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Bera Rammohan, Karmakar Samit, Das Chinmoy, Saha Arup, Kundu Amit, Sarkar Ratul, Karmakar Sanmoy, Adhikari Dipan, Sen Tuhinadri
BACKGROUND: Traditionally GS is used to treat diabetes mellitus. Drug-herb interaction of GS via cytochrome P450 enzyme system by substrate cocktail method using HLM has not been reported. OBJECTIVE: To evaluate the in-vitro modulatory effects of GS extracts (aqueous, methanol, ethyl acetate, chloroform and n-hexane) and deacylgymnemic acid (DGA) on human CYP1A2, 2C8, 2C9, 2D6 and 3A4 activities in HLM. MATERIAL AND METHODS: Probe substrate-based LCMS/MS method was established for all CYPs...
July 2016: Pharmacognosy Magazine
Julian A Michely, Sascha K Manier, Achim T Caspar, Simon D Brandt, Jason Wallach, Hans H Maurer
3-Methoxyphencyclidine (3-MeO-PCP) and 3-methoxyrolicyclidine (3-MeO-PCPy) are two new psychoactive substances (NPS). The aims of the present study were the elucidation of their metabolic fate in rat and pooled human liver microsomes (pHLM), the identification of the cytochrome P450 (CYP) isoenzymes involved, and the detectability using standard urine screening approaches (SUSA) after intake of common users' doses using gas chromatography-mass spectrometry (GC-MS), liquid chromatography-multi-stage mass spectrometry (LC-MSn), and liquid chromatography-high-resolution tandem mass spectrometry (LC-HR-MS/MS)...
October 18, 2016: Current Neuropharmacology
Ping-Ping Lin, Xue-Ning Li, Fei Yuan, Wei-Li Chen, Meng-Jie Yang, Hong-Rong Xu
Huperzine A (HupA), one of the reversible and selective acetylcholinesterase inhibitors derived from Chinese herb Huperzia Serrata, possesses affirmative action of ameliorating cognitive dysfunction of Alzheimer's disease. Up to now, the effects of HupA on human cytochrome P450s (CYPs) have not been fully elucidated. The purpose of the present study was to clarify the metabolic pathway of HupA in vitro and in vivo, and to evaluate the CYPs inhibition/induction profile of HupA in vitro. The catalytic activity of CYP enzymes (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4) was measured by the quantification of specific enzyme substrates using validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods...
October 14, 2016: Biochemical and Biophysical Research Communications
Shuai-Bing He, Man-Man Li, Bai-Xia Zhang, Xiao-Tong Ye, Ran-Feng Du, Yun Wang, Yan-Jiang Qiao
During the past decades, there have been continuous attempts in the prediction of metabolism mediated by cytochrome P450s (CYP450s) 3A4, 2D6, and 2C9. However, it has indeed remained a huge challenge to accurately predict the metabolism of xenobiotics mediated by these enzymes. To address this issue, microsomal metabolic reaction system (MMRS)-a novel concept, which integrates information about site of metabolism (SOM) and enzyme-was introduced. By incorporating the use of multiple feature selection (FS) techniques (ChiSquared (CHI), InfoGain (IG), GainRatio (GR), Relief) and hybrid classification procedures (Kstar, Bayes (BN), K-nearest neighbours (IBK), C4...
October 9, 2016: International Journal of Molecular Sciences
Hirotaka Amano, Daichi Kazamori, Kenji Itoh
Three major organosulfur compounds of aged garlic extract, S-allyl-L-cysteine (SAC), S-methyl-L-cysteine (SMC), and trans-S-1-propenyl-L-cysteine (S1PC), were examined for their effects on the activities of five major isoforms of human CYP enzymes: CYP1A2, 2C9, 2C19, 2D6, and 3A4. The metabolite formation from probe substrates for the CYP isoforms was examined in human liver microsomes in the presence of organosulfur compounds at 0.01-1 mM by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis...
2016: Biological & Pharmaceutical Bulletin
Shiv Bahadur, Pulok K Mukherjee, S K Milan Ahmmed, Amit Kar, Ranjit K Harwansh, Subrata Pandit
OBJECTIVE: Tinospora cordifolia is used for treatment of several diseases in Indian system of medicine. In the present study, the inhibition potential of T. cordifolia extracts and its constituent tinosporaside to cause herb-drug interactions through rat and human liver cytochrome enzymes was evaluated. MATERIALS AND METHODS: Bioactive compound was quantified through reverse phase high-performance liquid chromatography, to standardize the plant extracts and interaction potential of standardized extract...
September 2016: Indian Journal of Pharmacology
Bruce Green, Herta Crauwels, Thomas N Kakuda, Simon Vanveggel, Anne Brochot
BACKGROUND: Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of etravirine. METHODS: We used 4728 plasma concentrations from 817 adult subjects collected from four clinical studies to develop the population pharmacokinetic model...
September 24, 2016: Clinical Pharmacokinetics
Jinhua Zhang, Lihong Tian, Jinlong Huang, Sihan Huang, Tingting Chai, Jianzhen Shen
AIM: To assess the effect of Cytochrome P450 2C9 (CYP2C9) gene polymorphism on pediatric warfarin maintenance dosage requirement. METHODS: A previously developed search strategy was conducted in PubMed, EMBASE, and the Cochrane Library. Eligible studies published prior to January 27, 2016, were identified and compared against strict inclusion/exclusion criteria. Required data were extracted, and researchers were consulted for additional data if needed. Review Manager Version 5...
September 23, 2016: Cardiovascular Therapeutics
Tsutomu Shimada, Kensaku Kakimoto, Shigeo Takenaka, Nobuyuki Koga, Shotaro Uehara, Norie Murayama, Hiroshi Yamazaki, Donghak Kim, Frederick Peter Guengerich, Masayuki Komori
2,5,2',5'-Tetrachlorobiphenyl (TCB) induced Type I binding spectra with cytochrome P450 (P450 or CYP) 2A6 and 2A13, having Ks values of 9.4 and 0.51 μM, respectively. However, CYP2A6 oxidized 2,5,2',5'-TCB to form 4-hydroxylated products at a much higher rate (~1.0 min-1) than CYP2A13 (~0.02 min-1), based on analysis by LC-MS/MS. Formation of 4-hydroxy-2,5,2',5'-TCB by CYP2A6 was greater than that of 3-hydroxy-2,5,2',5'-TCB and three other hydroxylated products. Several human P450 enzymes, including CYP1A1, 1A2, 1B1, 2B6, 2D6, 2E1, 2C9, and 3A4, did not show any detectable activities in oxidizing 2,5,2',5'-TCB...
September 13, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Darcy R Flora, Allan E Rettie, Richard C Brundage, Timothy S Tracy
Multiple factors can impact warfarin therapy, including genetic variations in the drug-metabolizing enzyme cytochrome P450 2C9 (CYP2C9). Compared with individuals with the wild-type allele, CYP2C9*1, carriers of the common *3 variant have significantly impaired CYP2C9 metabolism. Genetic variations in CYP2C9, the primary enzyme governing the metabolic clearance of the more potent S-enantiomer of the racemic anticoagulant warfarin, may impact warfarin-drug interactions. To establish a baseline for such studies, plasma and urine concentrations of R- and S-warfarin and 10 warfarin metabolites were monitored for up to 360 hours following a 10-mg warfarin dose in healthy subjects with 4 different CYP2C9 genotypes: CYP2C9*1/*1 (n = 8), CYP2C9*1/*3 (n = 9), CYP2C9*2/*3 (n = 3), and CYP2C9*3/*3 (n = 4)...
August 19, 2016: Journal of Clinical Pharmacology
Takashi Satoh, Haruka Fujisawa, Ami Nakamura, Natsuko Takahashi, Kazuhiro Watanabe
PURPOSE: Green tea is a traditional beverage that has been enjoyed by the Japanese to this day. Recently, there has been an increase in the consumption of green tea beverage having high concentrations of catechins, such as (-)-epigallocatechin-3-O-gallate (EGCG). Many people tend to ingest large amounts of catechins through the frequent consumption of green tea beverage, and this dietary habit may lead to unwanted interactions between the catechins in green tea and medicinal drug. METHODS: The inhibitory effects of eight green tea catechins on drug metabolizing enzymes, cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4, were investigated in human liver microsomes...
April 2016: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
Wu-Tao Zeng, Qing Xu, Cheng-Hsun Li, Wei-Yan Chen, Xiu-Ting Sun, Xiang Wang, Yi-Ying Yang, Hui Shi, Zhi-Sheng Yang
PURPOSE: The aim of this study was to investigate whether any of the single-nucleotide polymorphisms (SNPs) in the POR gene were significantly associated with CYP activity and expression, and could contribute to the total variability in stable warfarin maintenance doses in Han Chinese. METHODS: A total of 408 patients treated at the First Affiliated Hospital of Sun Yat-Sen University were eligible for the study and had attained a stable warfarin maintenance dose at the start of the investigation...
November 2016: European Journal of Clinical Pharmacology
Elizabeth Marek, Jeremiah D Momper, Ronald N Hines, Cheryl M Takao, Joan C Gill, Vera Pravica, Andrea Gaedigk, Gilbert J Burckart, Kathleen A Neville
OBJECTIVES: The objective of this study was to evaluate the performance of pediatric pharmacogenetic-based dose prediction models by using an independent cohort of pediatric patients from a multicenter trial. METHODS: Clinical and genetic data (CYP2C9 [cytochrome P450 2C9] and VKORC1 [vitamin K epoxide reductase]) were collected from pediatric patients aged 3 months to 17 years who were receiving warfarin as part of standard care at 3 separate clinical sites. The accuracy of 8 previously published pediatric pharmacogenetic-based dose models was evaluated in the validation cohort by comparing predicted maintenance doses to actual stable warfarin doses...
May 2016: Journal of Pediatric Pharmacology and Therapeutics: JPPT: the Official Journal of PPAG
Steeve Gress, Claire Laurant, Nicolas Defarge, Carine Travert, Gilles-Éric Séralini
BACKGROUND: Plant medicinal extracts may be claimed to prevent or cure chemical intoxications. Few of these are tested for their mechanisms of actions in vivo and for their cellular impacts. In 2011, we demonstrated that hepatic cell mortality induced by environmentally realistic levels of the widely used herbicide Roundup (R) in vitro can be almost entirely prevented by plant extracts called Dig1 (D, Digeodren). METHODS: We tested the in vivo effects of D alone (1...
2016: BMC Complementary and Alternative Medicine
Chang Seon Ryu, Soo Jin Oh, Jung Min Oh, Ji-Yoon Lee, Sang Yoon Lee, Jung-Woo Chae, Kwang-Il Kwon, Sang Kyum Kim
Although propolis is one of the most popular functional foods for human health, there have been no comprehensive studies of herb-drug interactions through cytochrome P450 (CYP) inhibition. The purpose of this study was to determine the inhibitory effects of propolis on the activities of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 using pooled human liver microsomes (HLMs). Propolis inhibited CYP1A2, CYP2E1 and CYP2C19 with an IC50 value of 6.9, 16.8, and 43.1 μg/mL, respectively, whereas CYP2A6, 2B6, 2C9, 2D6, and 3A4 were unaffected...
July 2016: Toxicological Research
Kazuhide Iwasaki, Yusuke Kitsugi, Kanami Ikeda, Takahiro Yoshikawa, Shinya Hosaka, Shotaro Uehara, Yasuhiro Uno, Masahiro Utoh, Hiroshi Yamazaki
Cynomolgus monkeys are used frequently in preclinical studies for new drug development due to their evolutionary closeness to humans. An antiretroviral drug, efavirenz, is a typical probe substrate for human cytochrome P450 (P450) 2B6, but is mainly metabolized by cynomolgus monkey P450 2C9. In this study, plasma concentrations of efavirenz were assessed in six cynomolgus monkeys genotyped for P450 2C9 c.334 A > C (I112L) (three wild-type, one heterozygote and two homozygotes) by high performance liquid chromatography with tandem mass spectrometry...
September 2016: Biopharmaceutics & Drug Disposition
Shohei Miyazaki, Hiroki Satoh, Masayuki Ikenishi, Miyuki Sakurai, Mutsuaki Ueda, Kaori Kawahara, Rie Ueda, Tohru Ohtori, Kenji Matsuyama, Akiko Miki, Satoko Hori, Eiji Fukui, Eitaro Nakatsuka, Yasufumi Sawada
OBJECTIVE: Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. METHODS: We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner...
September 2016: International Journal of Clinical Pharmacology and Therapeutics
Manisha Bhateria, Rachumallu Ramakrishna, Santosh Kumar Puttrevu, Anil K Saxena, Rabi Sankar Bhatta
A significant number of new chemical entities (NCEs) fail in drug discovery due to inhibition of Cytochrome P450 (CYP) enzymes. Therefore, to avert costly drug failure at the clinical phase it becomes indispensable to evaluate the CYP inhibition profile of NCEs early in drug discovery. In light of these concerns, we envisioned to investigate the inhibitory effects of S002-333 [2-(4-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide], a novel and potent antithrombotic agent, on nine major CYP enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) of human liver microsomes (HLM)...
August 25, 2016: Chemico-biological Interactions
Shu-Ting Pan, Danfeng Xue, Zhi-Ling Li, Zhi-Wei Zhou, Zhi-Xu He, Yinxue Yang, Tianxin Yang, Jia-Xuan Qiu, Shu-Feng Zhou
The human cytochrome P450 (CYP) superfamily consisting of 57 functional genes is the most important group of Phase I drug metabolizing enzymes that oxidize a large number of xenobiotics and endogenous compounds, including therapeutic drugs and environmental toxicants. The CYP superfamily has been shown to expand itself through gene duplication, and some of them become pseudogenes due to gene mutations. Orthologs and paralogs are homologous genes resulting from speciation or duplication, respectively. To explore the evolutionary and functional relationships of human CYPs, we conducted this bioinformatic study to identify their corresponding paralogs, homologs, and orthologs...
2016: International Journal of Molecular Sciences
Rui Liu, Teresa W Tam, Jingqin Mao, Ammar Salem, John T Arnason, Anthony Krantis, Brian C Foster
BACKGROUND: Goji berry (Lycium barbarum) has been used as traditional Chinese medicine and a functional food in China. Goji tea may interact with drugs such as warfarin by inhibiting the cytochrome P450 (CYP) 2C9, and this study was undertaken to characterize the effect of Goji products on CYP2C9/19-, CYP2D6 *1/*10-, CYP3A4/5/7-, CYP19-, and flavin-containing monooxygenase (FMO) 3-mediated metabolism. METHODS: Goji juice, water, and ethanol extracts were examined for their effect on CYP2C9/19-, 2D6-, 3A4/5/7-, 4A11-, CYP19-, and FMO3-mediated metabolism by using in vitro bioassay...
June 28, 2016: Journal of Complementary & Integrative Medicine
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