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cytochrome p450 3A4

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https://www.readbyqxmd.com/read/28105513/pharmacokinetics-of-ginkgolides-a-b-and-k-after-single-and-multiple-intravenous-infusions-and-their-interactions-with-midazolam-in-healthy-chinese-male-subjects
#1
Feng Shao, Hongwen Zhang, Lijun Xie, Juan Chen, Sufeng Zhou, Jinsong Zhang, Jinru Lv, Weiwen Hao, Yunsu Ma, Yun Liu, Ning Ou, Wei Xiao
PURPOSE: Ginkgo terpene lactones meglumine injection (GMI) is a novel preparation of traditional Chinese medicine that contains ginkgolides A, B and K (GA, GB, GK, respectively) as its primary components. In this study we evaluated the safety, tolerability and pharmacokinetics of these three ginkgolides after single and multiple intravenous infusions of GMI. We also investigated the effect of GMI on cytochrome P450 3A4 (CYP3A4) in healthy Chinese volunteers. METHODS: In this open-label, placebo-controlled study 15 subjects were randomly assigned to receive GMI or matched placebo (4:1 ratio)...
January 20, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28105103/inhibition-of-p-glycoprotein-multidrug-resistance-associated-protein-2-and-cytochrome-p450-3a4-improves-the-oral-absorption-of-octreotide-in-rats-with-portal-hypertension
#2
Xiao-Yu Sun, Zhi-Jun Duan, Zhen Liu, Shun-Xiong Tang, Yang Li, Shou-Cheng He, Qiu-Ming Wang, Qing-Yong Chang
The aim of the present study was to increase the intestinal transport of octreotide (OCT) by targeting the first-pass impact to identify a potential method for decreasing portal vein pressure (PVP) using oral OCT. Thus, the bioavailability of intestinally absorbed OCT was evaluated in normal rats and rats with portal hypertension (PH) that had been administered P-glycoprotein/multidrug resistance-associated protein 2/cytochrome P450 3A4 (P-gp/MRP2/CYP3A4) inhibitors. The mRNA and protein expression levels of P-gp, MRP2 and CYP3A4 were evaluated in normal and PH rats with or without OCT and the inhibitors using RT-PCR, western blot and immunohistochemical analyses...
December 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28097004/rifampicin-decreases-exposure-to-sublingual-buprenorphine-in-healthy-subjects
#3
Nora M Hagelberg, Mari Fihlman, Tuija Hemmilä, Janne T Backman, Jouko Laitila, Pertti J Neuvonen, Kari Laine, Klaus T Olkkola, Teijo I Saari
Buprenorphine is mainly metabolized by the cytochrome P450 (CYP) 3A4 enzyme. The aim of this study was to evaluate the role of first-pass metabolism in the interaction of rifampicin and analgesic doses of buprenorphine. A four-session paired cross-over study design was used. Twelve subjects ingested either 600 mg oral rifampicin or placebo once daily in a randomized order for 7 days. In the first part of the study, subjects were given 0.6-mg (placebo phase) or 0.8-mg (rifampicin phase) buprenorphine sublingually on day 7...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28089783/characterization-of-rat-or-human-hepatocytes-cultured-in-microphysiological-systems-mps-to-identify-hepatotoxicity
#4
Shih-Yu Chang, Jenna L Voellinger, Kirk P Van Ness, Brian Chapron, Rachel M Shaffer, Thomas Neumann, Collin C White, Terrance J Kavanagh, Edward J Kelly, David L Eaton
The liver is the main site for drug and xenobiotics metabolism, including inactivation or bioactivation. In order to improve the predictability of drug safety and efficacy in clinical development, and to facilitate the evaluation of the potential human health effects from exposure to environmental contaminants, there is a critical need to accurately model human organ systems such as the liver in vitro. We are developing a microphysiological system (MPS) based on a new commercial microfluidic platform (Nortis, Inc...
January 12, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28089686/simulations-of-cytochrome-p450-3a4-mediated-drug-drug-interactions-by-simple-two-compartment-model-assisted-static-method
#5
Katsumi Iga, Akiko Kiriyama
In order to predict cytochrome P450 3A4 (CYP3A4)-mediated drug-drug interactions (DDIs), a simple two-compartment model assisted, overall inhibition-activity (Ai, overall) method was derived based upon two concepts. One concept was that the increase in blood victim-level and fold increase in the area under the blood victim-level curve (AUCR) produced by DDI are determined entirely by Ai, overall, the hepatic availability of the victim and fraction of urinary excreted unchanged victim, where Ai, overall is determined by the perpetrator-specific CYP isoform inhibition activities (Ai,CYPs, DDI predictor-1) and victim-specific fractional CYP isoform contributions (fm,CYPs, predictor-2)...
January 12, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28078726/dissecting-the-cytochrome-p450-1a2-and-3a4-mediated-metabolism-of-aflatoxin-b1-in-ligand-and-protein-contributions
#6
Lars Olsen, Flemming S Jørgensen, Silvia Bonomo
Aflatoxin B1 (AFB1) is a chemically intriguing compound because it has several potential sites of metabolism (SOMs) while only some of them are observed experimentally. Cytochrome P450 (CYP) 3A4 and 1A2 are the major isoforms involved in its metabolism. Here, we systematically investigate reactivity and accessibility of all possible SOMs in these two CYPs to elucidate AFB1 metabolism. Density functional theory (DFT) calculations were used to determine activation energies for each possible reaction. Aliphatic hydroxylation on position 9A and 3α are energetically favored, whereas position 9 is the preferred site for epoxidation...
January 12, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28073119/in-vitro-inhibition-of-human-cyp450s-1a2-2c9-3a4-5-2d6-and-2e1-by-grandisin
#7
Maísa Daniela Habenschus, Fernanda de Lima Moreira, Norberto Peporine Lopes, Anderson R M de Oliveira
Grandisin, a lignan isolated from many species of plants, such as Virola surinamensis, is a potential drug candidate due to its biological properties, highlighted by its antitumor and trypanocidal activities. In this study, the inhibitory effects of grandisin on the activities of human cytochrome P450 enzymes were investigated by using human liver microsomes. Results showed that grandisin is a competitive inhibitor of CYP2C9 and a competitive and mechanism-based inhibitor of CYP3A4/5. The apparent Ki value for CYP2C9 was 50...
January 10, 2017: Planta Medica
https://www.readbyqxmd.com/read/28069789/hypotension-induced-by-the-concomitant-use-of-a-calcium-channel-blocker-and-clarithromycin
#8
Sayako Takeuchi, Yuki Kotani, Toshihide Tsujimoto
In the elderly, calcium-channel blockers are the first-line treatment for hypertension, and macrolides are commonly prescribed antibiotics. Here we report a 78-year-old man taking nifedipine, diltiazem and carvedilol who presented with persistent hypotension and bradycardia after clarithromycin was prescribed. He was diagnosed with drug-induced hypotension and treated with fluid resuscitation and vasoactive agents. His symptoms gradually improved. He was transferred out of the intensive care unit 3 days after hospitalisation...
January 9, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28058783/characterization-of-phase-i-and-phase-ii-hepatic-metabolism-and-reactive-intermediates-of-larrea-nitida-cav-and-its-lignan-compounds
#9
Hyesoo Jeong, Soolin Kim, Jimin Lee, Jin Young Park, Wenmei Zhou, Xiyuan Liu, So Dam Kim, Yun Seon Song, Chang-Young Jang, Sei-Ryang Oh, Sangho Choi, Minsun Chang
Larrea nitida Cav. (LNC), which belongs to the family Zygophyllaceae, is widely indigenous and used in South America to treat various pathological conditions. It contains the antioxidant and antiinflammatory but toxic nordihydroguaiaretic acid (NDGA) as well as O-methylated metabolite of NDGA (MNDGA) as bioactive compounds. The hepatic metabolism-based toxicological potential of extracts of LNC (LNE), NDGA, and MNDGA has not previously been reported. The present study aimed to characterize the phase I and phase II hepatic metabolism and reactive intermediates of LNE, NDGA, and MNDGA and their effects on the major drug-metabolizing enzymes in vitro and ex vivo...
January 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28035588/clinical-pharmacokinetics-and-pharmacodynamics-of-naloxegol-a-peripherally-acting-%C3%A2%C2%B5-opioid-receptor-antagonist
#10
REVIEW
Khanh Bui, Diansong Zhou, Hongmei Xu, Eike Floettmann, Nidal Al-Huniti
Naloxegol is a peripherally acting µ-opioid receptor antagonist approved for use as an orally administered tablet (therapeutic doses of 12.5 and 25 mg) for the treatment of opioid-induced constipation. Over a wide dose range (i.e. single supratherapeutic doses up to 1000 mg in healthy volunteers), the pharmacokinetic properties of naloxegol appear to be time- and dose-independent. Naloxegol is rapidly absorbed, with mean time to maximum plasma concentration of <2 h. Following once-daily administration, steady state is achieved within 2-3 days and minimal accumulation is observed...
December 29, 2016: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28031486/structural-basis-for-regiospecific-midazolam-oxidation-by-human-cytochrome-p450-3a4
#11
Irina F Sevrioukova, Thomas L Poulos
Human cytochrome P450 3A4 (CYP3A4) is a major hepatic and intestinal enzyme that oxidizes more than 60% of administered therapeutics. Knowledge of how CYP3A4 adjusts and reshapes the active site to regioselectively oxidize chemically diverse compounds is critical for better understanding structure-function relations in this important enzyme, improving the outcomes for drug metabolism predictions, and developing pharmaceuticals that have a decreased ability to undergo metabolism and cause detrimental drug-drug interactions...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27995413/is-cytochrome-p450-3a4-regulated-by-menstrual-cycle-hormones-in-control-endometrium-and-endometriosis
#12
Carla A Piccinato, Rosa M Neme, Natália Torres, Renata Silvério, Vanessa Bitencourt Pazzini, Júlio C Rosa E Silva, Rui A Ferriani
The estrogen-metabolizing activities of cytochrome P450 (CYP) enzymes have been implicated in endometriosis. However, their regulation in various sources of endometrial tissue under different hormonal conditions has not been clarified. Our objective was to study the hormone regulation of a specific CYP enzyme, namely CYP3A4, in control (n = 15) and endometriosis patients (n = 42). To this end, we evaluated mRNA expression (using real-time PCR) of CYP3A4 in tissue samples classified according to the phase of menstrual cycle at which they were obtained as confirmed by the related circulating hormone levels...
December 19, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27994733/identification-synthesis-and-biological-evaluation-of-the-major-human-metabolite-of-nlrp3-inflammasome-inhibitor-mcc950
#13
Manohar Salla, Mark S Butler, Ruby Pelingon, Geraldine Kaeslin, Daniel E Croker, Janet C Reid, Jong Min Baek, Paul V Bernhardt, Elizabeth M J Gillam, Matthew A Cooper, Avril A B Robertson
MCC950 is an orally bioavailable small molecule inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that exhibits remarkable activity in multiple models of inflammatory disease. Incubation of MCC950 with human liver microsomes, and subsequent analysis by HPLC-MS/MS, revealed a major metabolite, where hydroxylation of MCC950 had occurred on the 1,2,3,5,6,7-hexahydro-s-indacene moiety. Three possible regioisomers were synthesized, and coelution using HPLC-MS/MS confirmed the structure of the metabolite...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27989148/chemical-reactivity-of-emodin-and-its-oxidative-metabolites-to-thiols
#14
Boyang Qin, Yang Xu, Jiaming Chen, Wenlin Huang, Ying Peng, Jiang Zheng
Polygonum multiflorum is an herbal medicine widely employed in China. Hepatotoxicity of the herbal medicine has been well documented, but the mechanisms of the toxicity remain unknown. Emodin (EM) is a major constituent of the herb and has been reported to be hepatotoxic. The main purpose of this study was to define the metabolic pathways of EM in order to characterize the potential reactive intermediates. EM was incubated with rat liver microsomes or human liver microsomes, followed by LC-MS/MS analysis to investigate the in vitro and in vivo metabolism of EM...
December 19, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27978469/highly-sensitive-lc-ms-ms-methods-for-the-determination-of-seven-human-cyp450-activities-using-small-oral-doses-of-probe-drugs-in-human
#15
Alexia Grangeon, Sophie Gravel, Fleur Gaudette, Jacques Turgeon, Veronique Michaud
Cocktails composed of several Cytochrome P450 (CYP450)-selective probe drugs have been shown of value to characterize in vivo drug-metabolism activities. Our objective was to develop and validate highly sensitive and selective LC-MS/MS assays allowing the determination of seven major human CYP450 isoenzyme activities following administration of low oral doses of a modified CYP450 probe-drug cocktail in patients. The seven-drug cocktail was composed of caffeine, bupropion, tolbutamide, omeprazole, dextromethorphan, midazolam (all administered concomitantly) and chlorzoxazone (administered separately) to phenotype for CYP1A2, 2B6, 2C9, 2C19, 2D6, 3A4/5 and 2E1, respectively...
January 1, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27974381/difference-in-mechanism-based-inhibition-of-cytochrome-p450-3a4-and-3a5-by-a-series-of-fluoroquinolone-antibacterial-agents
#16
Akiko Watanabe, Hideo Takakusa, Takako Kimura, Shin-Ichi Inoue, Hiroyuki Kusuhara, Osamu Ando
A series of fluoroquinolone antibacterial compounds were found to be irreversible (compounds 1 - 5) and quasi-irreversible (compounds 6 - 9) inhibitors of cytochrome P450 3A4 (CYP3A4). The purpose of this study was to evaluate their mechanism-based inhibition (MBI) potency against CYP3A5. Compounds 1 - 5 were also irreversible inhibitors of CYP3A5, whereas compounds 6 - 9 showed neither irreversible nor quasi-irreversible inhibition of CYP3A5. Compounds 6 and 8 did not form a metabolite-intermediate (MI) complex with the heme of CYP3A5 during incubation...
December 14, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27937048/effects-of-cytochrome-p450-3a4-and-non-genetic-factors-on-initial-voriconazole-serum-trough-concentrations-in-hematological-patients-with-different-cytochrome-p450-2c19-genotypes
#17
Beibei Shao, Yongcheng Ma, Qiaoyan Li, Yimeng Wang, Zunmin Zhu, Hongwei Zhao, Jun Sun, Lingfang Dong, Yingli Zhu, Ningmin Zhao, Yuhua Qin
1. Polymorphisms of cytochrome P450 2C19 (CYP2C19) is an important factor contributing to variability of voriconazole pharmacokinetics. Polymorphisms of CYP3A4, CYP3A5, CYP2C9 and non-genetic factors such as age, gender, body mass index (BMI), transaminase levels, concomitant medications might also affect voriconazole initial steady serum trough concentration (VICmin) in haematological patients, but the effects were not clear. 2. Eighteen single-nucleotide polymorphisms in CYP2C19, CYP3A4, CYP3A5, CYP2C9 were genotyped...
January 3, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27928738/effect-of-multiple-oral-doses-of-the-potent-cyp3a4-inhibitor-clarithromycin-on-the-pharmacokinetics-of-a-single-oral-dose-of-vonoprazan-a-phase-i-open-label-sequential-design-study
#18
Helen Jenkins, Richard Jenkins, Alain Patat
BACKGROUND AND OBJECTIVES: This phase I, open-label, sequential design study assessed the effect of multiple oral doses of the potent cytochrome P450 (CYP) 3A4 inhibitor clarithromycin on the pharmacokinetics of a single oral dose of vonoprazan. METHODS: During the 10-day treatment period, 16 healthy male subjects received vonoprazan 40 mg on days 1 and 8, and clarithromycin 1000 mg on days 3-9, with the pharmacokinetics of both examined. Primary endpoints included the maximum observed plasma concentration (C max) and area under the plasma concentration-time curve (AUC) of vonoprazan and its major metabolites (M-I, M-II, M-III, and M-IV-Sul)...
December 7, 2016: Clinical Drug Investigation
https://www.readbyqxmd.com/read/27925256/pharmacokinetic-drug-drug-interactions-of-tyrosine-kinase-inhibitors-a-focus-on-cytochrome-p450-transporters-and-acid-suppression-therapy
#19
REVIEW
Caroline Gay, Delphine Toulet, Pascal Le Corre
The extensive use of tyrosine kinase inhibitors (TKI's) in hematology and oncology has shown that these drugs have a significant potential for drug-drug interactions. Since these drugs have a rather low therapeutic window, some drug interactions are of particular clinical relevance either on drug toxicity or on patient's response. Significant interactions occur with concomitant use of acid-suppressive therapy leading to a decreased oral bioavailability. However, such interactions are drug dependent according to their solubility pattern and to the duration of action of acid-suppressive therapy, which is coprescribed...
December 7, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27909995/solithromycin-a-novel-fluoroketolide-for-the-treatment-of-community-acquired-bacterial-pneumonia
#20
REVIEW
George G Zhanel, Erika Hartel, Heather Adam, Sheryl Zelenitsky, Michael A Zhanel, Alyssa Golden, Frank Schweizer, Bala Gorityala, Philippe R S Lagacé-Wiens, Andrew J Walkty, Alfred S Gin, Daryl J Hoban, Joseph P Lynch, James A Karlowsky
Solithromycin is a novel fluoroketolide developed in both oral and intravenous formulations to address increasing macrolide resistance in pathogens causing community-acquired bacterial pneumonia (CABP). When compared with its macrolide and ketolide predecessors, solithromycin has several structural modifications which increase its ribosomal binding and reduce its propensity to known macrolide resistance mechanisms. Solithromycin, like telithromycin, affects 50S ribosomal subunit formation and function, as well as causing frame-shift errors during translation...
December 2016: Drugs
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