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https://www.readbyqxmd.com/read/28430654/alpha-ketoglutarate-suppresses-the-nf-%C3%AE%C2%BAb-mediated-inflammatory-pathway-and-enhances-the-pxr-regulated-detoxification-pathway
#1
Liuqin He, Huan Li, Niu Huang, Xihong Zhou, Junquan Tian, Tiejun Li, Jing Wu, Yanan Tian, Yulong Yin, Kang Yao
Alpha-ketoglutarate (AKG) is a critical nutritional factor in the maintenance of intestinal homeostasis. However, the relative mechanism of AKG has not been well understood. It was recently shown that the interaction between nuclear factor kappa B (NF-κB)-mediated inflammatory pathway and pregnane X receptor (PXR)-regulated detoxification pathway is a check and balance mechanism for keeping the homeostatic state of the intestine, preventing the onset of intestinal inflammation which may lead to cancer. In the current study we used lipopolysaccharide (LPS)-challenged piglet and intestinal porcine epithelial cells-J2 models to investigate the effects of dietary AKG supplementation on the intestinal immune system and PXR regulated target expression...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28419964/effects-of-paeonia-emodi-on-hepatic-cytochrome-p450-cyp3a2-and-cyp2c11-expression-and-pharmacokinetics-of-carbamazepine-in-rats
#2
Mohammad Raish, Ajaz Ahmad, Khalid M Alkharfy, Basit L Jan, Kazi Mohsin, Abdul Ahad, Fahad I Al-Jenoobi, Abdullah M Al-Mohizea
Herbal medicines, dietary supplements, and other foods may pharmacokinetically and/or pharmacodynamically interact with carbamazepine (CBZ), which could lead to potential clinical consequences. Paeonia emodi (PE) is one of the herbs used as complementary therapy in the treatment of epileptic patients in some cultures, and may also be co-administered with CBZ. This study evaluates the effects of PE on the pharmacokinetics of CBZ and determines a possible mechanism of interaction. Rats were administered vehicle saline or PE (200mg/kg, p...
April 15, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28408884/effect-of-cyp3a4-%C3%A2-1g-and-cyp3a5-%C3%A2-3-polymorphisms-on-pharmacokinetics-and-pharmacodynamics-of-ticagrelor-in-healthy-chinese-subjects
#3
Shuaibing Liu, Xiangfen Shi, Xin Tian, Xiaojian Zhang, Zhiyong Sun, Liyan Miao
Ticagrelor is the first reversible, direct-acting, potent P2Y12 receptor antagonist in management of acute coronary syndromes. It is rapidly absorbed and extensively metabolized. AR-C124910XX, the major active metabolite, antagonizes the P2Y12 receptor at approximately equal potency. The metabolism of ticagrelor to AR-C124910XX involves CYP3A4 and CYP3A5. CYP3A polymorphisms have been well documented, and CYP3A4(∗)1G (g.20230G>A, rs2242480) and CYP3A5(∗)3 (g.6986A>G, rs776746) are the most important single nucleotide polymorphisms in Chinese...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28399110/towards-better-dose-individualisation-metabolic-phenotyping-to-predict-cabazitaxel-pharmacokinetics-in-men-with-prostate-cancer
#4
A Janssen, C P M Verkleij, A van der Vlist, R H J Mathijssen, H J Bloemendal, R Ter Heine
BACKGROUND: Cabazitaxel is approved for treatment of castration-resistant metastatic prostate cancer. The current dosing strategy of cabazitaxel is based on body surface area (BSA). Body surface area is known as a poor predictor for total systemic exposure to drugs, since it does not take into account variability in activity of metabolising enzymes, necessary for clearance of drugs. As exposure to cabazitaxel is related to treatment response, it is essential to develop a better individualised dosing strategy...
April 11, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28393714/gender-difference-of-hepatic-and-intestinal-cyp3a4-in-cyp3a-humanized-mice-generated-by-a-human-chromosome-engineering-technique
#5
Kaoru Kobayashi, Chihiro Abe, Mika Endo, Yasuhiro Kazuki, Mitsuo Oshimura, Kan Chiba
BACKGROUND: Cytochrome P450 3A4 (CYP3A4) is an important drug-metabolizing enzyme that is expressed in the liver and small intestine of humans. Various factors influence the expression of CYP3A4, but gender difference in CYP3A4 expression remains debatable. OBJECTIVE: To clarify gender difference of hepatic and intestinal CYP3A4 in CYP3A-humanized mice generated by a human artificial chromosome (HAC) vector system. The CYP3A-humanized (CYP3A-HAC) mice have essential regulatory regions, including promoters and enhancers, and unknown elements affecting the expression of CYP3A4...
April 4, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28374976/ppar%C3%AE-activation-suppresses-cytochrome-p450-induction-potential-in-mice-treated-with-gemfibrozil
#6
Cunzhong Shi, Luo Min, Julin Yang, Manyun Dai, Danjun Song, Huiying Hua, Gangming Xu, Frank J Gonzalez, Aiming Liu
Gemfibrozil, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug-drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in Cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild-type mice were first fed gemfibrozil-containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose-response relationship for CYP induction. Then, wild-type mice and Pparα-null mice were treated with a 0...
April 4, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28370390/auto-inhibitory-properties-of-the-parent-but-not-of-the-n-oxide-metabolite-contribute-to-infusion-rate-dependent-voriconazole-pharmacokinetics
#7
Nicolas Hohmann, Rebecca Kreuter, Antje Blank, Johanna Weiss, Jürgen Burhenne, Walter E Haefeli, Gerd Mikus
PURPOSE: The pharmacokinetics of voriconazole show a non-linear dose-exposure relationship caused by inhibition of its own CYP3A-dependent metabolism. Because the magnitude of auto-inhibition also depends on voriconazole concentrations, infusion rate might modulate voriconazole exposure. The impact of four different infusion rates on voriconazole pharmacokinetics was investigated. METHODS: Twelve healthy participants received 100 mg voriconazole i.v. over 4 h, 400 mg over 6 h, 4 h, and 2 h in a crossover design...
March 29, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28368100/halogen-%C3%AF-interactions-in-the-cytochrome-p450-active-site-structural-insights-into-human-cyp2b6-substrate-selectivity
#8
Manish B Shah, Jingbao Liu, Qinghai Zhang, C David Stout, James R Halpert
Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited dual orientations in the active site with the predominant orientation revealing a bromine-π bond with the Phe108 side chain. Bornane demonstrated two orientations with equal occupancy; in both, the C2 atom that bears the bromine in bornyl bromide was displaced by more than 2...
April 6, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28353169/the-effect-of-single-and-multiple-doses-of-rifampin-on-the-pharmacokinetics-of-doravirine-in-healthy-subjects
#9
Ka Lai Yee, Sauzanne G Khalilieh, Rosa I Sanchez, Rachael Liu, Matt S Anderson, Helen Manthos, Timothy Judge, John Brejda, Joan R Butterton
BACKGROUND AND OBJECTIVE: Doravirine is a novel, next-generation, non-nucleoside reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretrovirals. Doravirine is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein. Rifampin (rifampicin) is used for treating tuberculosis in patients who are co-infected with human immunodeficiency virus. Rifampin demonstrates organic anion-transporting polypeptide 1B1 and P-glycoprotein inhibition after single-dose administration and CYP3A and P-glycoprotein induction after multiple-dose administration...
March 28, 2017: Clinical Drug Investigation
https://www.readbyqxmd.com/read/28350814/compensatory-changes-in-cyp-expression-in-three-different-toxicology-mouse-models-car-null-cyp3a-null-and-cyp2b9-10-13-null-mice
#10
Ramiya Kumar, Linda C Mota, Elizabeth J Litoff, John P Rooney, W Tyler Boswell, Elliott Courter, Charles M Henderson, Juan P Hernandez, J Christopher Corton, David D Moore, William S Baldwin
Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model...
2017: PloS One
https://www.readbyqxmd.com/read/28345929/utility-of-cyp3a4-and-pxr-car-cyp3a4-3a7-transgenic-mouse-models-to-assess-the-magnitude-of-cyp3a4-mediated-drug-drug-interactions
#11
Justin Q Ly, Kirsten Messick, Ann Qin, Ryan H Takahashi, Edna F Choo
Species differences in the expression, activity, regulation, and substrate specificity of metabolizing enzymes preclude the use of animal models to predict clinical drug-drug interactions (DDIs). The objective of this work is to determine if the transgenic (Tg) Cyp3a(-/-)Tg-3A4Hep/Int and Nr1i2/Nr1i3(-/-)-Cyp3a(-/-)Tg-PXR-CAR-3A4/3A7Hep/Int (PXR-CAR-CYP3A4/3A7) mouse models could be used to predict in vivo DDI of 10 drugs; alprazolam, bosutinib, crizotinib, dasatinib, gefitinib, ibrutinib, regorafenib, sorafenib, triazolam, and vandetinib (as victims); with varying magnitudes of reported CYP3A4 clinical DDI...
April 7, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28344076/inhibition-of-human-cyp3a4-and-cyp3a5-enzymes-by-gomisin-c-and-gomisin-g-two-lignan-analogs-derived-from-schisandra-chinensis
#12
Jin Zhao, Tao Sun, Jing-Jing Wu, Yun-Feng Cao, Zhong-Ze Fang, Hong-Zhi Sun, Zhi-Tu Zhu, Kun Yang, Yong-Zhe Liu, Frank J Gonzalez, Jun Yin
Gomisin C (GC) and gomisin G (GG) are two lignan analogs isolated from the Traditional Chinese Medicine Schisandra chinensis which possesses multiple pharmacological activities. However, the potential herb-drug interactions (HDI) between these lignans and other drugs through inhibiting human cytochrome P450 3A4 (CYP3A4) and CYP3A5 remains unclear. In the present study, the inhibitory action of GC and GG on CYP3A4 and CYP3A5 were investigated. The results demonstrated that both GC and GG strongly inhibited CYP3A-mediated midazolam 1'-hydroxylation, nifedipine oxidation and testosterone 6β-hydroxylation...
March 24, 2017: Fitoterapia
https://www.readbyqxmd.com/read/28341123/acetaminophen-analog-n-acetyl-m-aminophenol-but-not-its-reactive-metabolite-n-acetyl-p-benzoquinone-imine-induces-cyp3a-activity-via-inhibition-of-protein-degradation
#13
Masataka Santoh, Seigo Sanoh, Yuya Ohtsuki, Yoko Ejiri, Yaichiro Kotake, Shigeru Ohta
Cytochrome P450 (CYP) 3A subfamily members are known to metabolize various types of drugs, highlighting the importance of understanding drug-drug interactions (DDI) depending on CYP3A induction or inhibition. While transcriptional regulation of CYP3A members is widely understood, post-translational regulation needs to be elucidated. We previously reported that acetaminophen (APAP) induces CYP3A activity via inhibition of protein degradation and proposed a novel DDI concept. N-Acetyl-p-benzoquinone imine (NAPQI), the reactive metabolite of APAP formed by CYP, is known to cause adverse events related to depletion of intracellular reduced glutathione (GSH)...
March 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28340122/potential-role-of-patients-cyp3a-status-in-clozapine-pharmacokinetics
#14
Katalin Tóth, Gábor Csukly, Dávid Sirok, Ales Belic, Ádám Kiss, Edit Háfra, Máté Déri, Ádám Menus, István Bitter, Katalin Monostory
Background: The atypical antipsychotic clozapine is effective in treatment-resistant schizophrenia; however, the success or failure of clozapine therapy is substantially affected by the variables that impact the clozapine blood concentration. Thus, elucidating the inter-individual differences in clozapine pharmacokinetics can facilitate the personalized therapy. Methods: Since potential role in clozapine metabolism is assigned to CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes, the association between the patients' CYP-status (CYP genotypes, CYP expression) and clozapine clearance was evaluated in 92 psychiatric patients...
March 18, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28338641/nerolidol-and-farnesol-inhibit-some-cytochrome-p450-activities-but-did-not-affect-other-xenobiotic-metabolizing-enzymes-in-rat-and-human-hepatic-subcellular-fractions
#15
Alena Špičáková, Barbora Szotáková, Diana Dimunová, Zuzana Myslivečková, Vladimír Kubíček, Martin Ambrož, Kateřina Lněničková, Kristýna Krasulová, Pavel Anzenbacher, Lenka Skálová
Sesquiterpenes, 15-carbon compounds formed from three isoprenoid units, are the main components of plant essential oils. Sesquiterpenes occur in human food, but they are principally taken as components of many folk medicines and dietary supplements. The aim of our study was to test and compare the potential inhibitory effect of acyclic sesquiterpenes, trans-nerolidol, cis-nerolidol and farnesol, on the activities of the main xenobiotic-metabolizing enzymes in rat and human liver in vitro. Rat and human subcellular fractions, relatively specific substrates, corresponding coenzymes and HPLC, spectrophotometric or spectrofluorometric analysis of product formation were used...
March 24, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28326038/ganoderic-acid-a-metabolites-and-their-metabolic-kinetics
#16
Fang-Rui Cao, Li Feng, Lin-Hu Ye, Li-Sha Wang, Bing-Xin Xiao, Xue Tao, Qi Chang
Ganoderic acid A (GAA), a representative active triterpenoid from Ganoderma lucidum, has been reported to exhibit antinociceptive, antioxidative, cytotoxic, hepatoprotective and anticancer activities. The present study aims (1) to identify GAA metabolites, in vivo by analyzing the bile, plasma and urine after intravenous administration to rats (20 mg/kg), and in vitro by incubating with rat liver microsomes (RLMs) and human liver microsomes (HLMs); (2) to investigate the metabolic kinetics of main GAA metabolites...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28324194/sex-differences-in-the-blood-concentration-of-tacrolimus-in-systemic-lupus-erythematosus-and-rheumatoid-arthritis-patients-with-cyp3a5-3-3
#17
Ayano Ito, Yuko Okada, Tadahiro Hashita, Tohru Aomori, Keiju Hiromura, Yoshihisa Nojima, Tomonori Nakamura, Takuya Araki, Koujirou Yamamoto
The purpose of this study was to describe the impact of sex and cytochrome P450 3A5 (CYP3A5) variant on the blood concentration of tacrolimus in patients with systemic lupus erythematosus or rheumatoid arthritis. The blood concentration of tacrolimus (ng/mL) divided by the daily dose of tacrolimus (mg/day) and the patient's weight (kg) (C/D) was obtained from 55 patients. The C/D value was analysed according to genetic variation in CYP3A5 or ATP binding cassette subfamily B member 1 (ABCB1), sex, and age. The C/D value in the CYP3A5*3/*3 group was significantly higher than in the CYP3A5*1/*1 and *1/*3 groups (p < 0...
March 21, 2017: Biochemical Genetics
https://www.readbyqxmd.com/read/28316274/co-treatment-with-indole-3-carbinol-and-resveratrol-modify-porcine-cyp1a-and-cyp3a-activities-and-expression
#18
Galia Zamaratskaia, Rebekka Thøgersen, Marjeta Čandek-Potokar, Martin Krøyer Rasmussen
1. Humans and animals are commonly exposed to indole-3-carbinol (I3C) and resveratrol (RES) via food or beverages. Moreover, these compounds have been demonstrated to potentially cause food-drug interactions. However, information about their combined effects is limited. Therefore, we investigated the effects of I3C and RES, both as single compounds and in combination, on cytochrome P450 1A and 3A activity and gene expression. 2. Using porcine microsomes, we demonstrated that RES caused non-competitive inhibition of CYP1A activity and un-competitive inhibition of CYP3A activity...
March 19, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28272018/genetic-polymorphisms-of-cytochrome-p450-enzymes-cyp2c9-cyp2c19-cyp2d6-cyp3a4-and-cyp3a5-in-the-croatian-population
#19
Lana Ganoci, Tamara Božina, Nikica Mirošević Skvrce, Mila Lovrić, Petar Mas, Nada Božina
BACKGROUND: Data on the frequency of pharmacogenetic polymorphisms in the Croatian population are limited. We determined and analyzed frequencies for the most important CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 genetic variants in the Croatian population. METHODS: 2637 subjects were included. Genotyping was performed by real-time polymerase chain reaction (PCR) using TaqMan® DME or TaqMan® SNP Genotyping Assays, and by PCR, and PCR-RFLP analysis. RESULTS: For CYP2C9, allele frequencies of *2 and *3 variant were 14...
March 1, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/28270565/midostaurin-a-novel-protein-kinase-inhibitor-for-the-treatment-of-acute-myelogenous-leukemia-insights-from-human-absorption-metabolism-and-excretion-studies-of-a-bddcs-ii-drug
#20
Handan He, Phi Tran, Helen Gu, Vivienne Tedesco, Jin Zhang, Wen Lin, Ewa Gatlik, Kai Klein, Tycho Heimbach
The absorption, metabolism, and excretion of midostaurin, a potent class III tyrosine protein kinase inhibitor for acute myelogenous leukemia, were evaluated in healthy subjects. A microemulsion formulation was chosen to optimize absorption. After a 50-mg [(14)C]midostaurin dose, oral absorption was high (>90%) and relatively rapid. In plasma, the major circulating components were midostaurin (22%), CGP52421 (32.7%), and CGP62221 (27.7%). Long plasma half-lives were observed for midostaurin (20.3 hours), CGP52421 (495 hours), and CGP62221 (33...
May 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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