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CYP3A5

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https://www.readbyqxmd.com/read/29162334/results-of-asertaa-a-randomized-prospective-crossover-pharmacogenetic-study-of-immediate-release-versus-extended-release-tacrolimus-in-african-american-kidney-transplant-recipients
#1
Jennifer Trofe-Clark, Daniel C Brennan, Patricia West-Thielke, Michael C Milone, Mary Ann Lim, Robin Neubauer, Vincenza Nigro, Roy D Bloom
BACKGROUND: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile...
November 18, 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/29161757/impact-of-cyp3a5-genomic-variances-on-clinical-outcomes-among-african-american-kidney-transplant-recipients
#2
Tomefa E Asempa, Lorita M Rebellato, Suzanne Hudson, Kimberly Briley, Angela Q Maldonado
Little is known about the impact of CYP3A5 polymorphisms on transplantation outcomes among African-American (AA) kidney transplant recipients. To assess this issue, clinical outcomes were compared between AA CYP3A5*1 expressers versus non-expressers. This retrospective cohort study analyzed AA kidney transplant recipients. Biopsy-proven acute rejection (BPAR), delayed graft function (DGF), glomerular filtration rate (GFR), infections and tacrolimus dosing requirements were examined in 106 immunologically high-risk AA kidney transplant patients over a 2 year follow-up period...
November 21, 2017: Clinical Transplantation
https://www.readbyqxmd.com/read/29160300/genome-wide-association-study-identifies-the-common-variants-in-cyp3a4-and-cyp3a5-responsible-for-variation-in-tacrolimus-trough-concentration-in-caucasian-kidney-transplant-recipients
#3
W S Oetting, B Wu, D P Schladt, W Guan, R P Remmel, R B Mannon, A J Matas, A K Israni, P A Jacobson
The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study...
November 21, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/29136555/non-targeted-metabolomics-guided-sildenafil-metabolism-study-in-human-liver-microsomes
#4
Ju-Hyun Kim, Jun Hyun Jo, Kyung-Ah Seo, Hayoung Hwang, Hye Suk Lee, Sangkyu Lee
Metabolomics combined with high-resolution mass spectrometry (HR-MS) and multivariate data analysis has broad applications in the study of xenobiotic metabolism. Although information about xenobiotic metabolism is essential to understand toxic mechanisms, pharmacokinetic parameters and excretion pathways, it is limited to predict all generated metabolites in biological fluids. Here, we revisited sildenafil metabolism in human liver microsomes using a metabolomics approach to achieve a global picture of sildenafil phase 1 metabolism...
November 7, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29135906/effect-of-age-and-allele-variants-of-cyp3a5-cyp3a4-and-por-genes-on-the-pharmacokinetics-of-cyclosporin-a-in-pediatric-renal-transplant-recipients-from-serbia
#5
Mirjana Cvetković, Maja Zivković, Maja Bundalo, Ivana Gojković, Brankica Spasojević-Dimitrijeva, Aleksandra Stanković, Mirjana Kostić
BACKGROUND: The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene (POR*28). The aim of this study was to assess the impact of age, CYP3A5*3, CYP3A4*22, and POR*28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients. METHODS: Renal transplant patients receiving CsA (n = 47) were genotyped for CYP3A5*3, CYP3A4*22, and POR*28...
December 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29123971/concepts-of-genomics-in-kidney-transplantation
#6
William S Oetting, Casey Dorr, Rory P Remmel, Arthur J Matas, Ajay K Israni, Pamala A Jacobson
Purpose of review: Identification of genetic variants to aid in individualized treatment of solid organ allograft recipients would improve graft survival. We will review the current state of knowledge for associations of variants with transplant outcomes. Recent findings: Many studies have yet to exhibit robust and reproducible results, however, pharmacogenomic studies focusing on cytochrome P450 (CYP) enzymes, transporters and HLA variants have shown strong associations with outcomes and have relevance towards drugs used in transplant...
June 2017: Current Transplantation Reports
https://www.readbyqxmd.com/read/29123154/modification-of-single-nucleotide-polymorphism-in-a-fully-humanized-cyp3a-mouse-by-genome-editing-technology
#7
Satoshi Abe, Kaoru Kobayashi, Asami Oji, Tetsushi Sakuma, Kanako Kazuki, Shoko Takehara, Kazuomi Nakamura, Azusa Okada, Yasuko Tsukazaki, Naoto Senda, Kazuhisa Honma, Takashi Yamamoto, Masahito Ikawa, Kan Chiba, Mitsuo Oshimura, Yasuhiro Kazuki
Cytochrome P450, family 3, subfamily A (CYP3A) enzymes metabolize approximately 50% of commercially available drugs. Recently, we developed fully humanized transchromosomic (Tc) CYP3A mice with the CYP3A cluster including CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Our humanized CYP3A mice have the CYP3A5*3 (g.6986G) allele, resulting in the almost absence of CYP3A5 protein expression in the liver and intestine. To produce model mice for predicting CYP3A5's contribution to pharmacokinetics, we performed a single-nucleotide polymorphism (SNP) modification of CYP3A5 (g...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29115708/cyp3a5-genotype-and-its-impact-on-vincristine-pharmacokinetics-and-development-of-neuropathy-in-kenyan-children-with-cancer
#8
Jodi L Skiles, ChienWei Chiang, Claire H Li, Steve Martin, Ellen L Smith, Gilbert Olbara, David R Jones, Terry A Vik, Saskia Mostert, Floor Abbink, Gertjan J Kaspers, Lang Li, Festus Njuguna, Tammy J Sajdyk, Jamie L Renbarger
BACKGROUND: Vincristine (VCR) is a critical part of treatment in pediatric malignancies and is associated with dose-dependent peripheral neuropathy (vincristine-induced peripheral neuropathy [VIPN]). Our previous findings show VCR metabolism is regulated by the CYP3A5 gene. Individuals who are low CYP3A5 expressers metabolize VCR slower and experience more severe VIPN as compared to high expressers. Preliminary observations suggest that Caucasians experience more severe VIPN as compared to nonCaucasians...
November 8, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29113387/tacrolimus-dose-requirement-based-on-the-cyp3a5-genotype-in-renal-transplant-patients
#9
Lihui Qu, Yingying Lu, Meike Ying, Bingjue Li, Chunhua Weng, Zhoutao Xie, Ludan Liang, Chuan Lin, Xian Yang, Shi Feng, Yucheng Wang, Xiujin Shen, Qin Zhou, Ying Chen, Zhimin Chen, Jianyong Wu, Weiqiang Lin, Yi Shen, Jing Qin, Hang Xu, Feng Xu, Junwen Wang, Jianghua Chen, Hong Jiang, Hongfeng Huang
Tacrolimus (FK506) and cyclosporine A (CsA) are widely used to protect graft function after renal transplantation. The aim of the present study is to determine whether the single nucleotide polymorphism of CYP3A5 is a predictive index of FK506 dose requirement, and also the selection yardstick of FK506 or CsA treatment.We tested archival peripheral blood of 218 kidney recipients for CYP3A5 genotyping with PCR-SSP. Meanwhile, the dose of FK506 and CsA was recorded, blood concentration of the drugs was measured, and graft outcome was monitored...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29095105/genotype-based-tacrolimus-dosing-guidelines-with-or-without-cyp3a4-22
#10
Laure Elens, Vincent Haufroid
AIM: To test the relevance of revisiting the genotype classification based on CYP3A5*3 solely by incorporating CYP3A4*22 information. METHODS: Discriminant analysis of principal component was performed to evaluate the relevance of either the CYP3A (CYP3A5 + CYP3A4 genotypes) or CYP3A5*3 classification variables. This analysis was based on a linear combination of noncompartmental pharmacokinetics parameters. RESULTS: Discriminant analysis of principal component gave better results with CYP3A compared with CYP3A5*3 clustering...
November 2, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/29066969/improved-progression-free-survival-in-irinotecan-treated-metastatic-colorectal-cancer-patients-carrying-the-hnf1a-coding-variant-p-i27l
#11
Adrien Labriet, Elena De Mattia, Erika Cecchin, Éric Lévesque, Derek Jonker, Félix Couture, Angela Buonadonna, Mario D'Andrea, Lyne Villeneuve, Giuseppe Toffoli, Chantal Guillemette
Hepatocyte nuclear factor 1-alpha (HNF1A) is a liver-enriched transcription factor that plays a key role in many aspects of hepatic functions including detoxification processes. We examined whether HNF1A polymorphisms are associated with clinical outcomes in two independent cohorts combining 417 European ancestry patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based chemotherapy. The intronic rs2244608A>G marker was predictive of an improved progression-free survival with a trend in the Canadian cohort and reaching significance in the Italian cohort, with hazard ratios (HR) of 0...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29061081/pharmacogenetics-of-trazodone-in-healthy-volunteers-association-with-pharmacokinetics-pharmacodynamics-and-safety
#12
Miriam Saiz-Rodríguez, Carmen Belmonte, Nieves Derqui-Fernández, Teresa Cabaleiro, Manuel Román, Dolores Ochoa, María Talegón, María C Ovejero-Benito, Francisco Abad-Santos
AIM: The aim was to evaluate the effect of polymorphisms in metabolizing enzymes and transporters on the pharmacokinetics, pharmacodynamics and adverse effects of trazodone in healthy volunteers. MATERIALS & METHODS: 36 healthy volunteers receiving a single 100-mg oral dose of trazodone were genotyped for 11 variants in CYP3A4, CYP3A5, CYP2D6 and ABCB1 by real-time PCR. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry method...
October 24, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/29050522/metabolism-of-megestrol-acetate-in-vitro-and-the-role-of-oxidative-metabolites
#13
Larry House, Michael Seminerio, Snezana Mirkov, Jacqueline Ramirez, Maxwell Skor, Joseph Sachleben, Masis Isikbay, Hari Singhal, Geoffrey Greene, Donald Vander Griend, Suzanne Conzen, Mark J Ratain
There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for identifying specific drug-metabolizing enzymes. We determined the cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) that metabolize MA, identified oxidative metabolites, and determined pharmacologic activity at the progesterone, androgen and glucocorticoid receptors (PR, AR, and GR, respectively). Oxidative metabolites were produced using human liver microsomes (HLMs), and isolated for mass spectral (MS) and nuclear magnetic resonance (NMR) analyses...
October 20, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29050321/interaction-among-cyp2c8-gpiiia-and-p2y12-variants-increase-susceptibility-to-ischemic-stroke-in-chinese-population
#14
Xingyang Yi, Jing Lin, Yanfen Wang, Ju Zhou, Qiang Zhou
PURPOSE: Genetic variants in cytochrome P450 (CYP), platelet membrane receptor (P2Y12, P2Y1), and glycoprotein IIIa (GPIIIa) genes are associated with the efficacy of clopidogrel and adverse clinical events on ischemic stroke (IS) patients. However, few studies have assessed whether gene-gene interactions among these genes influence the risk of IS. The aim of the present study was to investigate the association of fifteen variants with IS and to determine whether these gene-gene interactions increase the risk of IS...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050276/a-new-donors-cyp3a5-and-recipients-cyp3a4-cluster-predicting-tacrolimus-disposition-and-new-onset-hypertension-in-chinese-liver-transplant-patients
#15
Yuan Liu, Tao Zhang, Xiaoqing Zhang, Ling Ye, Haitao Gu, Lin Zhong, Hongcheng Sun, Chenlong Song, Zhihai Peng, Junwei Fan
AIM: The purpose of the current study was to investigate individualized therapy of tacrolimus (Tac), as well as complications after liver transplantation (LT) with the known genetic determinants and clinical factors. METHODS: In this retrospective study, two cohorts (n=170) from the China Liver Transplant Registry (CLTR) database from July 2007 to March 2015 were included. RESULTS: Both donors' CYP3A5*3 and recipients' CYP3A4*1G had a correlation with Tac pharmacokinetics at four weeks (all P<0...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29043584/determination-of-the-human-cytochrome-p450-monooxygenase-catalyzing-the-enantioselective-oxidation-of-2-2-3-5-6-pentachlorobiphenyl-pcb-95-and-2-2-3-4-4-5-6-heptachlorobiphenyl-pcb-183
#16
Haruna Nagayoshi, Kensaku Kakimoto, Yoshimasa Konishi, Keiji Kajimura, Takeshi Nakano
2,2',3,5',6-Pentachlorobiphenyl (PCB 95) and 2,2',3,4,4',5',6-heptachlorobiphenyl (PCB 183) possess axial chirality and form the aS and aR enantiomers. The enantiomers of these congeners have been reported to accumulate in the human body enantioselectively via unknown mechanisms. In this study, we determined the cytochrome P450 (CYP) monooxygenase responsible for the enantioselective oxidization of PCB 95 and PCB 183, using a recombinant human CYP monooxygenase. We evaluated 13 CYP monooxygenases, namely CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, CYP3A4, CYP3A5, CYP4F2, and aromatase (CYP19), and revealed that CYP2A6 preferably oxidizes aS-PCB 95 enantioselectively; however, it did not oxidize PCB 183...
October 17, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/29043387/cyp3a-genotypes-of-donors-but-not-those-of-the-patients-increase-the-risk-of-acute-rejection-in-renal-transplant-recipients-on-calcineurin-inhibitors-a-pilot-study
#17
Guillermo Gervasini, Guadalupe García-Pino, Esther Vergara, Sonia Mota-Zamorano, Montserrat García-Cerrada, Enrique Luna
PURPOSE: We aimed to determine whether polymorphisms in CYP3A genes may affect the risk of acute rejection episodes (ARE) in renal transplant recipients treated with calcineurin inhibitors (CNIs). METHODS: One hundred and thirty seven patients and their respective donors were screened, by RT-PCR techniques, for three polymorphisms previously related with CNI pharmacokinetics and pharmacodynamics (CYP3A4*1B, CYP3A4*22 and CYP3A5*3). Genotypes of donors and recipients were associated by logistic regression models with ARE risk and exposure to CNIs...
October 18, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29022838/pharmacogenomics-of-triazole-antifungal-agents-implications-for-safety-tolerability-and-efficacy
#18
REVIEW
Jarrett R Amsden, Paul O Gubbins
Triazole antifungal agents are prescribed to treat invasive fungal infections in neutropenic and non-neutropenic patients. These antifungal agents are substrates and inhibitors of cytochrome P450 (CYP). Genetic polymorphisms in CYP2C9, CYP2C19 and CYP3A5 can lead to large population-specific variations in drug efficacy and safety, optimal dosing, or contribute to drug interactions associated with this class. Areas covered: This manuscript reviews the pharmacogenomics (i.e. the influence of genetics on drug disposition) of triazole antifungal agents related to their CYP-mediated metabolism and summarizes their implications on triazole efficacy, safety, and tolerability...
November 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28986606/effect-of-breviscapine-on-cyp3a-metabolic-activity-in-healthy-volunteers
#19
Xuan Zhou, Yang-Yang Gao, Jian-Yong Hu, Yu Dong, Hai-Zhu Zhang, Yong Lai
OBJECTIVE: The purpose of this study was to investigate the influence of breviscapine on the pharmacokinetics of concomitantly administered midazolam (MID) and its associations with and effects on genetic polymorphism of the gene encoding cytochrome P450 3A5 (CYP3A5) in healthy volunteers. METHODS: The study group comprised 17 healthy volunteers who had been genotyped for CYP3A5*3 prior to start of the study. These volunteers were given daily doses of 120 mg (40 mg, three times a day) of breviscapine or a placebo for 14 days, followed by 7...
October 6, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28976882/genetic-polymorphisms-of-cyp2c9-cyp2c19-and-cyp3a5-in-kosovar-population
#20
Valon Krasniqi, Aleksandar Dimovski, Hasime Qorraj Bytyqi, Aleksandar Eftimov, Livija Šimičević, Nada Božina
Cytochrome P450 genetic polymorphisms are responsible for individual variations in drug metabolism and drug-drug interactions. They are very important for pharmacogenetics, and their frequency varies across different populations. There is a big gap in the knowledge about the CYP gene family polymorphisms in the population of Kosovo, and the aim of our study was to fill that gap by determining the frequency of the most important variant alleles of CYP2C9, CYP2C19, and CYP3A5 in 234 nonrelated Kosovars. The allele frequencies of CYP2C9*2 and 2C9*3 were 17...
September 26, 2017: Arhiv za Higijenu Rada i Toksikologiju
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