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https://www.readbyqxmd.com/read/28808272/a-combinatorial-approach-for-the-discovery-of-cytochrome-p450-2d6-inhibitors-from-nature
#1
Johannes Hochleitner, Muhammad Akram, Martina Ueberall, Rohan A Davis, Birgit Waltenberger, Hermann Stuppner, Sonja Sturm, Florian Ueberall, Johanna M Gostner, Daniela Schuster
The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico - in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28782945/fame-2-simple-and-effective-machine-learning-model-of-cytochrome-p450-regioselectivity
#2
Martin Šícho, Christina de Bruyn Kops, Conrad Stork, Daniel Svozil, Johannes Kirchmair
We report on the further development of FAst MEtabolizer (FAME; J. Chem. Inf. MODEL: 2013, 53, 2896-2907), a collection of random forest models for the prediction of sites of metabolism (SoMs) of xenobiotics. A broad set of descriptors was explored, from simple 2D descriptors such as those used in FAME, to quantum chemical descriptors employed in some of the most accurate models for SoM prediction currently available. In line with the original FAME approach, our objective was to keep things simple and to come up with accurate and robust models that are based on a small number of 2D descriptors...
August 7, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28726718/inhibitory-effects-of-trapping-agents-of-sulfur-drug-reactive-intermediates-against-major-human-cytochrome-p450-isoforms
#3
Jasleen K Sodhi, Erlie Marie Delarosa, Jason S Halladay, James P Driscoll, Teresa Mulder, Patrick M Dansette, S Cyrus Khojasteh
In some cases, the formation of reactive species from the metabolism of xenobiotics has been linked to toxicity and therefore it is imperative to detect potential bioactivation for candidate drugs during drug discovery. Reactive species can covalently bind to trapping agents in in vitro incubations of compound with human liver microsomes (HLM) fortified with β-nicotinamide adenine dinucleotide phosphate (NADPH), resulting in a stable conjugate of trapping agent and reactive species, thereby facilitating analytical detection and providing evidence of short-lived reactive metabolites...
July 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28716517/lethal-suicide-attempt-with-a-mixed-drug-intoxication-of-metoprolol-and-propafenone-a-first-pediatric-case-report
#4
Ivana Kacirova, Milan Grundmann, Martin Kolek, Erika Vyskocilova-Hrudikova, Romana Urinovska, Petr Handlos
INTRODUCTION: The β1 adrenergic receptor blocker metoprolol is often prescribed together with the antiarrhythmic drug propafenone. Both are metabolized by cytochrome P450 2D6 and propafenone is also an inhibitor of this enzyme. We present a pediatric case showing metoprolol and propafenone intoxication in combination. CASE: A 14-year-old girl was admitted to a local emergency department after ingestion of metoprolol (probably 1g) and propafenone (probably 1.5-3g) in a suicide attempt...
June 29, 2017: Forensic Science International
https://www.readbyqxmd.com/read/28696416/cytochrome-p450-interactions-are-common-and-consequential-in-massachusetts-hospital-discharges
#5
T H McCoy, V M Castro, A Cagan, L Snapper, A Roberson, R H Perlis
Despite the recognition that drug-drug interactions contribute substantially to preventable health-care costs, the prevalence of such interactions related to the cytochrome P450 system in clinical practice remains poorly characterized. This study drew retrospective hospital discharge cohorts from a large health claims data set and a large health system data set. For every hospital discharge, frequency of co-occurrence of substrates and inducers or inhibitors at cytochrome P450 2D6, 2C19, 3A4 and 1A2 were determined...
July 11, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28663285/inhibitory-effects-of-selected-antituberculosis-drugs-on-common-human-hepatic-cytochrome-p450-and-udp-glucuronosyltransferase-enzymes
#6
Lei Cao, David J Greenblatt, Awewura Kwara
The comorbidities of tuberculosis and diseases such as HIV require long-term treatment with multiple medications. Despite substantial in vitro and in vivo information on effects of rifampicin and isoniazid on human CYPs, there is limited published data regarding the inhibitory effects of other anti-TB drugs on human CYPs and UGTs. The inhibitory effects of five first-line anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and rifabutin), and the newly approved bedaquiline, were evaluated for six common human hepatic UGT enzymes (UGT1A1, 1A4, 1A6, 1A9, 2B7 and 2B15) in vitro using HLMs...
September 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28653752/the-potential-of-epimedium-koreanum-nakai-for-herb-drug-interaction
#7
Qingxiang Zhong, Ziqi Shi, Li Zhang, Rongling Zhong, Zhi Xia, Jing Wang, Hao Wu, Yutong Jiang, E Sun, Yingjie Wei, Liang Feng, Zhenhai Zhang, Dan Liu, Jie Song, Xiaobin Jia
OBJECTIVES: This study aims to investigate potential herb-drug interactions (HDI) of Epimedium koreanum Nakai. METHODS: Human liver microsomes (HLMs) were used to determine the enzyme kinetics of the major human cytochrome P450s (CYPs). Inducible potential of E. koreanum on CYP1A2, 2B6, 2C19 and 3A4 activities of human primary hepatocytes was also examined. KEY FINDINGS: Ethanol extract of E. koreanum showed direct inhibitory potency for CYP1A2 (IC50  = 121...
June 27, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28648140/oxidation-of-1-chloropyrene-by-human-cyp1-family-and-cyp2a-subfamily-cytochrome-p450-enzymes-catalytic-roles-of-two-cyp1b1-and-five-cyp2a13-allelic-variants
#8
Tsutomu Shimada, Norie Murayama, Kensaku Kakimoto, Shigeo Takenaka, Young-Ran Lim, Sora Yeom, Donghak Kim, Hiroshi Yamazaki, F Peter Guengerich, Masayuki Komori
1. 1-Chloropyrene, one of the major chlorinated polycyclic aromatic hydrocarbon contaminants, was incubated with human cytochrome P450 (P450 or CYP) enzymes including CYP1A1, 1A2, 1B1, 2A6, 2A13, 2B6, 2C9, 2D6, 2E1, 3A4 and 3A5. Catalytic differences in 1-chloropyrene oxidation by polymorphic two CYP1B1 and five CYP2A13 allelic variants were also examined. 2. CYP1A1 oxidized 1-chloropyrene at the 6- and 8-positions more actively than at the 3-position, while both CYP1B1.1 and 1B1.3 preferentially catalyzed 6-hydroxylation...
July 21, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28648122/phase-1-study-to-investigate-the-pharmacokinetic-properties-of-dacomitinib-in-healthy-adult-chinese-subjects-genotyped-for-cyp2d6
#9
Xia Chen, Ji Jiang, Nagdeep Giri, Pei Hu
1. This study aimed to characterise the pharmacokinetics of dacomitinib, a pan-human epidermal growth factor receptor tyrosine kinase inhibitor, and its metabolite, PF-05199265, in healthy Chinese subjects. 2. In this open-label, single-centre, nonrandomised study (NCT02097433), 14 subjects received a single dacomitinib 45-mg oral dose. Pharmacokinetic samples for dacomitinib and PF-05199265 were collected pre- and postdose. Subjects were genotyped for cytochrome P450 (CYP)2D6 metaboliser status. Safety was assessed throughout the study...
June 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28614988/in-vitro-inhibitory-effects-of-dihydromyricetin-on-human-liver-cytochrome-p450-enzymes
#10
Lu Liu, Sen Sun, Hongbing Rui, Xiaohua Li
CONTEXT: Dihydromyricetin (DHM) is the most abundant and active flavonoid component isolated from Ampelopsis grossedentata (Hand-Mazz) W.T. Wang (Vitaceae) and it possesses numerous pharmacological activities. However, whether DHM affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. MATERIALS AND METHODS: The inhibitory effects of DHM on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs)...
December 2017: Pharmaceutical Biology
https://www.readbyqxmd.com/read/28603633/in-vitro-metabolism-of-exemestane-by-hepatic-cytochrome-p450s-impact-of-nonsynonymous-polymorphisms-on-formation-of-the-active-metabolite-17%C3%AE-dihydroexemestane
#11
Amity Peterson, Zuping Xia, Gang Chen, Philip Lazarus
Exemestane (EXE) is an endocrine therapy commonly used by postmenopausal women with hormone-responsive breast cancer due to its potency in inhibiting aromatase-catalyzed estrogen synthesis. Preliminary in vitro studies sought to identify phase I EXE metabolites and hepatic cytochrome P450s (CYP450s) that participate in EXE biotransformation. Phase I metabolites were identified by incubating EXE with HEK293-overexpressed CYP450s. CYP450s 1A2, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5 produce 17β-dihydroexemestane (17β-DHE), an active major metabolite, as well as two inactive metabolites...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28601707/enhancement-of-biocompatibility-and-photoacoustic-contrast-activity-of-metal-clusters
#12
Arijit Bag, Pradip Kr Ghorai
Organometallic carbonyl clusters (OMCC) of group VIII elements are water soluble, bio-compatible and stable high-contrast photoacoustic agents for live cell imaging. But, they have limited application due to weak absorption within 700-1000nm wavelength which is known as the biological window of absorption. In this article, we report that hexa-nuclear iron (Fe6) carbonyl cluster derivatized with sodium thio-propanoate has very good absorption within 700-1600nm wave length. This modeled compound is water soluble and bio-compatible...
May 19, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28594282/availability-of-cyp2d6-genotyping-results-in-general-practitioner-and-community-pharmacy-medical-records
#13
Mirjam Simoons, Hans Mulder, Robert A Schoevers, Henricus G Ruhé, Eric N van Roon
AIM: To investigate the availability of CYP450-2D6 (CYP2D6) genotyping results in general practitioner (GP) and/or community pharmacy records, and the influence thereof on psychotropic CYP2D6 substrate dosing. MATERIALS & METHODS: Primary outcome was the percentage of patients genotyped for CYP2D6 with their genotype/phenotype registered in GP and/or pharmacy records. Secondary outcome was the number of defined daily doses of psychotropic CYP2D6 substrates prescribed after genotyping...
June 8, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28552654/microrna-hsa-mir-370-3p-suppresses-the-expression-and-induction-of-cyp2d6-by-facilitating-mrna-degradation
#14
Linjuan Zeng, Yinting Chen, Yong Wang, Li-Rong Yu, Bridgett Knox, Jiwei Chen, Tieliu Shi, Si Chen, Zhen Ren, Lei Guo, Yuanfeng Wu, David Liu, Kaihong Huang, Weida Tong, Dianke Yu, Baitang Ning
Cytochrome P450 2D6 (CYP2D6) participates in the metabolism of approximately 20-25% of prescribed drugs. Genetic polymorphisms influence the expression and/or activity of CYP2D6, and inter-individual differences in drug activation and elimination caused by CYP2D6 genetic variants were reported. However, little is known about the potential modulation of CYP2D6 expression by microRNAs (miRNAs). In the current study, by using in silico prediction of the stabilities of miRNA/mRNA complexes, we screened 38 miRNA candidates that may interact with the transcript of CYP2D6...
September 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28552479/biopharmaceutic-parameters-pharmacokinetics-transport-and-cyp-mediated-drug-interactions-of-iiim-017-a-novel-nitroimidazooxazole-analogue-with-anti-tuberculosis-activity
#15
Gurleen Kour, Parvinder Pal Singh, Asha Bhagat, Zabeer Ahmed
Nitroimidazoles are emerging as a new class of therapeutic agents with potent anti-tubercular activity. CSIR-IIIM has synthesized a novel nitrohydroimidazooxazole (NHIO) analogue, IIIM-017 with a MIC of 0.37μg/ml (against H37Rv). Here, we aim at further exploration of physicochemical properties and preclinical absorption, metabolism, disposition and pharmacokinetics of IIIM-017. In this study, in silico physicochemical parameters, lipophilicity, permeability, transport, hepatotoxicity, CYP mediated drug interactions and pharmacokinetics of IIIM-017 were investigated...
August 30, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28540639/exploiting-pharmacokinetic-models-of-tamoxifen-and-endoxifen-to-identify-factors-causing-subtherapeutic-concentrations-in-breast-cancer-patients
#16
Lena Klopp-Schulze, Markus Joerger, Sebastian G Wicha, Rob Ter Heine, Chantal Csajka, Zinnia P Parra-Guillen, Charlotte Kloft
BACKGROUND AND OBJECTIVES: A better understanding of the highly variable pharmacokinetics (PK) of tamoxifen and its active metabolite endoxifen in breast cancer patients is crucial to support individualised treatment. This study used a modelling and simulation approach to quantitatively assess the influence of cytochrome P450 (CYP) 2D6 activity and other relevant factors on tamoxifen and endoxifen PK to identify subgroups at risk for subtherapeutic endoxifen concentrations. METHODS: Simulations were performed using two previously published PK models jointly describing tamoxifen and endoxifen with CYP2D6 and CYP3A4/5 enzyme activities implemented as covariates...
May 24, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28526056/the-blood-schizonticidal-activity-of-tafenoquine-makes-an-essential-contribution-to-its-prophylactic-efficacy-in-nonimmune-subjects-at-the-intended-dose-200%C3%A2-mg
#17
REVIEW
Geoffrey Dow, Bryan Smith
Tafenoquine (TQ) is an 8-aminoquinoline anti-malarial being developed for malaria prophylaxis. It has been generally assumed that TQ, administered prophylactically, acts primarily on the developing exoerythrocytic stages of malaria parasites (causal prophylaxis), and that polymorphisms in metabolic enzymes thought to impact the activity of other 8-aminoquinolines also inhibit this property of TQ. Furthermore, it has been suggested that a diagnostic test for CYP2D6 metabolizer status might be required. In field studies in which metabolic status was not an exclusion criteria, TQ has been shown to exhibit similar prophylactic efficacy as blood schizonticidal drugs (mefloquine)...
May 19, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28495902/regio-and-stereo-selective-oxidation-of-a-cardiovascular-drug-metoprolol-mediated-by-cytochrome-p450-2d-and-3a-enzymes-in-marmoset-livers
#18
Shotaro Uehahara, Sakura Ishii, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
A β-blocker metoprolol is one of the in vivo probes for human cytochrome P450 (P450) 2D6. Investigation of non-human primate P450 enzymes helps improve accuracy of the extrapolation of pharmacokinetic data from animals into humans. Common marmosets (Callithrix jacchus) are a potential primate model for preclinical research, but detailed roles of marmoset P450 enzymes in metoprolol oxidations remained unknown. In this study, regio- and stereo-selectivity of metoprolol oxidations by a variety of P450 enzymes in marmoset and human livers were investigated in vitro...
May 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28484907/inhibition-of-cytochrome-p450-and-uridine-5-diphospho-glucuronosyltransferases-by-mam-2201-in-human-liver-microsomes
#19
Tae Yeon Kong, Ju-Hyun Kim, Soon-Sang Kwon, Jae Chul Cheong, Hee Seung Kim, Moon Kyo In, Hye Suk Lee
MAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors and is increasingly used as an illicit recreational drug. The inhibitory effects of MAM-2201 on major drug-metabolizing enzymes such as cytochrome P450s (CYPs) and uridine 5'-diphospho-glucuronosyltransferases (UGTs) have not yet been investigated although it is widely abused, sometimes in combination with other drugs. We evaluated the inhibitory effects of MAM-2201 on eight major human CYPs (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six UGTs (UGTs 1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) of pooled human liver microsomes; we thus explored potential MAM-2201-induced drug interactions...
May 8, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28473326/reduced-carboxylesterase-1-is-associated-with-endothelial-injury-in-methamphetamine-induced-pulmonary-arterial-hypertension
#20
Mark E Orcholski, Artyom Khurshudyan, Elya A Shamskhou, Ke Yuan, Ian Y Chen, Sean D Kodani, Christophe Morisseau, Bruce D Hammock, Ellen M Hong, Ludmila Alexandrova, Tero-Pekka Alastalo, Gerald Berry, Roham T Zamanian, Vinicio A de Jesus Perez
Pulmonary arterial hypertension is a complication of methamphetamine use (METH-PAH) but the pathogenic mechanisms are unknown. Given that cytochrome P450 2D6 (CYP2D6) and carboxylesterase 1 (CES1) are involved in metabolism of METH and other amphetamine-like compounds, we postulated that loss of function variants could contribute to METH-PAH. While no difference in CYP2D6 expression was seen by lung immunofluorescence, CES1 expression was significantly reduced in endothelium of METH-PAH microvessels. Mass spectrometry analysis showed that healthy pulmonary microvascular endothelial cells (PMVECs) have the capacity to both internalize and metabolize METH...
May 4, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
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