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https://www.readbyqxmd.com/read/29239000/minimal-physiologically-based-pharmacokinetic-and-drug-drug-disease-interaction-model-of-rivaroxaban-and-verapamil-in-healthy-and-renally-impaired-subjects
#1
Mohamed Ismail, Vincent H Lee, Christina R Chow, Christopher M Rubino
Current dosing recommendations for rivaroxaban advocate dosage reduction in patients with moderate to severe renal impairment and avoidance of concomitant strong inhibitors of CYP3A or P-glycoprotein. However, rivaroxaban dosing in patients with mild renal impairment taking concomitant moderate inhibitors of CYP3A and P-glycoprotein is not addressed. To quantify the impacts of concomitant verapamil administration and renal impairment on rivaroxaban pharmacokinetics, a minimal physiologically based pharmacokinetic model system was developed and used to evaluate potential increases in rivaroxaban exposure and the consequent increase in risk of major bleeding...
December 14, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29237391/utility-of-pooled-cryopreserved-human-enterocytes-as-an-in-vitro-model-for-assessing-intestinal-clearance-and-drug-drug-interactions
#2
Zhengyin Yan, Susan Wong, Jane Kelly, Hoa Le, Ning Liu, Mika Kosaka, Suzanne Tey, Peter Vuong, Albert Li
A recent advancement in isolation and cryopreservation has resulted in commercially available primary human enterocytes that express various drug metabolizing enzymes (DMEs) and transporters. The main objective of this study was to further evaluate the utility of pooled cryopreserved enterocytes, specifically MetMax™ cryopreserved human enterocytes (In Vitro ADMET Laboratories), as an in vitro model for assessing intestinal clearance in comparison to hepatocytes. It was found that, for CYP3A4 substrates such as midazolam, amprenavir and loperamide, in vitro metabolic clearance is generally lower in enterocytes compared to that of hepatocytes, which is consistent with the relative abundance of the enzyme between the intestine and liver...
December 12, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29204052/pregnane-x-receptor-and-constitutive-androstane-receptor-modulate-differently-cyp3a-mediated-metabolism-in-early-and-late-stage-cholestasis
#3
Daniela Gabbia, Arianna Dalla Pozza, Laura Albertoni, Roberta Lazzari, Giorgia Zigiotto, Maria Carrara, Vincenzo Baldo, Tatjana Baldovin, Annarosa Floreani, Sara De Martin
AIM: To ascertain whether cholestasis affects the expression of two CYP3A isoforms (CYP3A1 and CYP3A2) and of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). METHODS: Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin...
November 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29197246/combined-toxicity-of-endosulfan-and-phenanthrene-mixtures-and-induced-molecular-changes-in-adult-zebrafish-danio-rerio
#4
Kyeongnam Kim, Hwang-Ju Jeon, Sung-Deuk Choi, Daniel C W Tsang, Patryk Oleszczuk, Yong Sik Ok, Hoi-Seon Lee, Sung-Eun Lee
Individual and combined toxicities of endosulfan (ENDO) with phenanthrene (PHE) were evaluated using zebrafish (Danio rerio) adults. The 96-h LC50 values for ENDO and PHE were 4.6 μg L-1 and 920 μg L-1, respectively. To evaluate the mixture toxicity, LC10 and LC50 concentrations were grouped into four combinations as ENDO-LC10 + PHE-LC10, ENDO-LC10 + PHE-LC50, ENDO-LC50 + PHE-LC10, and ENDO-LC50 + PHE-LC50, and their acute toxicities were determined. The combination of LC50-ENDO and LC10-PHE exhibited a synergistic effect...
November 23, 2017: Chemosphere
https://www.readbyqxmd.com/read/29194698/impaired-rivaroxaban-clearance-in-mild-renal-insufficiency-with-verapamil-coadministration-potential-implications-for-bleeding-risk-and-dose-selection
#5
David J Greenblatt, Maulik Patel, Jerold S Harmatz, Wayne T Nicholson, Christopher M Rubino, Christina R Chow
Pharmacokinetics and antithrombotic effects of the Factor Xa inhibitor rivaroxaban were studied in subjects with mild renal insufficiency concurrently taking the P-glycoprotein and moderate CYP3A inhibitor verapamil, a drug commonly administered to patients with hypertension, ischemic heart disease, or atrial fibrillation. Age-matched controls with normal renal function were studied concurrently. Subjects' overall mean age was 59 years. Mean creatinine clearance values in the 2 groups were 105 and 71 mL/min...
November 30, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29177473/skeletal-muscle-interleukin-6-regulates-hepatic-cytochrome-p450-expression-effects-of-16-weeks-high-fat-diet-and-exercise
#6
Jakob G Knudsen, Lærke Bertholdt, Anders Gudiksen, Sabine Gerbal-Chaloin, Martin Krøyer Rasmussen
High fat diet (HFD) induce several changes to the pathways regulating energy homeostasis and changes the expression of the hepatic cytochrome p450 (Cyp) enzyme-system. Despite these pervious findings, it is still unclear how the effects of HFD and especially HFD in combination with treadmill running affect hepatic Cyp expression. In the present study, we investigated the mRNA and protein expression of selected Cyp's in mice subjected to 16 weeks of HFD and treadmill running. To understand the regulatory mechanisms behind the exercise-induced reversion of the HFD induced changes in Cyp expression, we used a model in which the exercise induced myokine and known regulator of hepatic Cyp's, interleukin-6 (IL-6), was knocked out specifically in skeletal muscle...
November 21, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29176011/estimation-of-fractions-metabolized-by-hepatic-cyp-enzymes-using-a-concept-of-inter-system-extrapolation-factors-isefs-a-comparison-with-the-chemical-inhibition-method
#7
Ken-Ichi Umehara, Felix Huth, Helen Gu, Hilmar Schiller, Tycho Heimbach, Handan He
BACKGROUND: For estimation of fractions metabolized (fm) by different hepatic recombinant human CYP enzymes (rhCYP), calculation of inter-system extrapolation factors (ISEFs) has been proposed. METHODS: ISEF values for CYP1A2, CYP2C19 and CYP3A4/5 were measured. A CYP2C9 ISEF was taken from a previous report. Using a set of compounds, fractions metabolized by CYP enzymes (fm,CYP) values calculated with the ISEFs based on rhCYP data were compared with those from the chemical inhibition data...
November 27, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/29171002/pharmacokinetic-pharmacodynamic-analysis-of-adjunctive-perampanel-in-subjects-with-partial-onset-seizures
#8
O Takenaka, J Ferry, K Saeki, A Laurenza
OBJECTIVES: Explore perampanel pharmacokinetics (PK) in all subjects (aged ≥12 years) vs adolescents (aged ≥12 to ≤17 years) with partial-onset seizures (POS) and identify factors explaining between-subject variability in efficacy using a population PK/pharmacodynamic (PD) analysis. MATERIALS & METHODS: Population PK analysis was performed using nonlinear mixed-effect modeling with data from phase II/III randomized, double-blind, placebo-controlled studies of adjunctive perampanel in POS...
November 23, 2017: Acta Neurologica Scandinavica
https://www.readbyqxmd.com/read/29165700/epigenetic-therapy-novel-translational-implications-for-arrest-of-environmental-dioxin-induced-disease-in-females
#9
Zaraq Khan, Ye Zheng, Tiffanny L Jones, Abigail A Delaney, Luiz F Correa, Chandra C Shenoy, Khashayarsha Khazaie, Gaurang S Daftary
Increased toxicant exposure and resultant environmentally-induced diseases are a tradeoff of industrial productivity. Dioxin (TCDD: 2,3,7,8 tetrachlorodibenzo-p-dioxin), a ubiquitous by-product is associated with a spectrum of diseases including endometriosis, a common, chronic disease in women. TCDD activates cytochrome p450 (CYP) metabolic enzymes, which alters organ function to cause disease. In contrast, the transcription factor, Krüppel-Like Factor (KLF) 11 represses these enzymes via epigenetic mechanisms...
November 17, 2017: Endocrinology
https://www.readbyqxmd.com/read/29160125/effects-of-paeoniflorin-on-the-activities-and-mrna-expression-of-rat-cyp1a2-cyp2c11-and-cyp3a1-enzymes-in-vivo
#10
Sicong Li, Xuting Li, Dingsheng Yuan, Bin Wang, Rui Yang, Min Zhang, Jinliang Li, Fuqiang Zeng
1. Paeoniflorin is the major constituent in extracts of the peony root, the purpose of the present study was to assess the effects of paeoniflorin on the activities and mRNA expression of the rat hepatic drug-metabolizing enzymes cytochrome P450 (CYP1A2), CYP2C11 and CYP3A1 in vivo. 2. Sprague-Dawley (SD) male rats were treated with paeoniflorin at the dosage of 25, 50 and 100 mg/kg or 0.9% sodium chloride solution by intragastric administration for 7 days, then were given probe drugs phenacetin (CYP1A2), tolbutamide (CYP2C11), or midazolam (CYP3A1) orally on the eighth day...
November 21, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29155017/p-glycoprotein-mdr1-abcb1-and-breast-cancer-resistance-protein-bcrp-abcg2-affect-brain-accumulation-and-intestinal-disposition-of-encorafenib-in-mice
#11
Jing Wang, Changpei Gan, Rolf W Sparidans, Els Wagenaar, Stéphanie van Hoppe, Jos H Beijnen, Alfred H Schinkel
Encorafenib (LGX818) is a promising BRAF(V600E) inhibitor that has efficacy against metastatic melanoma. To better understand its pharmacokinetics, we studied its interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A. In polarized MDCK-II cells, encorafenib was efficiently transported by canine and human ABCB1 and ABCG2 and by mouse Abcg2. Upon oral administration to wild-type, Abcb1a/1b(-/-), Abcg2(-/-), and Abcb1a/1b;Abcg2(-/-) mice, encorafenib was absorbed very quickly and to very high plasma levels, but without clear changes in oral availability between the strains...
November 14, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29145161/cyp450-enzyme-specific-enantioselective-species-specific-response-for-metalaxyl-in-in-vitro-hepatic-cells
#12
Wei Xie, Fangxing Yang
Although enantioselective accumulation of chiral pesticide has been reported in organisms, the mechanisms remain unclear. In this study, the effects of chiral pesticide metalaxyl on CYP1A1, CYP1A2, CYP2B1, CYP2B2, CYP2E1 and CYP3A were investigated in human hepatoma HepG2, rat hepatic H4IIE, chicken hepatic LMH and grass carp hepatic L8824 cells. Moreover, the residual concentrations and enantiomeric ratios (ERs) of metalaxyl were also detected in the medium. The results showed the responses of these CYP450s to metalaxyl were enzyme-dependent and species-dependent in the four cells...
November 13, 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/29135906/effect-of-age-and-allele-variants-of-cyp3a5-cyp3a4-and-por-genes-on-the-pharmacokinetics-of-cyclosporin-a-in-pediatric-renal-transplant-recipients-from-serbia
#13
Mirjana Cvetković, Maja Zivković, Maja Bundalo, Ivana Gojković, Brankica Spasojević-Dimitrijeva, Aleksandra Stanković, Mirjana Kostić
BACKGROUND: The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene (POR*28). The aim of this study was to assess the impact of age, CYP3A5*3, CYP3A4*22, and POR*28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients. METHODS: Renal transplant patients receiving CsA (n = 47) were genotyped for CYP3A5*3, CYP3A4*22, and POR*28...
December 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29134945/drug-drug-interaction-potential-of-the-hepatitis-b-and-hepatitis-d-virus-entry-inhibitor-myrcludex-b-assessed-in-vitro
#14
Antje Blank, Katrin Meier, Stephan Urban, Walter Emil Haefeli, Johanna Weiss
BACKGROUND: Myrcludex B is a first-in-class virus entry inhibitor for patients with chronic hepatitis B or B/D infections. In patients it will be co-administered with drugs needed for the disease or comorbidities. We aimed to define the risk of drug-drug interactions by characterizing the influence of myrcludex B on relevant drug transporting and metabolizing enzymes in vitro. METHODS: Inhibition of P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP/ABCG2), and the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3) was measured in cells over-expressing the respective transporter using fluorogenic substrates...
November 14, 2017: Antiviral Therapy
https://www.readbyqxmd.com/read/29134244/modulation-of-cyp3a-enzyme-activity-by-diosmin-and-its-consequence-on-carbamazepine-pharmacokinetics-in-rats
#15
Satish Kumar Bedada, Prasad Neerati
Diosmin is a widely used flavonoid for the treatment of varicose veins and hemorrhoids. Epileptic patients with hemorrhoids and varicose veins may use diosmin along with carbamazepine (CBZ) therapy, which leads to pharmacokinetic interaction between diosmin and CBZ. Therefore, the present study was performed to evaluate the effect of diosmin on the pharmacokinetics of CBZ in rats. Diosmin-mediated altered CYP3A enzyme activity in human and rat liver microsomes was examined using CYP3A dependent erythromycin N-demethylase assay...
November 14, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/29129847/effects-of-ketoconazole-on-cyclophosphamide-metabolism-evaluation-of-cyp3a4-inhibition-effect-using-the-in-vitro-and-in-vivo-models
#16
Le Yang, Chenyang Yan, Feng Zhang, Bo Jiang, Shouhong Gao, Youtian Liang, Lifeng Huang, Wansheng Chen
Cyclophosphamide (CP) is widely used in anticancer therapy regimens and 2-dechloroethylcyclophosphamide (DECP) is its side-chain dechloroethylated metabolite. N-dechloroethylation of CP mediated by the enzyme CYP3A4 yields nephrotoxic and neurotoxic chloroacetaldehyde (CAA) in equimolar amount to DECP. This study aimed to evaluate the inhibitory effect of ketoconazole (KTZ) on CP metabolism through in vitro and in vivo drug-drug interaction (DDI) research. Long-term treatment of KTZ induces hepatic injury; thus single doses of KTZ at low, middle, and high levels (10, 20, and 40 mg/kg) were investigated for pharmacokinetic DDI with CP...
November 13, 2017: Experimental Animals
https://www.readbyqxmd.com/read/29125184/hepatic-and-hippocampal-cytochrome-p450-enzyme-overexpression-during-spontaneous-recurrent-seizures
#17
Leonie Runtz, Benoit Girard, Marion Toussenot, Julie Espallergues, Alexis Fayd'Herbe De Maudave, Alexandre Milman, Frederic deBock, Chaitali Ghosh, Nathalie C Guérineau, Jean-Marc Pascussi, Federica Bertaso, Nicola Marchi
OBJECTIVE: Available evidence points to a role of cytochrome P450 (Cyp) drug biotransformation enzymes in central nervous system diseases, including epilepsy. Deviations in drug pharmacokinetic profiles may impact therapeutic outcomes. Here, we ask whether spontaneous recurrent seizure (SRS) activity is sufficient to modulate the expression of major Cyp enzymes in the liver and brain. METHODS: Unilateral intrahippocampal (IH) kainic acid (KA) injections were used to elicit nonconvulsive status epilepticus (SE), epileptogenesis, and SRS, as monitored by video-electroencephalography...
November 10, 2017: Epilepsia
https://www.readbyqxmd.com/read/29123154/modification-of-single-nucleotide-polymorphism-in-a-fully-humanized-cyp3a-mouse-by-genome-editing-technology
#18
Satoshi Abe, Kaoru Kobayashi, Asami Oji, Tetsushi Sakuma, Kanako Kazuki, Shoko Takehara, Kazuomi Nakamura, Azusa Okada, Yasuko Tsukazaki, Naoto Senda, Kazuhisa Honma, Takashi Yamamoto, Masahito Ikawa, Kan Chiba, Mitsuo Oshimura, Yasuhiro Kazuki
Cytochrome P450, family 3, subfamily A (CYP3A) enzymes metabolize approximately 50% of commercially available drugs. Recently, we developed fully humanized transchromosomic (Tc) CYP3A mice with the CYP3A cluster including CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Our humanized CYP3A mice have the CYP3A5*3 (g.6986G) allele, resulting in the almost absence of CYP3A5 protein expression in the liver and intestine. To produce model mice for predicting CYP3A5's contribution to pharmacokinetics, we performed a single-nucleotide polymorphism (SNP) modification of CYP3A5 (g...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29120670/correlation-between-steroid-induced-osteonecrosis-of-the-femoral-head-and-hepatic-cyp3a-activity-a-systematic-review-and-meta-analysis
#19
Fa-Qi Guo, Min Deng
BACKGROUND: Steroid-induced osteonecrosis of the femoral head (ONFH) in young adults is a challenging disorder that can impairs the quality of life of a patient. The disease also leads to frequent occurrences of collapse of the femoral head and resultant dysfunction of the hip joint. In recent years, some scholars have studied steroid-induced lipid metabolism disorder and achieved the effect of steroid-induced ONFH treatment. This study aims to review the investigations on the hepatic CYP3A (cytochrome P4503A enzyme) genetic polymorphisms in steroid-induced ONFH patients...
November 9, 2017: Journal of Investigative Surgery: the Official Journal of the Academy of Surgical Research
https://www.readbyqxmd.com/read/29119968/time-dependent-pharmacokinetics-of-dexamethasone-and-its-efficacy-in-human-breast-cancer-xenograft-mice-a-semi-mechanism-based-pharmacokinetic-pharmacodynamic-model
#20
Jian Li, Rong Chen, Qing-Yu Yao, Sheng-Jun Liu, Xiu-Yun Tian, Chun-Yi Hao, Wei Lu, Tian-Yan Zhou
Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect...
November 9, 2017: Acta Pharmacologica Sinica
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