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CYP3A

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https://www.readbyqxmd.com/read/28523515/distribution-of-exogenous-and-endogenous-cyp3a-markers-and-related-factors-in-healthy-males-and-females
#1
Jieon Lee, Andrew HyoungJin Kim, SoJeong Yi, SeungHwan Lee, Seo Hyun Yoon, Kyung-Sang Yu, In-Jin Jang, Joo-Youn Cho
Cytochrome P450 (CYP) 3A is an important drug-metabolizing enzyme in humans. Assessing CYP3A activity is necessary for predicting therapeutic outcomes or the potential adverse events of various therapeutics. This study sought to evaluate the distribution of endogenous and exogenous markers reflecting hepatic CYP3A activity and related factors affecting its activity in healthy male and female. Each subject was given a single 1 mg dose of midazolam intravenously. Pharmacokinetics, pharmacometabolomics, and pharmacogenomics analyses were performed to evaluate CYP3A activity...
May 18, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28503781/assessment-of-effect-of-cyp3a-inhibition-cyp-induction-oatp1b-inhibition-and-high-fat-meal-on-pharmacokinetics-of-the-jak1-inhibitor-upadacitinib
#2
Mohamed-Eslam F Mohamed, Steven Jungerwirth, Armen Asatryan, Ping Jiang, Ahmed A Othman
AIMS: Upadacitinib (ABT-494) is a selective Janus kinase 1 inhibitor developed for treatment of auto-immune inflammatory disorders. This work evaluated effects of high-fat meal, cytochrome P450 (CYP) 3A inhibition, CYP induction, and organic anion transporting polypeptide (OATP) 1B inhibition on upadacitinib pharmacokinetics. METHODS: Two Phase 1 evaluations were conducted, each in 12 healthy subjects. In Study 1, using a randomized, 2-sequence cross-over design, a 3 mg dose of upadacitinib (immediate-release capsules) was administered alone under fasting conditions, after high-fat meal, or on Day 4 of a 6-day regimen of 400 mg once-daily ketoconazole...
May 14, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28500872/cyp3a-genes-and-the-association-between-prenatal-methylmercury-exposure-and-neurodevelopment
#3
Sabrina Llop, Van Tran, Ferran Ballester, Fabio Barbone, Aikaterini Sofianou-Katsoulis, Jordi Sunyer, Karin Engström, Ayman Alhamdow, Tanzy M Love, Gene E Watson, Mariona Bustamante, Mario Murcia, Carmen Iñiguez, Conrad F Shamlaye, Valentina Rosolen, Marika Mariuz, Milena Horvat, Janja S Tratnik, Darja Mazej, Edwin van Wijngaarden, Philip W Davidson, Gary J Myers, Matthew D Rand, Karin Broberg
BACKGROUND: Results on the association between prenatal exposure to methylmercury (MeHg) and child neuropsychological development are heterogeneous. Underlying genetic differences across study populations could contribute to this varied response to MeHg. Studies in Drosophila have identified the cytochrome p450 3A (CYP3A) family as candidate MeHg susceptibility genes. OBJECTIVES: We evaluated whether genetic variation in CYP3A genes influences the association between prenatal exposure to MeHg and child neuropsychological development...
May 9, 2017: Environment International
https://www.readbyqxmd.com/read/28495568/quantitative-analyses-of-the-influence-of-parameters-governing-rate-determining-process-of-hepatic-elimination-of-drugs-on-the-magnitudes-of-drug-drug-interactions-via-hepatic-oatps-and-cyp3a-using-physiologically-based-pharmacokinetic-models
#4
Takashi Yoshikado, Maeda Kazuya, Hiroyuki Kusuhara, Ken-Ichi Furihata, Yuichi Sugiyama
Physiologically-based pharmacokinetic (PBPK) models were constructed for hepatic organic anion transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) substrates (bosentan, repaglinide, clarithromycin, and simeprevir), a CYP3A probe substrate (midazolam), and selective inhibitors for OATPs (rifampicin) and CYP3A (itraconazole), though the role of OATPs in the hepatic uptake of clarithromycin is unclear. The pharmacokinetic data were obtained from our previous clinical drug-drug interaction (DDI) study...
May 8, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28495029/the-pharmacokinetics-of-the-cyp3a-substrate-midazolam-after-steady-state-dosing-of-delafloxacin
#5
Susan K Paulson, Rebecca N Wood-Horrall, Randall Hoover, Megan Quintas, Laura E Lawrence, Sue K Cammarata
PURPOSE: Delafloxacin is a novel anionic fluoroquinolone in Phase III development for the treatment of serious skin infections. The objective of this study was to evaluate the effects of delafloxacin on the pharmacokinetics of midazolam, a cytochrome P450 (CYP) 3A substrate. METHODS: CYP3A activity using midazolam as a probe was assessed before and after multiple doses of delafloxacin to reach steady state. In this nonrandomized, open-label, single-sequence, Phase I study, 22 healthy male and female subjects were administered a single 5-mg oral dose of midazolam on days 1 and 8, with oral delafloxacin 450 mg every 12 hours administered from days 3 to 8...
May 8, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28484975/a-clinical-cassette-dosing-study-for-evaluating-the-contribution-of-hepatic-oatps-and-cyp3a-to-drug-drug-interactions
#6
Takashi Yoshikado, Kazuya Maeda, Sawako Furihata, Hanano Terashima, Takeshi Nakayama, Keiko Ishigame, Kazunobu Tsunemoto, Hiroyuki Kusuhara, Ken-Ichi Furihata, Yuichi Sugiyama
PURPOSE: To demonstrate the relative importance of organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) in the hepatic elimination of substrate drugs. METHODS: A cocktail of subtherapeutic doses of bosentan, repaglinide, clarithromycin, darunavir, simeprevir, and midazolam (CYP3A probe) was administered orally to eight healthy volunteers. Rifampicin (OATP inhibitor; 600 mg, p.o.) and itraconazole (CYP3A inhibitor; 200 mg, i.v.) were coadministered with the cocktail in the second and third phases, respectively...
May 8, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28483778/mechanisms-and-predictions-of-drug-drug-interactions-of-the-hepatitis-c-virus-3-direct-acting-antiviral-3d-regimen-paritaprevir-ritonavir-ombitasvir-and-dasabuvir
#7
Mohamad Shebley, Jinrong Liu, Olga Kavetskaia, Jens Sydor, Sonia M de Morais, Volker Fischer, Marjoleen Jma Nijsen, Daniel Aj Bow
To assess drug-drug interaction (DDI) potential for the 3 direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir and paritaprevir, in vitro studies profiled drug metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UGT1A1, OATP1B1/1B3, BCRP and P-gp. Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations but for drug transporters, additional PBPK modeling was necessary to achieve the same...
May 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28483425/risk-assessment-using-cytochrome-p450-time-dependent-inhibition-assays-at-single-time-and-concentration-in-the-early-stage-of-drug-discovery
#8
Mai Kosaka, Yohei Kosugi, Hideki Hirabayashi
In this article, we proposed a risk assessment strategy for CYP3A time-dependent inhibition (TDI) during drug discovery based on a through retrospective study of 13 reference drugs, some of which are known to have in vitro TDI potential, but have unknown clinical relevance. First, the traditional parameter kinact/KI, recommended by regulatory authorities for necessity decision-making in clinical drug-drug interaction (DDI) studies, was investigated as a predictive index for clinical TDI liability. The cutoff value of 1...
May 5, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28475098/genetic-polymorphisms-of-cytochrome-p450-enzymes-cyp2c9-cyp2c19-cyp2d6-cyp3a4-and-cyp3a5-in-the-croatian-population
#9
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...
February 11, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/28458904/fluticasone-furoate-induced-iatrogenic-cushing-syndrome-in-a-pediatric-patient-receiving-anti-retroviral-therapy
#10
S A A van den Berg, N E van 't Veer, J M A Emmen, R H T van Beek
SUMMARY: We present a case of iatrogenic Cushing's syndrome, induced by treatment with fluticasone furoate (1-2 dd, 27.5 µg in each nostril) in a pediatric patient treated for congenital HIV. The pediatric patient described in this case report is a young girl of African descent, treated for congenital HIV with a combination therapy of Lopinavir/Ritonavir (1 dd 320/80 mg), Lamivudine (1 dd 160 mg) and Abacavir (1 dd 320 mg). Our pediatric patient presented with typical Cushingoid features (i...
2017: Endocrinology, Diabetes & Metabolism Case Reports
https://www.readbyqxmd.com/read/28442500/high-fat-diet-feeding-alters-expression-of-hepatic-drug-metabolizing-enzymes-in-mice
#11
Miaoran Ning, Hyunyoung Jeong
Medical conditions accompanying obesity often require drug therapy, but whether and how obesity alters the expression of drug-metabolizing enzymes and thus drug pharmacokinetics is poorly defined. Previous studies have shown that high fat diet (HFD) feeding and subsequent obesity in mice lead to altered expression of transcriptional regulators for cytochrome P450 (CYP) 2D6, including hepatocyte nuclear factor 4α (HNF4α, a transcriptional activator of CYP2D6) and small heterodimer partner (SHP, a transcriptional repressor of CYP2D6)...
April 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28441491/a-naturally-occurring-isoform-specific-probe-for-highly-selective-and-sensitive-detection-of-human-cytochrome-p450-3a5
#12
Jing-Jing Wu, Yun-Feng Cao, Liang Feng, Yu-Qi He, James Y Hong, Tong-Yi Dou, Ping Wang, Da-Cheng Hao, Guang-Bo Ge, Ling Yang
Cytochrome P450 (CYP) 3A5 characterized with polymorphic and extensive expression in multiple tissues is the most important P450 enzyme among the minor CYP3A isoforms. However, a selective and sensitive probe for CYP3A5 remains unavailable. In this study, we identified and characterized a naturally occurring lignan 12 (schisantherin E) as an isoform-specific probe for selective detection of CYP3A5 activity in complex biological samples. With thorough characterization including LC-MS and NMR, we found that 12 can be metabolized by CYP3A5 to generate a major metabolite 2-O-demethylated 12...
May 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28440407/effects-of-cytochrome-p450-family-3-subfamily-a-member%C3%A2-5-gene-polymorphisms-on-daunorubicin-metabolism-and-adverse-reactions-in-patients-with-acute-leukemia
#13
Zhen Huang, Juxiang Wang, Jiangchao Qian, Yuan Li, Zhisheng Xu, Min Chen, Hongfei Tong
The present study aimed to investigate the association between the genetic polymorphism of cytochrome P450 family 3 subfamily A member 5 (CYP3A5) and the activity of CYP3A and plasma concentrations of daunorubicin (DNR) in patients with acute leukemia. A total of 36 children with newly diagnosed acute lymphoblastic leukemia were enrolled in the study. Polymerase chain reaction (PCR)‑restriction fragment length polymorphism and PCR product sequencing were used to detect the genotype of CYP3A5*3. PCR was then used to express the mRNA expression of CYP3A5...
June 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28433553/identification-and-validation-of-micrornas-directly-regulating-the-udp-glucuronosyltransferase-1a-subfamily-enzymes-by-a-functional-genomics-approach
#14
Ioannis Papageorgiou, Michael H Court
Posttranscriptional repression of UDP-glucuronosyltransferase (UGT) 1A expression by microRNAs (miRNAs) may be an important mechanism underlying interindividual variability in drug glucuronidation. Furthermore, the UGT1A 3'-UTR shared by all UGT1A enzymes is polymorphic, containing three linked SNPs (rs10929303, rs1042640, and rs8330) that could influence miRNA binding. The aim of this study was to identify the complete complement of miRNAs that could regulate UGT1A expression through binding to the reference and/or common variant UGT1A 3'-UTR...
April 19, 2017: Biochemical Pharmacology
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
#15
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
#16
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...
June 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
#17
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
#18
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...
May 9, 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
#19
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
#20
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
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