centered retrospective study was conducted on 630 patients who underwent CYP3A4*1G genetic testing. Their relevant information on epidemiology and etiology was collected. Laboratory testing, including CYP3A4*1G genotype, liver function tests, and serum lipid measurements were performed...
2023: PloS One
https://read.qxmd.com/read/38108609/study-of-the-ketohexokinase-inhibitor-pf-06835919-as-a-clinical-cytochrome-p450-3a-inducer-integrated-use-of-oral-midazolam-and-liquid-biopsy
#39
JOURNAL ARTICLE
Ruolun Qiu, Kari Fonseca, Arthur Bergman, Jian Lin, David Tess, Lauren Newman, Alia Fahmy, Zivile Useckaite, Andrew Rowland, Manoli Vourvahis, David Rodrigues
PF-06835919, a ketohexokinase inhibitor, presented as an inducer of cytochrome P450 3A4 (CYP3A4) in vitro (human primary hepatocytes), and static mechanistic modeling exercises predicted significant induction in vivo (oral midazolam area under the plasma concentration-time curve [AUC] ratio [AUCR] = 0.23-0.79). Therefore, a drug-drug interaction study was conducted to evaluate the effect of multiple doses of PF-06835919 (300 mg once daily × 10 days; N = 10 healthy participants) on the pharmacokinetics of a single oral midazolam 7...
December 18, 2023: Clinical and Translational Science
https://read.qxmd.com/read/38108269/transferable-machine-learning-interatomic-potential-for-bond-dissociation-energy-prediction-of-drug-like-molecules
#40
JOURNAL ARTICLE
Elena Gelžinytė, Mario Öeren, Matthew D Segall, Gábor Csányi
We present a transferable MACE interatomic potential that is applicable to open- and closed-shell drug-like molecules containing hydrogen, carbon, and oxygen atoms. Including an accurate description of radical species extends the scope of possible applications to bond dissociation energy (BDE) prediction, for example, in the context of cytochrome P450 (CYP) metabolism. The transferability of the MACE potential was validated on the COMP6 data set, containing only closed-shell molecules, where it reaches better accuracy than the readily available general ANI-2x potential...
December 18, 2023: Journal of Chemical Theory and Computation
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