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https://www.readbyqxmd.com/read/28136132/r-warfarin-clearances-from-plasma-associated-with-polymorphic-cytochrome-p450-2c19-and-simulated-by-individual-physiologically-based-pharmacokinetic-models-for-11-cynomolgus-monkeys
#1
Masahiro Utoh, Takashi Kusama, Tomonori Miura, Marina Mitsui, Mirai Kawano, Takahiro Hirano, Makiko Shimizu, Yasuhiro Uno, Hiroshi Yamazaki
1. Cynomolgus monkey cytochrome P450 2C19 (formerly known as P450 2C75), homologous to human P450 2C19, has been identified as R-warfarin 7-hydroxylase. In this study, simulations of R-warfarin clearance in individual cynomolgus monkeys genotyped for P450 2C19 p.[(Phe100Asn; Ala103Val; Ile112Leu)] were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling. 2. Pharmacokinetic parameters and absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearances for individual PBPK models were estimated for eleven cynomolgus monkeys...
January 30, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28119166/in-vitro-toxicological-evaluation-of-ncs-382-a-high-affinity-antagonist-of-%C3%AE-hydroxybutyrate-ghb-binding
#2
K R Vogel, G R Ainslie, J-B Roullet, A McConnell, K M Gibson
γ-Hydroxybutyric acid (GHB), a minor metabolite of the inhibitory neurotransmitter GABA, can accumulate to significant concentrations in the heritable disorder of GABA degradation, succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD). Moreover, GHB may be employed in therapeutic settings (treatment of narcolepsy), as well as instances of illicit activity, including acquaintance sexual assault and the induction of euphoria. High-affinity binding sites for GHB in the brain have been identified, although the absolute identity of these receptors remains unclear...
January 22, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28117433/cost-effectiveness-of-cytochrome-p450-2c19-2-genotype-guided-selection-of-clopidogrel-or-ticagrelor-in-chinese-patients-with-acute-coronary-syndrome
#3
Y Wang, B P Yan, D Liew, V W Y Lee
The choice of antiplatelet therapy among Asian populations for the treatment of acute coronary syndrome (ACS) is complicated owing to the high prevalence of cytochrome P450 2C19 (CYP2C19) genetic polymorphism that has been associated with reduced efficacy of clopidogrel. Ticagrelor is a potent but more expensive alternative antiplatelet agent that is not affected by CYP2C19 polymorphism. This study aimed to evaluate the cost-effectiveness, from the Hong Kong health-care provider's perspective, of CYP2C19*2 genotype-guided selection of antiplatelet therapy compared with the universal use of clopidogrel or ticagrelor among ACS patients who undergo percutaneous coronary intervention (PCI)...
January 24, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28056947/triptolide-induces-hepatotoxicity-via-inhibition-of-cyp450s-in-rat-liver-microsomes
#4
Yan Lu, Tong Xie, Yajie Zhang, Fuqiong Zhou, Jie Ruan, Weina Zhu, Huaxu Zhu, Zhe Feng, Xueping Zhou
BACKGROUND: Triptolide (TP), an active constituent of Tripterygium wilfordii, possesses numerous pharmacological activities. However, its effects on cytochrome P450 enzymes (CYP450s) in rats remain unexplored. METHODS: In this study, the effects of triptolide on the six main CYP450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A) were investigated both in vivo and in vitro. We monitored the body weight, survival proportions, liver index, changes in pathology, and biochemical index upon TP administration, in vivo...
January 5, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28032016/rapid-naked-eye-discrimination-of-cytochrome-p450-genetic-polymorphism-through-non-crosslinking-aggregation-of-dna-functionalized-gold-nanoparticles
#5
Yoshitsugu Akiyama, Guoqing Wang, Shota Shiraishi, Naoki Kanayama, Tohru Takarada, Mizuo Maeda
Involvement of single-nucleotide polymorphism (SNP) genotyping in healthcare should allow for more effective use of pharmacogenomics. However, user-friendly assays without the requirement of a special instrument still remain unavailable. This study describes naked-eye SNP discrimination in exon 5 of the human cytochrome P450 2C19 monooxygenase gene, CYP2C19*1 (the wild-type allele) and CYP2C19*2 (the variant allele with G681A point mutation). The present assay is composed of allele-specific single-base primer extension and salt-induced aggregation of DNA-modified gold nanoparticles (DNA-AuNPs)...
December 2016: ChemistryOpen
https://www.readbyqxmd.com/read/28032015/rapid-naked-eye-discrimination-of-cytochrome-p450-genetic-polymorphism-through-non-crosslinking-aggregation-of-dna-functionalized-gold-nanoparticles
#6
Yoshitsugu Akiyama, Guoqing Wang, Shota Shiraishi, Naoki Kanayama, Tohru Takarada, Mizuo Maeda
The front cover artwork is provided by the group of Tohru Takarada at RIKEN (Japan). The image shows a colorimetric single-nucleotide polymorphism (SNP) genotyping method that uses spontaneous aggregation of DNA-modified gold nanoparticles (DNA-AuNPs) for the simple and rapid SNP genotyping of the human cytochrome P450 2C19 monooxygenase gene. For more details, read the full text of the Full Paper at p. 508.
December 2016: ChemistryOpen
https://www.readbyqxmd.com/read/28032014/cover-picture-rapid-naked-eye-discrimination-of-cytochrome-p450-genetic-polymorphism-through-non-crosslinking-aggregation-of-dna-functionalized-gold-nanoparticles-chemistryopen-6-2016
#7
Yoshitsugu Akiyama, Guoqing Wang, Shota Shiraishi, Naoki Kanayama, Tohru Takarada, Mizuo Maeda
The Front Cover picture shows a colorimetric single-nucleotide polymorphism (SNP) genotyping method using spontaneous aggregation of DNA-modified gold nanoparticles (DNA-AuNPs). Simple and rapid SNP genotyping of the human cytochrome P450 2C19 monooxygenase gene is reported. Allele-specific single-base primer extension using a fragment of the gene isolated from human hair roots, followed by salt-induced aggregation of DNA-AuNPs, results in a rapid color change from red to blue or no color change, thereby allowing SNP discrimination by the naked eye...
December 2016: ChemistryOpen
https://www.readbyqxmd.com/read/27994733/identification-synthesis-and-biological-evaluation-of-the-major-human-metabolite-of-nlrp3-inflammasome-inhibitor-mcc950
#8
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
#9
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
#10
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/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
#11
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/27935899/-algorithm-for-selection-of-individual-therapy-with-clopidogrel-in-vascular-surgical-practice
#12
A I Shevela, A A Slepukhina, E M Zelenskaya, T A Seredina, G I Lifshits
For treatment of patients with diseases of lower limb arteries and prevention of cardiovascular complications in high-risk patients (those with diabetes mellitus, arterial hypertension, dyslipidemia, obesity) permanent antiplatelet therapy is indicated. A problem is variable individual sensitivity to therapeutic agents. For antiplatelet therapy in patients with atherosclerosis of lower limb arteries there has been obtained an evidence-supported base concerning efficacy of long-term administration of clopidogrel preparations, unlike patients with acute coronary syndrome, for whom there has been accumulated an evidence-confirmed base of administering clopidogrel preparations, as well as ticagrelor and prasugrel in various clinical situations...
2016: Angiologii︠a︡ i Sosudistai︠a︡ Khirurgii︠a︡, Angiology and Vascular Surgery
https://www.readbyqxmd.com/read/27932982/impact-of-cyp2c19-variants-on-clinical-efficacy-of-clopidogrel-and-1-year-clinical-outcomes-in-coronary-heart-patients-undergoing-percutaneous-coronary-intervention
#13
Hong Sun, Qiang Qu, Zhen-Fan Chen, Sheng-Lan Tan, Hai-Jun Zhou, Jian Qu, Hui Chen
The impact of pharmacogenetic variants of cytochrome P450 2C19 (CYP2C19) on clopidogrel-mediated effects on platelet inhibition, inflammatory response and endothelial function, as well as risk of major adverse cardiovascular events (MACE), in coronary heart patients undergoing percutaneous coronary intervention (PCI) was investigated. To this end, we assessed the residual platelet aggregation rate (RPA), maximal aggregation rate (MAR) and plasma levels of sCD40L, sP-selectin, MMP-9, sVCAM-1 and sE-selectin after 24 h of PCI in 559 patients treated with clopidogrel and followed up for 1 year for evidence of MACE...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27886818/genetic-determinants-of-p2y12-inhibitors-and-clinical-implications
#14
REVIEW
Larisa H Cavallari, Aniwaa Owusu Obeng
There is significant interpatient variability in clopidogrel effectiveness, which is due in part to cytochrome P450 (CYP) 2C19 genotype. Approximately 30% of individuals carry CYP2C19 loss-of-function alleles, which have been consistently shown to reduce clopidogrel effectiveness after an acute coronary syndrome and percutaneous coronary intervention. Guidelines recommend consideration of prasugrel or ticagrelor in these patients. A clinical trial examining outcomes with CYP2C19 genotype-guided antiplatelet therapy is ongoing...
January 2017: Interventional cardiology clinics
https://www.readbyqxmd.com/read/27853934/evaluation-of-in-vitro-cytochrome-p450-inhibition-and-in-vitro-fate-of-structurally-diverse-n-oxide-metabolites-case-studies-with-clozapine-levofloxacin-roflumilast-voriconazole-and-zopiclone
#15
Poonam Giri, Sneha Naidu, Nirmal Patel, Harilal Patel, Nuggehally R Srinivas
BACKGROUND AND OBJECTIVES: The role of metabolite(s) to elicit potential clinical drug-drug interaction (DDI) via cytochrome P450 enzymes (CYP) is gaining momentum. In this context, the role of N-oxides for in vitro CYP inhibition has not been evaluated. The objectives of this study were: (a) to examine in vitro CYP inhibition of N-oxides of clozapine, levofloxacin, roflumilast, voriconazole and zopiclone in a tiered approach and (b) evaluate in vitro fate of aforementioned N-oxides examined in recombinant CYPs, human microsomes and hepatocytes...
November 16, 2016: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27842484/strong-induction-of-cytochrome-p450-1a-3a-but-not-p450-2b-in-cultured-hepatocytes-from-common-marmosets-and-cynomolgus-monkeys-by-typical-human-p450-inducing-agents
#16
Shotaro Uehara, Yasuhiro Uno, Takako Suzuki, Takashi Inoue, Masahiro Utoh, Erika Sasaki, Hiroshi Yamazaki
BACKGROUND: Common marmosets (Callithrix jacchus) and cynomolgus monkeys (Macaca fascicularis) are used as non-human primate models in preclinical studies for drug development. OBJECTIVE: The assessment of P450 induction in hepatocytes from marmosets and cynomolgus monkeys was performed using typical P450 inducers. METHODS: Induction of cytochrome P450 1-4 family enzymes was analyzed in two lots of cultured hepatocytes from common marmosets and cynomolgus monkeys after 24-h treatment with typical human P450 inducing agents by real-time reverse transcription-polymerase chain reaction...
November 14, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27819189/inhibitory-effects-of-curculigoside-on-human-liver-cytochrome-p450-enzymes
#17
Jixiao Lang, Wei Li, Jingming Zhao, Kaiyou Wang, Dexi Chen
1. Curculigoside possesses numerous pharmacological activities, and however, little data available for the effects of curculigoside on the activity of human liver cytochrome P450 (CYP) enzymes. 2. This study investigates the inhibitory effects of curculigoside on the main human liver CYP isoforms. In this study, the inhibitory effects of curculigoside on the eight human liver CYP isoforms 1A2, 2A6, 2E1, 2D6, 2C9, 2C19, 2C8, and 3A4 were investigated in human liver microsomes. 3. The results indicated that curculigoside could inhibit the activity of CYP1A2, CYP2C8, and CYP3A4, with IC50 values of 15...
November 5, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27800629/the-combination-of-pharmacogenetic-and-pharmacokinetic-analyses-to-optimize-clomipramine-dosing-in-major-depression-a-case-report
#18
Stefania Antoniazzi, Alessandro Tatulli, Felicia S Falvella, Michela Cigliobianco, Riccardo A Paoli, Dario Cattaneo, Stefania Cheli, Francesca F Bernardi, Emilio Clementi, Carlo A Altamura
WHAT IS KNOWN AND OBJECTIVE: Polymorphisms in cytochrome P450 2D6 and 2C19 can lead to interindividual differences in drug plasma concentrations, affecting clomipramine efficacy. Pharmacokinetic and pharmacogenetic analyses may improve drug therapy. CASE SUMMARY: We report the case of a depressed woman requiring higher doses than standard of clomipramine. Identification of low plasma drug levels led to extensive pharmacogenetic analyses of all genes and major functional polymorphisms reported to affect clomipramine metabolism...
February 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/27783977/targeting-the-entry-region-of-hsp90-s-atp-binding-pocket-with-a-novel-6-7-dihydrothieno-3-2-c-pyridin-5-4h-yl-amide
#19
Ju Hui Jeong, Yong Jin Oh, Yunmee Lho, Sun You Park, Kwang-Hyeon Liu, Eunyoung Ha, Young Ho Seo
The molecular chaperone Hsp90 plays an important role in cancer cell survival and proliferation by regulating the maturation and stabilization of numerous oncogenic proteins. Due to its potential to simultaneously disable multiple signaling pathways, Hsp90 has emerged as an attractive therapeutic target for cancer treatment. In this study, the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors are described. Among the synthetic compounds, 6,7-dihydrothieno [3,2-c]pyridin-5(4H)-yl amide 19 exhibits a remarkable binding affinity to the N-terminus of Hsp90 in a fluorescence polarization (FP) binding assay (IC50 = 50...
November 29, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27758707/new-psychoactive-substances-3-methoxyphencyclidine-3-meo-pcp-and-3-methoxyrolicyclidine-3-meo-pcpy-metabolic-fate-elucidated-with-rat-urine-and-human-liver-preparations-and-their-detectability-in-urine-by-gc-ms-lc-high-resolution-msn-and-lc-high-resolution
#20
Julian A Michely, Sascha K Manier, Achim T Caspar, Simon D Brandt, Jason Wallach, Hans H Maurer
3-Methoxyphencyclidine (3-MeO-PCP) and 3-methoxyrolicyclidine (3-MeO-PCPy) are two new psychoactive substances (NPS). The aims of the present study were the elucidation of their metabolic fate in rat and pooled human liver microsomes (pHLM), the identification of the cytochrome P450 (CYP) isoenzymes involved, and the detectability using standard urine screening approaches (SUSA) after intake of common users' doses using gas chromatography-mass spectrometry (GC-MS), liquid chromatography-multi-stage mass spectrometry (LC-MSn), and liquid chromatography-high-resolution tandem mass spectrometry (LC-HR-MS/MS)...
October 18, 2016: Current Neuropharmacology
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