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CYP2C9

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https://www.readbyqxmd.com/read/28099407/effects-of-functional-cyp2c8-cyp2c9-cyp3a5-and-abcb1-genetic-variants-on-the-pharmacokinetics-of-insulin-sensitizer-pioglitazone-in-chinese-han-individuals
#1
Sheng-Ju Yin, Hui-Min Qi, Xin Wang, Pu Zhang, Yuan Lu, Min-Ji Wei, Pu Li, Guang-Zhao Qi, Ya-Qing Lou, Chuang Lu, Guo-Liang Zhang
BACKGROUND AND OBJECTIVES: Pioglitazone is a thiazolidinedione antihyperglycemic drug with insulin-sensitizing properties. We investigated whether the variant genotypes of cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP3A5 and transporter ABCB1 influence the pharmacokinetic phenotype of the substrate pioglitazone in Chinese individuals. PARTICIPANTS AND METHODS: Single-nucleotide polymorphisms were determined by the PCR-restriction fragment length polymorphism method in 244 (CYP2C8 and CYP2C9) healthy Chinese Han individuals...
January 17, 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28097507/in-vitro-phase-i-and-phase-ii-drug-metabolism-in-the-liver-of-juvenile-and-adult-g%C3%A3-ttingen-minipigs
#2
Els Van Peer, Frank Jacobs, Jan Snoeys, Jos Van Houdt, Ils Pijpers, Christophe Casteleyn, Chris Van Ginneken, Steven Van Cruchten
PURPOSE: In view of pediatric drug development, juvenile animal studies are gaining importance. However, data on drug metabolizing capacities of juvenile animals are scarce, especially in non-rodent species. Therefore, we aimed to characterize the in vitro biotransformation of four human CYP450 substrates and one UGT substrate in the livers of developing Göttingen minipigs. METHODS: Liver microsomes from late fetal, Day 1, Day 3, Day 7, Day 28, and adult male and female Göttingen minipigs were incubated with a cocktail of CYP450 substrates, including phenacetin, tolbutamide, dextromethorphan, and midazolam...
January 17, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28081475/add-on-stiripentol-elevates-serum-valproate-levels-in-patients-with-or-without-concomitant-topiramate-therapy
#3
Toshihiro Jogamoto, Yoshiaki Yamamoto, Mitsumasa Fukuda, Yuka Suzuki, Katsumi Imai, Yukitoshi Takahashi, Yushi Inoue, Yoko Ohtsuka
OBJECTIVE: Stiripentol (STP), valproate (VPA) and topiramate (TPM) are reported to have efficacy for Dravet syndrome. In this study, we sought to elucidate the mechanisms underlying the increased serum VPA concentrations following STP adjunctive therapy in patients with Dravet syndrome. METHODS: Twenty-eight patients with Dravet syndrome (age range, 1-35 years) undergoing combination therapy with VPA and STP were included in this study. We evaluated VPA and clobazam (CLB) serum concentrations before and after add-on STP...
December 26, 2016: Epilepsy Research
https://www.readbyqxmd.com/read/28079798/clinical-and-genetic-factors-associated-with-warfarin-maintenance-dose-in-northern-chinese-patients-with-mechanical-heart-valve-replacement
#4
Rui Liu, Jian Cao, Qian Zhang, Xin-Miao Shi, Xiao-Dong Pan, Ran Dong
The effects of genetic variants on warfarin dosing vary among different ethnic groups, especially in the Chinese population. The objective of this study was to recruit patients through a rigorous experimental design and to perform a comprehensive screen to identify gene polymorphisms that may influence warfarin dosing in northern Han Chinese patients with mechanical heart valve replacement. Consenting patients (n = 183) with a stable warfarin dose were included in this study. Ninety-six single nucleotide polymorphisms (SNPs) in 30 genes involved in warfarin pharmacological pathways were genotyped using the Illumina SNP GoldenGate Assay, and their associations with warfarin dosing were assessed using univariate regression analysis with post hoc comparison using least significant difference analysis...
January 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28074333/rosiglitazone-metabolism-in-human-liver-microsomes-using-a-substrate-depletion-method
#5
Maryam Bazargan, David J R Foster, Andrew K Davey, Beverly S Muhlhausler
BACKGROUND: Elimination of rosiglitazone in humans is via hepatic metabolism. The existing studies suggest that CYP2C8 is the major enzyme responsible, with a minor contribution from CYP2C9; however, other studies suggest the involvement of additional cytochrome P450 enzymes and metabolic pathways. Thus a full picture of rosiglitazone metabolism is unclear. OBJECTIVE: This study aimed to improve the current understanding of potential drug-drug interactions and implications for therapy by evaluating the kinetics of rosiglitazone metabolism and examining the impact of specific inhibitors on its metabolism using the substrate depletion method...
January 10, 2017: Drugs in R&D
https://www.readbyqxmd.com/read/28073119/in-vitro-inhibition-of-human-cyp450s-1a2-2c9-3a4-5-2d6-and-2e1-by-grandisin
#6
Maísa Daniela Habenschus, Fernanda de Lima Moreira, Norberto Peporine Lopes, Anderson R M de Oliveira
Grandisin, a lignan isolated from many species of plants, such as Virola surinamensis, is a potential drug candidate due to its biological properties, highlighted by its antitumor and trypanocidal activities. In this study, the inhibitory effects of grandisin on the activities of human cytochrome P450 enzymes were investigated by using human liver microsomes. Results showed that grandisin is a competitive inhibitor of CYP2C9 and a competitive and mechanism-based inhibitor of CYP3A4/5. The apparent Ki value for CYP2C9 was 50...
January 10, 2017: Planta Medica
https://www.readbyqxmd.com/read/28073118/in-vitro-metabolism-of-artepillin-c-by-rat-and-human-liver-microsomes
#7
Daniel Blascke Carrão, Nayara Cristina Perez de Albuquerque, Lucas Maciel Mauriz Marques, Antônio Eduardo Miller Crotti, Alan Cesar Pilon, Vanderlan Da Silva Bolzani, Andresa Aparecida Berretta, Anderson Rodrigo Moraes de Oliveira
Artepillin C, a natural product present in the Brazilian green propolis, has several biological properties. Among these properties, the antitumor action of this product is noteworthy and makes it a promising drug candidate for the treatment of several types of cancer. This paper describes the in vitro metabolism of Artepillin C in rat and human liver microsomes. The rat model suggested a sigmoidal profile for the metabolism, adapted to the Hill's kinetic model. The enzymatic kinetic parameters were as follows: maximal velocity = 0...
January 10, 2017: Planta Medica
https://www.readbyqxmd.com/read/28067999/evaluation-of-pharmacokinetic-interactions-between-lesinurad-a-new-selective-urate-reabsorption-inhibitor-and-cyp-enzyme-substrates-sildenafil-amlodipine-tolbutamide-and-repaglinide
#8
Michael Gillen, Chun Yang, David Wilson, Shakti Valdez, Caroline Lee, Bradley Kerr, Zancong Shen
Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. In vitro assays indicate that lesinurad is an inducer of CYPs in the order CYP3A > CYP2C8 > CYP2C9 > CYP2C19 > CYP2B6 and an inhibitor of CYP2C8 and CYP2C9. To investigate the drug interaction potential of lesinurad, clinical drug interaction studies were conducted. Open-label studies in volunteers investigated the effects of single-/multiple-dose lesinurad on the pharmacokinetics of sildenafil and amlodipine (CYP3A4 induction), tolbutamide (CYP2C9 inhibition/induction), and repaglinide (CYP2C8 inhibition/induction)...
January 9, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28063245/dosing-algorithms-for-vitamin-k-antagonists-across-vkorc1-and-cyp2c9-genotypes
#9
Ekaterina V Baranova, Talitha I Verhoef, Georgia Ragia, Saskia Le Cessie, Folkert W Asselbergs, Anthonius de Boer, Vangelis G Manolopoulos, Anke H Maitland-van der Zee
BACKGROUND: The multicenter, single-blind, randomized EU-PACT trial compared safety and efficacy of genotype-guided and non-genetic dosing algorithms for acenocoumarol and phenprocoumon in patients with atrial fibrillation or deep venous thrombosis. The trial showed no differences in the primary outcome between the two dosing strategies. OBJECTIVES: To explore possible reasons for the lack of differences between trial arms this secondary analysis of EU-PACT data evaluated the performance of both dosing algorithms across VKORC1-CYP2C9 genetic sub-groups...
January 7, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28058783/characterization-of-phase-i-and-phase-ii-hepatic-metabolism-and-reactive-intermediates-of-larrea-nitida-cav-and-its-lignan-compounds
#10
Hyesoo Jeong, Soolin Kim, Jimin Lee, Jin Young Park, Wenmei Zhou, Xiyuan Liu, So Dam Kim, Yun Seon Song, Chang-Young Jang, Sei-Ryang Oh, Sangho Choi, Minsun Chang
Larrea nitida Cav. (LNC), which belongs to the family Zygophyllaceae, is widely indigenous and used in South America to treat various pathological conditions. It contains the antioxidant and antiinflammatory but toxic nordihydroguaiaretic acid (NDGA) as well as O-methylated metabolite of NDGA (MNDGA) as bioactive compounds. The hepatic metabolism-based toxicological potential of extracts of LNC (LNE), NDGA, and MNDGA has not previously been reported. The present study aimed to characterize the phase I and phase II hepatic metabolism and reactive intermediates of LNE, NDGA, and MNDGA and their effects on the major drug-metabolizing enzymes in vitro and ex vivo...
January 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28057172/substrate-specificity-of-human-cytochrome-p450-cyp-2c-subfamily-and-effect-of-azole-antifungal-agents-on-cyp2c8
#11
Toshiro Niwa, Yurie Imagawa
PURPOSE: The metabolic activities of aminopyrine N-demethylation and tolbutamide methylhydroxylation by the human hepatic cytochrome P450 (P450 or CYP) 2C subfamily were compared and the effects of azole antifungal agent on the drug-metabolizing activity of CYP2C8 were investigated. METHODS: Aminopyrine N-demethylation and tolbutamide methylhydroxylation by CYP2C8, CYP2C9, and CYP2C19 were determined by the previous reported methods. The effects of five azole antifungal agents, fluconazole, itraconazole, ketoconazole, miconazole, and voriconazole, on the aminopyrine N-demethylation activity by CYP2C8 were investigated...
October 2016: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28056947/triptolide-induces-hepatotoxicity-via-inhibition-of-cyp450s-in-rat-liver-microsomes
#12
Yan Lu, Tong Xie, Yajie Zhang, Fuqiong Zhou, Jie Ruan, Weina Zhu, Huaxu Zhu, Zhe Feng, Xueping Zhou
BACKGROUND: Triptolide (TP), an active constituent of Tripterygium wilfordii, possesses numerous pharmacological activities. However, its effects on cytochrome P450 enzymes (CYP450s) in rats remain unexplored. METHODS: In this study, the effects of triptolide on the six main CYP450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A) were investigated both in vivo and in vitro. We monitored the body weight, survival proportions, liver index, changes in pathology, and biochemical index upon TP administration, in vivo...
January 5, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28052106/a-prediction-algorithm-for-drug-response-in-patients-with-mesial-temporal-lobe-epilepsy-based-on-clinical-and-genetic-information
#13
Mariana S Silva-Alves, Rodrigo Secolin, Benilton S Carvalho, Clarissa L Yasuda, Elizabeth Bilevicius, Marina K M Alvim, Renato O Santos, Claudia V Maurer-Morelli, Fernando Cendes, Iscia Lopes-Cendes
Mesial temporal lobe epilepsy is the most common form of adult epilepsy in surgical series. Currently, the only characteristic used to predict poor response to clinical treatment in this syndrome is the presence of hippocampal sclerosis. Single nucleotide polymorphisms (SNPs) located in genes encoding drug transporter and metabolism proteins could influence response to therapy. Therefore, we aimed to evaluate whether combining information from clinical variables as well as SNPs in candidate genes could improve the accuracy of predicting response to drug therapy in patients with mesial temporal lobe epilepsy...
2017: PloS One
https://www.readbyqxmd.com/read/28049362/warfarin-dose-model-for-the-prediction-of-stable-maintenance-dose-in-indian-patients
#14
Tejasvita Gaikwad, Kanjaksha Ghosh, Peter Avery, Farhad Kamali, Shrimati Shetty
The main aim of this study was to screen various genetic and nongenetic factors that are known to alter warfarin response and to generate a model to predict stable warfarin maintenance dose for Indian patients. The study comprised of 300 warfarin-treated patients. Followed by extensive literature review, 10 single-nucleotide polymorphisms, that is, VKORC1-1639 G>A (rs9923231), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), FVII R353Q (rs6046), GGCX 12970 C>G (rs11676382), CALU c.*4A>G (rs1043550), EPHX1 c...
January 1, 2017: Clinical and Applied Thrombosis/hemostasis
https://www.readbyqxmd.com/read/28046094/analysis-of-genetic-variation-in-cyp450-genes-for-clinical-implementation
#15
Liuh Ling Goh, Chia Wei Lim, Wey Cheng Sim, Li Xian Toh, Khai Pang Leong
BACKGROUND: Genetic determinants of drug response remain stable throughout life and offer great promise to patient-tailored drug therapy. The adoption of pharmacogenetic (PGx) testing in patient care requires accurate, cost effective and rapid genotyping with clear guidance on the use of the results. Hence, we evaluated a 32 SNPs panel for implementing PGx testing in clinical laboratories. METHODS: We designed a 32-SNP panel for PGx testing in clinical laboratories...
2017: PloS One
https://www.readbyqxmd.com/read/28033245/vkorc1-and-cyp2c9-polymorphisms-related-to-adverse-events-in-case-control-cohort-of-anticoagulated-patients
#16
Silvia Misasi, Giuliana Martini, Oriana Paoletti, Stefano Calza, Giovanni Scovoli, Alessandra Marengoni, Sophie Testa, Luigi Caimi, Eleonora Marchina
Vitamin K antagonists (VKAs) are highly effective but have a narrow therapeutic index and require routine monitoring of the INR. The primary aim of pharmacogenetics (PGx) is to optimize patient care, achieving drug treatments that are personalized according to the genetic profile of each patient. The best-characterized genes involved in VKA PGx involve pharmacokinetics (VKORC1) and pharmacodynamics (CYP2C9) of VKA metabolism. The role of these genes in clinical outcomes (bleeding and thrombosis) during oral anticoagulant (OAC) therapy is controversial...
December 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28032893/anticoagulation-endpoints-with-clinical-implementation-of-warfarin-pharmacogenetic-dosing-in-a-real-world-setting-a-proposal-for-a-new-pharmacogenetic-dosing-approach
#17
M J Arwood, J Deng, K Drozda, O Pugach, E A Nutescu, S Schmidt, J D Duarte, L H Cavallari
Achieving therapeutic anticoagulation efficiently with warfarin is important to reduce thrombotic and bleeding risks and is influenced by genotype. Utilizing data from a diverse population of 257 patients who received VKORC1 and CYP2C9 genotype-guided warfarin dosing, we aimed to examine genotype-associated differences in anticoagulation endpoints and derive a novel pharmacogenetic nomogram to more optimally dose warfarin. We observed significant differences across patients with 0, 1, or ≥2 reduced-function VKORC1 or CYP2C9 alleles, respectively, in time to achieve therapeutic international normalized ratio (INR) (7...
November 5, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28007398/development-of-gc-ms-based-cytochrome-p450-assay-for-the-investigation-of-multi-herb-interaction
#18
Hyun-A Oh, Hyunbeom Lee, Donghak Kim, Byung Hwa Jung
As drug interactions with cytochrome P450 enzymes become increasingly important in the field of drug discovery, a high-throughput screening method for analysing the effects of a drug is needed. We have developed a simple and rapid simultaneous analytical method using a cocktail approach for measuring the activities of seven cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4). Human liver microsomes were used as a source for the seven cytochrome P450 enzymes, and a gas chromatography-mass spectrometry (GC-MS) was used for analysing their activities...
February 15, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/27995809/correlations-between-the-enantio-and-regio-selective-metabolisms-of-warfarin
#19
Harumi Takahashi, Minami Ohara, Soichi Shibata, Ming Ta Michael Lee, Larisa H Cavallari, Edith A Nutescu, Maria G Scordo, Vittorio Pengo, Roberto Padrini, Koichiro Atsuda, Hajime Matsubara, Yuan Tsong Chen, Hirotoshi Echizen
AIM: To clarify whether the activities of multiple CYPs associated with warfarin metabolism would be correlated with each other. METHODS: Oral clearances (CLpo) of warfarin enantiomers were estimated in 378 Chinese, Caucasians and African-Americans. The partial metabolic clearances (CLm) for 7-hydroxywarfarin enantiomers were also measured. In addition, CLpo and CLm were determined in a patient on warfarin and rifampicin. RESULTS: Correlations between CLpo for warfarin enantiomers existed across the three populations...
January 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/27992547/the-impact-of-genetic-and-non-genetic-factors-on-warfarin-dose-prediction-in-mena-region-a-systematic-review
#20
Loulia Akram Bader, Hazem Elewa
BACKGROUND: Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing...
2016: PloS One
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