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https://www.readbyqxmd.com/read/28211700/from-genotype-to-phenotype-cytochrome-p450-2d6-mediated-drug-clearance-in-humans
#1
Jie Gao, Xin Tian, Jun Zhou, Ming-Zhu Cui, Hai-Feng Zhang, Na Gao, Qiang Wen, Hai-Ling Qiao
How genotypic variation results in phenotypic differences is still a challenge for biology. In the field of drug metabolism the means by which specific cytochrome P4502D6 (CYP2D6) genotypes yield different phenotypes at various levels (molecular, cellular, and organismal) is an important question, as differences in CYP2D6 activity can contribute to adverse drug reactions. Herein, the genotype of CYP2D6 was determined along with the absolute content of CYP2D6 and microsomal protein per gram of liver in human liver microsomes, the molecular, cellular (microsomal, tissue, organ), and organismal phenotype of CYP2D6 determined; the effect of genotype on each phenotype of CYP2D6-mediated dextromethorphan clearance (CL) was delineated, and the overall genotype-phenotype relationship for CYP2D6 was charted...
February 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28209351/an-indirect-stereoselective-analysis-of-nebivolol-glucuronides-in-plasma-by-lc-ms-ms-application-to-clinical-pharmacokinetics
#2
Carolina Pinto Vieira, Daniel Valente Neves, Evandro José Cesarino, Adriana Rocha, Séverine Poirier, Vera Lucia Lanchote
Nebivolol is a racemate of the d-isomer responsible for β1 adrenergic receptor antagonism and the l-isomer responsible for the release of nitric oxide from endothelial cells. Nebivolol is mainly metabolized to nebivolol glucuronide, which also contribute to the nebivolol β1 adrenoreceptor antagonism. This study reports the development and validation of an indirect stereoselective method of analysis of nebivolol glucuronides in plasma by LC-MS/MS. The method was applied to the investigation of stereoselectivity in the glucuronidation of nebivolol in elderly hypertensive patients (n=11) CYP2D6 phenotyped as EM and treated with a single oral dose of the racemate...
February 3, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28199000/overexpression-of-pregnane-x-and-glucocorticoid-receptors-and-the-regulation-of-cytochrome-p450-in-human-epileptic-brain-endothelial-cells
#3
Chaitali Ghosh, Mohammed Hossain, Jesal Solanki, Imad M Najm, Nicola Marchi, Damir Janigro
OBJECTIVE: Recent evidence suggests a metabolic contribution of cytochrome P450 enzymes (CYPs) to the drug-resistant phenotype in human epilepsy. However, the upstream molecular regulators of CYP in the epileptic brain remain understudied. We therefore investigated the expression and function of pregnane xenobiotic (PXR) and glucocorticoid (GR) nuclear receptors in endothelial cells established from post-epilepsy surgery brain samples. METHODS: PXR/GR localization was evaluated by immunohistochemistry in specimens from subjects who underwent temporal lobe resections to relieve drug-resistant seizures...
February 15, 2017: Epilepsia
https://www.readbyqxmd.com/read/28181117/cyp2d6-genetic-variation-and-beta-blocker-maintenance-dose-in-patients-with-heart-failure
#4
Jasmine A Luzum, Kevin M Sweet, Philip F Binkley, Tara J Schmidlen, Joseph P Jarvis, Michael F Christman, Wolfgang Sadee, Joseph P Kitzmiller
PURPOSE: This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure. METHODS: Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n = 65) or metoprolol (n = 33)...
February 8, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28178648/polymorphisms-of-esr1-ugt1a1-hcn1-map3k1-and-cyp2b6-are-associated-with-the-prognosis-of-hormone-receptor-positive-early-breast-cancer
#5
Sung-Hsin Kuo, Shi-Yi Yang, San-Lin You, Huang-Chun Lien, Ching-Hung Lin, Po-Han Lin, Chiun-Sheng Huang
In this study, we investigated whether single nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) (MAP3K1, FGFR2, TNRC9, HCN1, and 5p12), and SNPs involved in the metabolism of estrogen (CYP19, COMT, ESR1, and UGT1A1), tamoxifen (CYP2C9, CYP2C19, CYP3A5, and CYP2D6), and chemotherapeutic agents (ABCB1, ALDH3A1, and CYP2B6) are associated with the prognoses of 414 hormone receptor (HR)-positive early breast cancers with negative or 1 to 3 nodal metastases. At a median follow-up period of 10...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28170339/genotyping-cyp2d6-by-three-different-methods-advantages-and-disadvantages
#6
Carolina Ribeiro, Patrícia Martins, Manuela Grazina
BACKGROUND: CYP2D6 belongs to P450 superfamily, and is responsible for the metabolism of 25% of the drugs used clinically. Genetic variability of CYP2D6 affects individual drug or toxic response leading to differences in the drug outcome or toxicity mediating adverse drug effects. The different variant alleles are associated with increased, decreased, or abolished enzyme hydroxylation functions. The CYP2D6*10 (rs1065852, c.100C>T) allele is associated with reduced function and is one of the most studied alleles...
February 7, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/28160505/cytochrome-p450-mediated-interaction-between-perazine-and-risperidone-implications-for-antipsychotic-polypharmacy
#7
Michael Paulzen, Ekkehard Haen, Christoph Hiemke, Benedikt Stegmann, Sarah E Lammertz, Gerhard Gründer, Georgios Schoretsanitis
BACKGROUND: Although clinically very widespread, scientific evidence for antipsychotic polypharmacy is still limited. Combining different drugs increases the potential for drug-drug interactions enhancing the risk of adverse drug reactions. We aimed to unravel potential pharmacokinetic interactions between risperidone and perazine. METHODS: A therapeutic drug monitoring database contained plasma concentrations of risperidone (RIS) and its active metabolite (9-OH-RIS)...
February 4, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28155129/drug-interaction-potential-of-osilodrostat-lci699-based-on-its-effect-on-the-pharmacokinetics-of-probe-drugs-of-cytochrome-p450-enzymes-in-healthy-adults
#8
Sara Armani, Lillian Ting, Nicholas Sauter, Christelle Darstein, Anadya Prakash Tripathi, Lai Wang, Bing Zhu, Helen Gu, Dung Yu Chun, Heidi J Einolf, Swarupa Kulkarni
BACKGROUND AND OBJECTIVES: Osilodrostat (LCI699) is an adrenal steroidogenesis inhibitor currently in late-phase clinical development as a potential treatment for Cushing's disease. This study evaluated the inhibitory effect of osilodrostat on the pharmacokinetics of probe substrates of the cytochrome P450 (CYP) enzymes CYP1A2, CYP2C19, CYP2D6, and CYP3A4. METHODS: Healthy adult volunteers received single-dose cocktail probe substrates [caffeine (100 mg), omeprazole (20 mg), dextromethorphan (30 mg), and midazolam (2 mg)] followed by a 6-day washout...
February 2, 2017: Clinical Drug Investigation
https://www.readbyqxmd.com/read/28153841/cholic-acid-feeding-leads-to-increased-cyp2d6-expression-in-cyp2d6-humanized-mice
#9
Xian Pan, Rebecca Kent, Kyoung-Jae Won, Hyunyoung Jeong
Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme, but factors governing transcriptional regulation of its expression remain poorly understood. Based on previous reports of small heterodimer partner (SHP) playing an important role as a transcriptional repressor of CYP2D6 expression, here we investigated how a known upstream regulator of SHP expression, namely cholestasis triggered by cholic acid (CA) feeding in mice, can lead to altered CYP2D6 expression. To this end, CYP2D6-humanized (Tg-CYP2D6) mice were fed with CA-supplemented or control diet for 14 days, and hepatic expression of multiple genes was examined...
February 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28139969/a-meta-analysis-of-the-effect-of-cyp2d6-polymorphism-on-the-pharmacokinetics-and-pharmacodynamics-of-metoprolol%C3%A2
#10
Shuchun Li, Han Lin, WenHuan Sun, YingLi Wang, YouFang Ding, HuanHu Zhao, ShangJian Liu
OBJECTIVE: To conduct a meta-analysis on the effect of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of metoprolol. METHODS: A systematic review and meta-analysis of studies on the effect of CYP2D6 polymorphism on metoprolol pharmacokinetics and pharmacodynamics was performed by using the China national knowledge infrastructure (CNKI), database for Chinese technical periodicals (VIP), Wanfang, and PubMed databases up to the end of January 2015...
January 30, 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28133766/exposure-response-analysis-after-subcutaneous-administration-of-rbp-7000-a-once-a-month-long-acting-atrigel-formulation-of-risperidone
#11
Vijay Ivaturi, Mathangi Gopalakrishnan, Jogarao V S Gobburu, Weiyan Zhang, Yongzhen Liu, Christian Heidbreder, Celine M Laffont
AIM: A new, long-acting, subcutaneous (SC) formulation of risperidone (RBP-7000) has been developed for the treatment of schizophrenia to address issues of non-adherence associated with oral risperidone treatment. The objective of this work was to establish an exposure-response relationship between total active moiety plasma (AM) exposure (risperidone + 9-OH-risperidone) and Positive and Negative Syndrome Scale (PANSS) or Clinical Global Impressions severity (CGI-S) scores using data from a registration trial...
January 30, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28126395/a-pooled-analysis-of-adverse-events-in-393-adults-with-gaucher-disease-type-1-from-four-clinical-trials-of-oral-eliglustat-evaluation-of-frequency-timing-and-duration
#12
M Judith Peterschmitt, Gerald F Cox, Jennifer Ibrahim, James MacDougall, Lisa H Underhill, Palni Patel, Sebastiaan J M Gaemers
Eliglustat, an oral substrate reduction therapy, is a first-line therapy for adults with Gaucher disease type 1 and a compatible CYP2D6 metabolizer phenotype. Clinicians have requested more information about frequency, timing, and duration of adverse events associated with eliglustat. Adverse event data as of January 31, 2013 for all patients who received at least one dose of eliglustat were pooled from four eliglustat clinical trials (393 patients representing 535 patient-years of exposure). The following 10 adverse events noted in the eliglustat US Prescribing Information (USPI) and EU Summary of Product Characteristics (SmPC) were evaluated with regard to frequency, drug-relatedness, severity, seriousness, duration, and timing of onset: headache, arthralgia, diarrhea, nausea, fatigue, flatulence, abdominal pain, upper abdominal pain, back pain, and extremity pain...
January 13, 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28118673/an-appraisal-of-drug-drug-interactions-with-green-tea-camellia-sinensis
#13
Ahmed A Albassam, John S Markowitz
This review summarizes published in vitro, animal, and clinical studies investigating the effects of green tea (Camellia sinensis) extract and associated catechins on drug-metabolizing enzymes and drug transporters. In vitro studies suggest that green tea extract and its main catechin, (-)-epigallocatechin-3-gallate, to varying degrees, inhibit the activity of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. UGT1A1 and UGT1A4 isoforms were also inhibited by (-)-epigallocatechin-3-gallate. Animal studies suggest green tea extract and/or (-)-epigallocatechin-3-gallate significantly increase the bioavailability of diltazem, verapamil, tamoxifen simvastatin, 5-fluorouracil, and nicardipine...
January 24, 2017: Planta Medica
https://www.readbyqxmd.com/read/28114735/effects-of-type-2-diabetes-mellitus-in-patients-on-treatment-with-glibenclamide-and-metformin-on-carvedilol-enantiomers-metabolism
#14
Glauco H B Nardotto, Eduardo B Coelho, Carlos E Paiva, Vera L Lanchote
Carvedilol is available in clinical practice as a racemate in which (S)-(-)-carvedilol is a β- and α1 -adrenergic antagonist and (R)-(+)-carvedilol is only an α1 -adrenergic antagonist. Carvedilol is mainly metabolized by glucuronidation, by CYP2D6 to hydroxyphenylcarvedilol (OHC), and by CYP2C9 to O-desmethylcarvedilol (DMC). This study evaluated the pharmacokinetics of carvedilol enantiomers and their metabolites OHC and DMC in healthy volunteers (n = 13) and in type 2 diabetes mellitus patients with good glycemic control (n = 13)...
January 23, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28111763/cytochrome-p450-reaction-phenotyping-and-inhibition-and-induction-studies-of-pinostrobin-in-human-liver-microsomes-and-hepatocytes
#15
Shengnan Tan, Zhimin Dong, Jiashuo Zhang, Thomas Efferth, Yujie Fu, Xin Hua
Pinostrobin (PI, 5-hydroxy-7-methoxyflavanone) is a natural flavonoid known for its rich pharmacological activities. The objective of this study was to identify the human liver cytochrome P450 (CYP450) isoenzymes involved in the metabolism of PI. A single hydoxylated metabolite was obtained from PI after an incubation with pooled human liver microsomes (HLMs). The relative contributions of different CYP450s were evaluated using CYP450-selective inhibitors in HLMs and recombinant human CYP450 enzymes, and the results revealed the major involvement of CYP1A2, CYP2C9 and CYP2E1 in PI metabolism...
November 7, 2016: Biomedical Chromatography: BMC
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
#16
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/28087463/effect-of-22-cyp2d6-variants-found-in-the-chinese-population-on-tolterodine-metabolism-in%C3%A2-vitro
#17
Hao Wang, Da-Peng Dai, Peng Sun, Li-Ping Xu, Bing-Qing Liang, Jian-Ping Cai, Guo-Xin Hu
Cytochrome P450 2D6 (CYP2D6) is an important member of the cytochrome P450 enzyme superfamily. We recently identified 22 novel variants in the Chinese population using PCR and bidirectional sequencing methods. The aim of this study is to characterize the enzymatic activity of these variants and their effects on the metabolism of the antimuscarinic drug tolterodine in vitro. A baculovirus-mediated expression system was used to express wild-type CYP2D6 and 24 variants (CYP2D6*2, CYP2D6*10, and 22 novel CYP2D6 variants) at high levels...
February 25, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28087064/effect-of-cyp2d6-polymorphisms-on-the-pharmacokinetics-of-propafenone-and-its-two-main-metabolites
#18
Mohammad-Reza Rouini, Minoo Afshar
AIM OF THE STUDY: Propafenone (PPF) is an antiarrhythmic drug, metabolized mainly by CYP2D6 to 5-hydroxypropafenone (5OH-PPF) and by CYP3A4 to norpropafenone (NOR-PPF). CYP2D6 shows a high degree of genetic polymorphism which is associated with diminished antiarrhythmic efficacy or cardiac seizures/cardiotoxicity. This study aimed to investigate the effect of the CYP2D6 polymorphism on the pharmacokinetics of PPF and its two main metabolites. The usefulness of PPF/5OH-PPF ratio for CYP2D6 phenotyping in healthy adults was also evaluated...
December 19, 2016: Thérapie
https://www.readbyqxmd.com/read/28074989/-antidepressants-agents-in-breast-cancer-patients-using-tamoxifen-review-of-basic-and-clinical-evidence
#19
María Elisa Irarrázaval O, Leonardo Gaete G
Tamoxifen (Tmf), is a standard of care for women with estrogen receptor positive (ER+) breast cancer. Endoxifen is a Tmf metabolite generated by cytochrome P450 2D6 (CYP2D6). Antidepressive agents (AD) are often prescribed to women with breast cancer not only for depression, but also for anxiety and hot flashes. Some AD are substrates or inhibitors of the Tmf metabolic pathway. Therefore there may be interactions when Tmf and AD are prescribed simultaneously. Oncologic protection afforded by Tmf may become less effective or null when AD are indicated, especially in poor metabolizing patients...
October 2016: Revista Médica de Chile
https://www.readbyqxmd.com/read/28074333/rosiglitazone-metabolism-in-human-liver-microsomes-using-a-substrate-depletion-method
#20
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
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