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CYP3A

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https://www.readbyqxmd.com/read/28719598/the-predictive-value-of-abcb1-abcg2-cyp3a4-5-and-cyp2d6-polymorphisms-for-risperidone-and-aripiprazole-plasma-concentrations-and-the-occurrence-of-adverse-drug-reactions
#1
C Rafaniello, M Sessa, F F Bernardi, M Pozzi, S Cheli, D Cattaneo, S Baldelli, M Molteni, R Bernardini, F Rossi, E Clementi, C Bravaccio, S Radice, A Capuano
We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c...
July 18, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28716728/cytochrome-p450-3a-selectively-affects-the-pharmacokinetic-interaction-between-erlotinib-and-docetaxel-in-rats
#2
Xuan Qin, Jian Lu, Peili Wang, Peipei Xu, Mingyao Liu, Xin Wang
Erlotinib as a first-line drug is used in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations, while resistance to this drug will occur after several years of treatment. Therefore, the microtubule disturber docetaxel is introduced as combined regimen in clinical trials. This report investigated the potentials and mechanisms of drug-drug interaction (DDI) between erlotinib and docetaxel using wild type (WT) and Cyp3a1/2 knockout (KO) rats. The erlotinib O-demethylation and docetaxel hydroxylation reactions in the absence or the presence of another drug were analyzed in vitro via the assay of rat liver microsomes...
July 14, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28711984/clarithromycin-co-administration-does-not-increase-irinotecan-cpt-11-toxicity-in-colorectal-cancer-patients
#3
Katsuya Makihara, Sayaka Nakamura, Kazuyo Miyagi, Hiroyuki Ueno, Izumi Nakata
PURPOSE: Irinotecan (CPT-11) is used to treat advanced colorectal cancer. The drug is activated by carboxylesterases and rendered inactive by CYP3A4. Recently, the efficacy of combining CPT-11 and anti-epidermal growth factor receptor (EGFR) agents was confirmed in patients with KRAS wild-type metastatic colorectal cancer. Clarithromycin (CAM) is a strong CYP3A inhibitor often used to prevent rash associated with anti-EGFR therapy. The objective of this study was to evaluate the risk of increased neutropenia and diarrhea in combining CPT-11 and CAM...
July 15, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28704257/the-combination-of-cyp3a4-22-and-cyp3a5-3-single-nucleotide-polymorphisms-determines-tacrolimus-dose-requirement-after-kidney-transplantation
#4
Nuria Lloberas, Laure Elens, Ines Llaudó, Ariadna Padullés, Teun van Gelder, Dennis A Hesselink, Helena Colom, Franc Andreu, Joan Torras, Oriol Bestard, Josep M Cruzado, Salvador Gil-Vernet, Ron van Schaik, Josep M Grinyó
INTRODUCTION: Tacrolimus (Tac) has a narrow therapeutic window and shows large between-patient pharmacokinetic variability. As a result, over-immunosuppression and under-immunosuppression are frequently encountered in daily clinical practice. Unraveling the impact of genetic polymorphisms on Tac pharmacokinetics may help to refine therapy. In this study, the associations of single-nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes (CYP3A) with Tac pharmacokinetics were investigated in renal transplant recipients...
July 12, 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28700521/effect-of-cyp3a4-and-cyp3a5-genetic-polymorphisms-on-the-pharmacokinetics-of-sirolimus-in-healthy-chinese-volunteers
#5
Jing Zhang, Ying Dai, Zhihong Liu, Minxin Zhang, Chen Li, Dingxiong Chen, Hongtao Song
BACKGROUND: Sirolimus is a promising immunosuppressive drug for preventing the rejection of organ transplants. However, inter-individual variability in sirolimus pharmacokinetics causes adverse drug reactions, compromising therapeutic efficacy. Sirolimus is primarily metabolized by cytochrome CYP3A4 and CYP3A5. This study aimed to clarify the effect of CYP3A genetic polymorphisms, including the CYP3A4*1G and CYP3A5*3 polymorphisms, on the pharmacokinetics of sirolimus. METHODS: Thirty-one healthy Chinese volunteers were included in this study...
August 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28698977/pharmacogenetics-and-pharmacogenomics-of-targeted-therapeutics-in-chronic-myeloid-leukemia
#6
REVIEW
Aritro Nath, Jacqueline Wang, R Stephanie Huang
The advent of targeted therapeutics has greatly improved outcomes of chronic myeloid leukemia (CML) patients. Despite increased efficacy and better clinical responses over cytotoxic chemotherapies, many patients receiving targeted drugs exhibit a poor initial response, develop drug resistance, or undergo relapse after initial success. This inter-individual variation in response has heightened the interest in studying pharmacogenetics and pharmacogenomics (PGx) of cancer drugs. In this review, we discuss the influence of various germline and somatic factors on targeted drug response in CML...
July 11, 2017: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/28681206/protective-effect-of-ganoderma-lucidum-polysaccharide-against-carbon-tetrachloride-induced-hepatic-damage-in-precision-cut-carp-liver-slices
#7
Yingjuan Liu, Chunyun Zhang, Jinliang Du, Rui Jia, Liping Cao, Galina Jeney, Hiroki Teraoka, Pao Xu, Guojun Yin
The aim of the present study was to investigate the protective effects of Ganoderma lucidum polysaccharide (GLPS) against carbon tetrachloride (CCl4)-induced hepatotoxicity in vitro in common carp. Precision-cut liver slices (PCLSs), which closely resemble the organ from which they are derived, were employed as an in vitro model system. GLPS (0.1, 0.3, and 0.6 mg/ml) was added to PCLS culture system before the exposure to 12 mM CCl4. The supernatants and slices were collected to detect molecular and biochemical responses to CCl4 and PCLS treatments...
July 5, 2017: Fish Physiology and Biochemistry
https://www.readbyqxmd.com/read/28679023/notable-drug-drug-interaction-between-etizolam-and-itraconazole-in-poor-metabolizers-of-cytochrome-p450-2c19
#8
Takehito Yamamoto, Kenichi Furihata, Akihiro Hisaka, Takashi Moritoyo, Kazuaki Ogoe, Shizuko Kusayama, Keiju Motohashi, Akiko Mori, Takeshi Iwatsubo, Hiroshi Suzuki
In this study, impact of a polymorphism of CYP2C19 on drug-drug interaction (DDI) was examined for etizolam. The effect of itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics of etizolam (a substrate of CYP2C19 and CYP3A) was assessed in both extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19. Sixteen participants (8 EMs and 8 PMs) received a single oral dose of etizolam (0.25 mg) on day 1. The participants ingested itraconazole (200 mg twice a day) on days 2-5. On day 5, participants received an oral dose of etizolam (0...
July 5, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28675853/histopathological-effects-responses-of-oxidative-stress-inflammation-apoptosis-biomarkers-and-alteration-of-gene-expressions-related-to-apoptosis-oxidative-stress-and-reproductive-system-in-chlorpyrifos-exposed-common-carp-cyprinus-carpio-l
#9
Serdar Altun, Selçuk Özdemir, Harun Arslan
In this study, we aimed to identify the toxic effects of chlorpyrifos exposure on the tissues of common carp. For this purpose, we evaluated histopathological changes in the brain, gills, liver, kidney, testis, and ovaries after 21 days of chlorpyrifos exposure. Activation of 8-OHdG, cleaved caspase-3, and iNOS were assesed by immunofluorescence assay in chlorpyrifos-exposed brain and liver tissue. Additionally, we measured the expression levels of caspase-3, caspase-8, iNOS, MT1, CYP1A, and CYP3A genes in chlorpyrifos-exposed brain tissue, as well as the expression levels of FSH and LH genes in chlorpyrifos-exposed ovaries, using qRT-PCR...
July 1, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/28673024/ancestry-adjusted-vitamin-d-metabolite-concentrations-in-association-with-cytochrome-3a-cyp3a-polymorphisms
#10
Robin Taylor Wilson, Loren D Masters, Jill S Barnholtz-Sloan, Anna C Salzberg, Terryl J Hartman
This study investigates the association between genetic polymorphisms in CYP2R1, CYP24A1 and the CYP3A family with non-summer plasma concentrations of 25(OH)D3 and proportion 24,25(OH)2D3 among healthy individuals of Sub-Saharan African and European ancestry matched on age (±5 years; n = 188 in each ancestral group) in central suburban Pennsylvania (2006-09). Vitamin D metabolites were measured using high-performance liquid chromatography/tandem mass spectrometry. Paired multiple regression and adjusted least square means analyses were used to test for associations between genotype and log-transformed metabolite concentrations, adjusted for age, sex, West African genetic ancestry proportion, body mass index, oral contraceptive (OC) use, tanning bed use, vitamin D intake, days from summer solstice, time of day, and isoforms of the vitamin D receptor (VDR) and vitamin D binding protein...
June 30, 2017: American Journal of Epidemiology
https://www.readbyqxmd.com/read/28666968/in-vitro-phase-i-metabolism-of-gamabufotalin-and-arenobufagin-reveal-the-effect-of-substituent-group-on-metabolic-stability
#11
Yujie Feng, Chao Wang, Xiangge Tian, Xiaokui Huo, Lei Feng, Chengpeng Sun, Guangbo Ge, Ling Yang, Jing Ning, Xiaochi Ma
Bufadienolides are a major class of bioactive compounds derived from amphibian skin secretion. Gamabufotalin (GB) and arenobufagin (AB) are among the top of the intensively investigated natural bufadienolides for their outstanding biological activities. This study aimed to characterize the phase I metabolism of GB and AB with respect to the metabolic profiles, enzymes involved, and catalytic efficacy, thereafter tried to reveal substituent effects on metabolism. Two mono-hydroxylated products of GB and AB were detected in the incubation mixtures, and they were accurately identified as 1- and 5-hydroxylated bufadienolides by NMR and HPLC-MS techniques...
June 27, 2017: Fitoterapia
https://www.readbyqxmd.com/read/28665167/altered-hepatic-drug-metabolizing-activity-in-rats-suffering-from-hypoxemia-with-experimentally-induced-acute-lung-impairment
#12
Yuki Hori, Yasumasa Shimizu, Tetsuya Aiba
1. Hepatic drug-metabolizing activity was investigated in vitro with liver microsomes prepared from rats suffering from hypoxemia with experimentally induced acute lung impairment (ALI). 2. Male Wistar rats received an intrabronchial administration of dilute hydrochloride solution for ALI induction. Pooled liver microsomes were prepared for the normal and ALI rats, and the hepatic drug metabolism mediated by cytochrome P450 (CYP) 3A was examined in an incubation study with the microsomes. 3. The NADPH-dependent metabolism of midazolam significantly increases in ALI rats as compared with that in normal rats...
June 30, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28657423/in-vitro-metabolism-of-alectinib-a-novel-potent-alk-inhibitor-in-human-contribution-of-cyp3a-enzymes
#13
Toshito Nakagawa, Stephen Fowler, Kenji Takanashi, Kuresh Youdim, Tsuyoshi Yamauchi, Kosuke Kawashima, Mika Sato-Nakai, Li Yu, Masaki Ishigai
1. The in vitro metabolism of alectinib, a potent and highly selective oral anaplastic lymphoma kinase inhibitor, was investigated. 2. The main metabolite (M4) in primary human hepatocytes was identified, which is produced by deethylation at the morpholine ring. Three minor metabolites (M6, M1a, and M1b) were also identified, and a minor peak of hydroxylated alectinib (M5) was detected as a possible precursor of M4, M1a, and M1b. 3. M4, an important active major metabolite, was produced and further metabolized to M6 by CYP3A, indicating that CYP3A enzymes were the principal contributors to this route...
June 28, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28657402/in-vitro-evaluation-of-the-inhibition-and-induction-potential-of-olaparib-a-potent-poly-adp-ribose-polymerase-inhibitor-on-cytochrome-p450
#14
Alex McCormick, Helen Swaisland, Venkatesh Pilla Reddy, Maria Learoyd, Graeme Scarfe
1. In vitro studies were conducted to evaluate potential inhibitory and inductive effects of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, on cytochrome P450 (CYP) enzymes. Inhibitory effects were determined in human liver microsomes (HLM); inductive effects were evaluated in cultured human hepatocytes. 2. Olaparib did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2D6 or CYP2E1 and caused slight inhibition of CYP2C9, CYP2C19 and CYP3A4/5 in HLM up to a concentration of 100 µM. However, olaparib (17‒500 µM) inhibited CYP3A4/5 with an IC50 of 119 µM...
June 28, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28655393/the-role-of-single-nucleotide-polymorphisms-of-cyp3a-and-abcb1-on-tacrolimus-predose-concentration-in-kidney-transplant-recipients
#15
Gregor Mlinšek, Vita Dolžan, Katja Goričar, Jadranka Buturović-Ponikvar, Miha Arnol
BACKGROUND: Tacrolimus has a narrow therapeutic drug window but high inter- and intrapatient variability. Our aim is to construct a model able to predict optimal maintenance tacrolimus predose concentration (C0) in kidney transplant patients. Here we present our study design and genotype and variant allele frequencies for the selected single nucleotide polymorphisms of genes involved in tacrolimus metabolism in our national cohort of kidney transplant recipients. METHODS: In the observational part of the study, we intend to determine allelic variants of CYP3A4, CYP3A5, and ABCB1 gene in a national cohort of 700 kidney transplants recipients...
June 28, 2017: Clinical Nephrology
https://www.readbyqxmd.com/read/28644704/numerical-analysis-of-time-dependent-inhibition-kinetics-comparison-between-rat-liver-microsomes-and-rat-hepatocyte-data-for-mechanistic-model-fitting
#16
Chuong Pham, Swati Nagar, Ken Korzekwa
Time dependent inhibition (TDI) may confound drug interaction predictions. Recently, models were generated for an array of TDI kinetic schemes using numerical analysis of microsomal assays. Additionally, a distinct terminal inactivation step was identified for certain mechanism based inhibitors (MBI) following reversible metabolite intermediate complex (MIC) formation. Longer hepatocyte incubations potentially allow analysis of slow TDI and terminal inactivation. In the experiments presented here, we compared the quality of TDI parameterization by numerical analysis between hepatocyte and microsomal data...
June 23, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28643329/analgesic-plasma-concentrations-of-oxycodone-after-surgery-for-breast-cancer-which-factors-matter
#17
K Cajanus, M Neuvonen, O Koskela, M A Kaunisto, P J Neuvonen, M Niemi, E Kalso
We investigated factors affecting analgesic oxycodone concentrations after breast cancer surgery in 1,000 women. Preoperatively, we studied heat and cold pain sensitivities and anxiety scores. Postoperatively, rest and motion pain intensities were measured and intravenous oxycodone was administered until satisfactory analgesia. At this point, the mean oxycodone concentration (variation coefficient) was 33.3 ng/ml (66%), and it was 21.7 ng/ml (69%) when the patient requested oxycodone again. At both time points, the concentrations varied >100-fold between individuals...
June 23, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28642710/tacrolimus-updated-guidelines-through-poppk-modeling-how-to-benefit-more-from-cyp3a-pre-emptive-genotyping-prior-to-kidney-transplantation
#18
Jean-Baptiste Woillard, Michel Mourad, Michael Neely, Arnaud Capron, Ron H van Schaik, Teun van Gelder, Nuria Lloberas, Dennis A Hesselink, Pierre Marquet, Vincent Haufroid, Laure Elens
Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28642094/investigation-of-the-component-in-artemisia-annua-l-leading-to-enhanced-antiplasmodial-potency-of-artemisinin-via-regulation-of-its-metabolism
#19
Tian-Yu Cai, Yun-Rui Zhang, Jian-Bo Ji, Jie Xing
ETHNOPHARMACOLOGICAL RELEVANCE: The chemical matrix of the herb Artemisia annua L. (A. annua), from which artemisinin (QHS) is isolated, can enhance both the bioavailability and efficacy of QHS. However, the exact mechanism of this synergism remains unknown. The biotransformation of QHS and potential "enzyme inhibitors" in plant matrix could be of great importance in understanding the improved efficacy of QHS in A. annua, which has been limited to the synergism with flavonoid components...
June 19, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28638868/in-vivo-effect-of-ruta-chalepensis-extract-on-hepatic-cytochrome-3a1-in-rats
#20
Edith Fabiola Martínez-Pérez, Fernando Hernández-Terán, Luis Benjamín Serrano-Gallardo
BACKGROUND: Since the time when drugs began to be used, it became evident that they could produce a therapeutic effect, but also a clinical condition of toxicity or no effect at all on humans, despite using the same doses in different patients. Such untoward effects were termed "drug idiosyncrasy" and also "idiosyncratic drug effects", but the factors producing such diverse responses were never taken into account. MATERIALS AND METHODS: Ruta chalepensis L. (fringed rue) is an herbaceous plant of the Rutaceae family used in traditional medicine due to its properties, such as its analgesic and antipyretic effects...
2017: African Journal of Traditional, Complementary, and Alternative Medicines: AJTCAM
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