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CYP3A

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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
#1
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
#2
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
#3
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
#4
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 [14C]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 h), CGP52421 (495 h), and CGP62221 (33...
March 7, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28263535/exposure-of-rats-to-exogenous-endocrine-disruptors-17alpha-ethinylestradiol-and-benzo-a-pyrene-and-an-estrogenic-hormone-estradiol-induces-expression-of-cytochromes-p450-involved-in-their-metabolism
#5
Lucie Borek-Dohalska, Zuzana Klusonova, Jana Holecova, Marketa Martinkova, Frantisek Barta, Helena Dracinska, Tomas Cajthaml, Marie Stiborova
OBJECTIVES: The term "endocrine disruptor" (ED) is used for compounds that mimic or antagonize the effects of endogenous hormones. Synthetic estrogen 17α-ethinylestradiol (EE2) and a human carcinogen benzo[a]pyrene (BaP) are assigned as exogenous endocrine disruptors and an estrogenic hormone estradiol is a natural endogenous disruptor. Here, the potency of these three disruptors administered to rats individually and in combination to induce expression of cytochrome P450 (CYP) enzymes involved in their own metabolism (CYP1A1, 2C and 3A) in vivo was investigated...
December 18, 2016: Neuro Endocrinology Letters
https://www.readbyqxmd.com/read/28258380/clinical-pharmacokinetics-of-dasabuvir
#6
REVIEW
Jennifer R King, Jiuhong Zha, Amit Khatri, Sandeep Dutta, Rajeev M Menon
Dasabuvir is a nonstructural (NS) 5B non-nucleoside inhibitor of the hepatitis C virus (HCV) used in combination with ombitasvir/paritaprevir/ritonavir for the treatment of chronic HCV infection. It is primarily metabolized by cytochrome P450 (CYP) 2C8, with a minor contribution from CYP3A. Biotransformation of dasabuvir forms the M1 metabolite, which retains antiviral activity. Dasabuvir exhibits linear pharmacokinetics with a terminal half-life of approximately 5-8 h, allowing for twice-daily dosing. The M1 metabolite of dasabuvir is the major metabolite in plasma and has a half-life similar to that of dasabuvir...
March 4, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28257954/effects-of-tetrahydroberberine-and-tetrahydropalmatine-on-hepatic-cytochrome-p450-expression-and-their-toxicity-in-mice
#7
Dujun Wang, Kai Wang, Danjuan Sui, Zhen Ouyang, Haiyu Xu, Yuan Wei
The aim of this study was to investigate the effects of tetrahydroberberine (THB) and tetrahydropalmatine (THP) on the expression of mouse liver cytochrome P450s, and evaluate their liver toxicity in mice. Real-time polymerase chain reaction (PCR) and western blot analyses were used to analyze the expression of major P450 isoforms. Liver toxicity was evaluated by measuring serum biochemical parameters and performing histopathological analysis. The real-time PCR results showed that THB induced Cyp1a2 (1.66 ± 0...
February 28, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28257659/comprehensive-assessment-of-cucurbitacin-e-related-hepatotoxicity-and-drug-drug-interactions-involving-cyp3a-and-p-glycoprotein
#8
Jian Lu, Yuanjin Zhang, Min Sun, Mingyao Liu, Xin Wang
BACKGROUND: Cucurbitacin E (CuE), a tetracyclic triterpenoid isolated from Cucurbitaceae, possesses many pharmacological activities especially anti-cancer. PURPOSE: The aim of this investigation was to comprehensively assess CuE related hepatotoxicity and potential drug-drug interactions involving CYP3A and P-glycoprotein (P-gp). STUDY DESIGN AND METHODS: Four common cytotoxicity assays (MTS, SRB, NRU and apoptosis assays) were used to evaluate the hepatotoxicity of CuE in human hepatocellular carcinoma HepG2 cells...
March 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28244604/the-influence-of-cyp3a5-3-and-bcrpc421a-genetic-polymorphisms-on-the-pharmacokinetics-of-felodipine-in-healthy-chinese-volunteers
#9
Q Xiang, C Li, X Zhao, Y M Cui
WHAT IS KNOWN AND OBJECTIVE: The role of CYP3A5 in drug metabolism has been receiving attention because CYP3A5 may be more involved in the metabolism of CYP3A substrates in vivo than previously thought. The polymorphism of transporters, such as P-gp (P-glycoprotein) and breast cancer-related protein (BCRP), influences the metabolism of these substrates, and felodipine is a substrate of P-gp. The aim of this study was to evaluate the pharmacogenetic variability in the disposition of felodipine in healthy Chinese subjects...
February 28, 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/28219593/betel-nut-chewing-is-associated-with-reduced-tacrolimus-concentration-in-taiwanese-liver-transplant-recipients
#10
W-Y Chen, C-Y Lee, P-Y Lin, C-E Hsieh, C-J Ko, K-H Lin, C-C Lin, Y-Z Ming, Y-L Chen
PURPOSE: Studies have shown that arecoline, the major alkaloid component of betel nuts, alters the activity of enzymes in the cytochrome P450 (CYP-450) family. Tacrolimus, an immunosuppressant that protects against organ rejection in transplant recipients, not only is mainly metabolized by CYP3A enzymes but also has a narrow therapeutic range. We aimed to investigate whether dose-adjusted blood trough levels of tacrolimus differed over time between betel nut-chewing and non-betel nut-chewing liver transplant recipients...
March 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28218310/crispr-knockout-rat-cytochrome-p450-3a1-2-model-for-advancing-drug-metabolism-and-pharmacokinetics-research
#11
Jian Lu, Yanjiao Shao, Xuan Qin, Daozhi Liu, Ang Chen, Dali Li, Mingyao Liu, Xin Wang
Cytochrome P450 (CYP) 3A accounts for nearly 30% of the total CYP enzymes in the human liver and participates in the metabolism of over 50% of clinical drugs. Moreover, CYP3A plays an important role in chemical metabolism, toxicity, and carcinogenicity. New animal models are needed to investigate CYP3A functions, especially for drug metabolism. In this report, Cyp3a1/2 double knockout (KO) rats were generated by CRISPR-Cas9 technology, and then were characterized for viability and physiological status. The Cyp3a1/2 double KO rats were viable and fertile, and had no obvious physiological abnormities...
February 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28194792/semisimultaneous-midazolam-administration-to-evaluate-the-time-course-of-cyp3a-activation-by-a-single-oral-dose-of-efavirenz
#12
Gerd Mikus, Tilman Heinrich, Julia Bödigheimer, Claudia Röder, Anne-Kathrin Matthee, Johanna Weiss, Jürgen Burhenne, Walter E Haefeli
This study aimed to assess whether a single oral dose of the nonnucleoside reverse transcriptase inhibitor efavirenz can alter CYP3A in vivo. In 12 healthy participants individual CYP3A activity was quantified using a semisimultaneous methodology (midazolam orally and 6 hours later intravenously) both alone and during a period of 22 days after a single oral dose of 400 mg efavirenz. Twelve hours after efavirenz administration, midazolam apparent oral clearance was significantly increased by 70%, and midazolam systemic clearance after intravenous administration was significantly increased by 27%...
February 14, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28168728/reponse-to-bodyweight-adjustments-introduce-significant-correlations-between-cyp3a-metrics-and-tacrolimus-clearance
#13
Thomas Vanhove, Pieter Annaert, Dirk R J Kuypers
No abstract text is available yet for this article.
February 6, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28167538/application-of-physiologically-based-pharmacokinetic-modeling-to-the-understanding-of-bosutinib-pharmacokinetics-prediction-of-drug-drug-and-drug-disease-interactions
#14
Chiho Ono, Poe-Hirr Hsyu, Richat Abbas, Cho-Ming Loi, Shinji Yamazaki
Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Bosutinib is predominantly metabolized by CYP3A4 as the primary clearance mechanism. The main objectives of this study were to 1) develop physiologically based pharmacokinetic (PBPK) models of bosutinib; 2) verify and refine the PBPK models based on clinical study results of bosutinib single-dose drug-drug interaction (DDI) with ketoconazole and rifampin, as well as single-dose drug-disease interaction (DDZI) in patients with renal and hepatic impairment; 3) apply the PBPK models to predict DDI outcomes in patients with weak and moderate CYP3A inhibitors; and 4) apply the PBPK models to predict DDZI outcomes in renally and hepatically impaired patients after multiple-dose administration...
April 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28161120/management-of-venetoclax-posaconazole-interaction-in-acute-myeloid-leukemia-patients-evaluation-of-dose-adjustments
#15
Suresh K Agarwal, Courtney D DiNardo, Jalaja Potluri, Martin Dunbar, Hagop M Kantarjian, Rod A Humerickhouse, Shekman L Wong, Rajeev M Menon, Marina Y Konopleva, Ahmed Hamed Salem
PURPOSE: The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction. METHODS: Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m(2) of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20...
February 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28157069/delayed-de-induction-of-cyp2c9-compared-to-cyp3a-after-discontinuation-of-rifampicin-report-of-two-cases%C3%A2
#16
Soichi Shibata, Harumi Takahashi, Akiyasu Baba, Kei Takeshita, Koichiro Atsuda, Hajime Matsubara, Hirotoshi Echizen
OBJECTIVE: Timely dose reduction of concomitant medications is important after withdrawal of rifampicin, a CYP inducer. However, little is known about the differences in the time course of deinduction for various CYP isoforms. To clarify the time courses of deinduction of CYP2C9 and -CYP3A activities after rifampicin withdrawal, we monitored these enzyme activities in 2 patients over time after discontinuing rifampicin. MATERIALS AND METHODS: Two patients (aged 70 and 80 years) received warfarin and rifampicin for anticoagulation and antituberculosis therapy, respectively...
February 3, 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28146606/the-cyp3a-biomarker-4%C3%AE-hydroxycholesterol-does-not-improve-tacrolimus-dose-predictions-early-after-kidney-transplantation
#17
Elisabet Størset, Kristine Hole, Karsten Midtvedt, Stein Bergan, Espen Molden, Anders Åsberg
AIMS: Tacrolimus is a cornerstone in modern immunosuppressive therapy after kidney transplantation. Tacrolimus dosing is challenged by considerable pharmacokinetic variability, both between patients and over time after transplantation, partly due to variability in cytochrome P450 3A (CYP3A) activity. The aim of this study was to assess the value of the endogenous CYP3A marker 4β-hydroxycholesterol (4βOHC) for tacrolimus dose individualization early after kidney transplantation. METHODS: Data were obtained from 79 adult kidney transplant recipients who contributed a total of 625 4βOHC measurements and 1999 tacrolimus whole blood concentrations during the first two months after transplantation...
February 1, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28122787/a-physiologically-based-pharmacokinetic-modeling-approach-to-predict-drug-drug-interactions-of-sonidegib-lde225-with-perpetrators-of-cyp3a-in-cancer-patients
#18
Heidi J Einolf, Jocelyn Zhou, Christina Won, Lai Wang, Sam Rebello
Sonidegib (Odomzo®) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed. This data was used to verify a physiologically-based pharmacokinetic (PBPK) model developed to: 1) bridge the clinical drug-drug interaction (DDI) study of sonidegib with KTZ and RIF in healthy subjects to the marketed dose (200 mg) in patients, 2) predict acute (14 days) versus long-term dosing of the perpetrators with sonidegib at steady-state, and 3) predict the effect of moderate CYP3A perpetrators on sonidegib exposure in patients...
January 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28117738/in-vitro-biotransformation-of-two-human-cyp3a-probe-substrates-and-their-inhibition-during-early-zebrafish-development
#19
Evy Verbueken, Derek Alsop, Moayad A Saad, Casper Pype, Els M Van Peer, Christophe R Casteleyn, Chris J Van Ginneken, Joanna Wilson, Steven J Van Cruchten
At present, the zebrafish embryo is increasingly used as an alternative animal model to screen for developmental toxicity after exposure to xenobiotics. Since zebrafish embryos depend on their own drug-metabolizing capacity, knowledge of their intrinsic biotransformation is pivotal in order to correctly interpret the outcome of teratogenicity assays. Therefore, the aim of this in vitro study was to assess the activity of cytochrome P450 (CYP)-a group of drug-metabolizing enzymes-in microsomes from whole zebrafish embryos (ZEM) of 5, 24, 48, 72, 96 and 120 h post-fertilization (hpf) by means of a mammalian CYP substrate, i...
January 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28115221/epigallocatechin-gallate-induces-a-hepatospecific-decrease-in-the-cyp3a-expression-level-by-altering-intestinal-flora
#20
Nobutomo Ikarashi, Sosuke Ogawa, Ryuta Hirobe, Risako Kon, Yoshiki Kusunoki, Marin Yamashita, Nanaho Mizukami, Miho Kaneko, Nobuyuki Wakui, Yoshiaki Machida, Kiyoshi Sugiyama
In previous studies, we showed that a high-dose intake of green tea polyphenol (GP) induced a hepatospecific decrease in the expression and activity of the drug-metabolizing enzyme cytochrome P450 3A (CYP3A). In this study, we examined whether this decrease in CYP3A expression is induced by epigallocatechin gallate (EGCG), which is the main component of GP. After a diet containing 1.5% EGCG was given to mice, the hepatic CYP3A expression was measured. The level of intestinal bacteria of Clostridium spp., the concentration of lithocholic acid (LCA) in the feces, and the level of the translocation of pregnane X receptor (PXR) to the nucleus in the liver were examined...
March 30, 2017: European Journal of Pharmaceutical Sciences
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