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https://www.readbyqxmd.com/read/27904432/corrections-of-frequencies-of-cytochrome-p450-2b6-and-2c8-allelic-variants-in-the-mozambican-population
#1
COMMENT
Mostafa Saadat
No abstract text is available yet for this article.
September 2016: Malaysian Journal of Medical Sciences: MJMS
https://www.readbyqxmd.com/read/27860311/single-heteroatom-substitutions-in-the-efavirenz-oxazinone-ring-impact-metabolism-by-cyp2b6
#2
Philip M Cox, Namandjé N Bumpus
Previously, we observed that the oxazinone ring is important for cytochrome P450 2B6 (CYP2B6) activity toward efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one), a CYP2B6 substrate used to treat HIV. To further understand the structural characteristics of efavirenz that render it a CYP2B6 substrate, we tested the importance of each heteroatom of the oxazinone ring. We assembled a panel of five analogues: 6-chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-2-methyl-4-(trifluoromethyl)-2H-3,1-benzoxazine (1), (4S)-6-chloro-4-[(1E)-2-cyclopropylethenyl]-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (2), (4S)-6-chloro-4-(2-cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (3), 6-chloro-4-(cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinolinone (4), and 6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]dioxin-2-one (5)...
November 10, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27853934/evaluation-of-in-vitro-cytochrome-p450-inhibition-and-in-vitro-fate-of-structurally-diverse-n-oxide-metabolites-case-studies-with-clozapine-levofloxacin-roflumilast-voriconazole-and-zopiclone
#3
Poonam Giri, Sneha Naidu, Nirmal Patel, Harilal Patel, Nuggehally R Srinivas
BACKGROUND AND OBJECTIVES: The role of metabolite(s) to elicit potential clinical drug-drug interaction (DDI) via cytochrome P450 enzymes (CYP) is gaining momentum. In this context, the role of N-oxides for in vitro CYP inhibition has not been evaluated. The objectives of this study were: (a) to examine in vitro CYP inhibition of N-oxides of clozapine, levofloxacin, roflumilast, voriconazole and zopiclone in a tiered approach and (b) evaluate in vitro fate of aforementioned N-oxides examined in recombinant CYPs, human microsomes and hepatocytes...
November 16, 2016: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27842484/strong-induction-of-cytochrome-p450-1a-3a-but-not-p450-2b-in-cultured-hepatocytes-from-common-marmosets-and-cynomolgus-monkeys-by-typical-human-p450-inducing-agents
#4
Shotaro Uehara, Yasuhiro Uno, Takako Suzuki, Takashi Inoue, Masahiro Utoh, Erika Sasaki, Hiroshi Yamazaki
BACKGROUND: Common marmosets (Callithrix jacchus) and cynomolgus monkeys (Macaca fascicularis) are used as non-human primate models in preclinical studies for drug development. OBJECTIVE: The assessment of P450 induction in hepatocytes from marmosets and cynomolgus monkeys was performed using typical P450 inducers. METHODS: Induction of cytochrome P450 1-4 family enzymes was analyzed in two lots of cultured hepatocytes from common marmosets and cynomolgus monkeys after 24-h treatment with typical human P450 inducing agents by real-time reverse transcription-polymerase chain reaction...
November 14, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27779789/role-of-cytochrome-p450-2b6-pharmacogenomics-in-determining-efavirenz-mediated-central-nervous-system-toxicity-treatment-outcomes-and-dosage-adjustments-in-patients-with-human-immunodeficiency-virus-infection
#5
Teresa T Vo, Sheeba Varghese Gupta
For treatment-naïve patients with human immunodeficiency virus infection, efavirenz (EFV) together with tenofovir and emtricitabine were once widely prescribed given its efficacy and ease of administration in a combination pill. However, the high rate of central nervous system toxicities from EFV prompted the United States Department of Health and Human Services to move the EFV-based regimen from the recommended to the alternative category. For patients who do meet the criteria for newer recommended antiretroviral treatments, EFV is a viable option and is often the mainstay of treatment outside the United States, as newer antiretroviral treatments are more expensive...
October 25, 2016: Pharmacotherapy
https://www.readbyqxmd.com/read/27766562/a-physiologically-based-pharmacokinetic-model-to-predict-human-fetal-exposure-for-a-drug-metabolized-by-several-cyp450-pathways
#6
Maïlys De Sousa Mendes, Gabrielle Lui, Yi Zheng, Claire Pressiat, Deborah Hirt, Elodie Valade, Naïm Bouazza, Frantz Foissac, Stephane Blanche, Jean-Marc Treluyer, Saik Urien, Sihem Benaboud
BACKGROUND: Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful. METHODS: A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK)...
October 21, 2016: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/27758707/new-psychoactive-substances-3-methoxyphencyclidine-3-meo-pcp-and-3-methoxyrolicyclidine-3-meo-pcpy-metabolic-fate-elucidated-with-rat-urine-and-human-liver-preparations-and-their-detectability-in-urine-by-gc-ms-lc-high-resolution-msn-and-lc-high-resolution
#7
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
https://www.readbyqxmd.com/read/27749294/a-case-of-delayed-emergence-after-propofol-anesthesia-genetic-analysis
#8
Hiroshi Yonekura, Norie Murayama, Hiroshi Yamazaki, Kazuya Sobue
This case report describes a 71-year-old woman who experienced unusual delayed emergence from propofol, which lasted for 3 hours and resulted in admission to the intensive care unit. Because genetic variations of propofol-metabolizing enzymes are proposed to be causal factors, we explored genetic polymorphisms of cytochrome P450 2B6 (CYP2B6) and uridine 5'-diphospho-glucuronosyltransferase 1A9 (UGT1A9). Suggested high-risk factors (advanced age, CYP2B6 516 G/T, and UGT1A9 I399 C/C) were observed in this case of delayed propofol metabolism...
December 1, 2016: A & A Case Reports
https://www.readbyqxmd.com/read/27636207/a-case-of-3-4-dimethoxyamphetamine-3-4-dma-and-3-4-methylenedioxymethamphetamine-mdma-toxicity-with-possible-metabolic-interaction
#9
Michael A Darracq, Stephen L Thornton, Alicia B Minns, Roy R Gerona
: We present a case of "ecstasy" ingestion revealing 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-dimethoxyamphetamine (3,4-DMA) and absence of cytochrome P450 (CYP)-2D6 MDMA metabolites. CASE REPORT: A 19-year-old presented following a seizure. Initial vital signs were normal. Laboratories were normal with the exception of sodium 127 mEq/L and urine drugs of abuse screen positive for amphetamines. Twelve hours later, serum sodium was 114 mEq/L and a second seizure occurred...
November 2016: Journal of Psychoactive Drugs
https://www.readbyqxmd.com/read/27625140/roles-of-human-cyp2a6-and-monkey-cyp2a24-and-2a26-cytochrome-p450-enzymes-in-the-oxidation-of-2-5-2-5-tetrachlorobiphenyl
#10
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
https://www.readbyqxmd.com/read/27616666/gene-expression-study-of-phase-i-and-ii-metabolizing-enzymes-in-rptec-tert1-cell-line-application-in-in-vitro-nephrotoxicity-prediction
#11
Heta Shah, Manish Patel, Neeta Shrivastava
1. The phase I and II metabolizing enzymes of kidneys play an important role in the metabolism of xenobiotic as well as endogenous compounds and proximal tubules of kidney constitute high concentration of these metabolizing enzymes compared with the other parts. 2. It has been shown previously that differential enzyme expression among human and rodent/non-rodent species can be a roadblock in drug discovery and development process. Currently, proximal tubule cell lines of human origin such as RPTEC/TERT1 and HK-2 are used to understand the pathophysiology of kidney diseases, therapeutic efficacy of drugs, and nephrotoxicity of compounds...
October 3, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27600044/inhibition-of-cyp2b6-activity-by-voriconazole-profiled-using-efavirenz-disposition-in-healthy-volunteers
#12
Zeruesenay Desta, Ingrid F Metzger, Nancy Thong, Jessica B L Lu, John T Callaghan, Todd C Skaar, David A Flockhart, Raymond E Galinsky
Cytochrome P450 (CYP) 2B6 metabolizes clinically important drugs and other compounds. Its expression and activity varies widely among individuals, but quantitative estimation is hampered by the lack of safe and selective in vivo probe of CYP2B6 activity. Efavirenz, a non-nucleoside HIV-1 reverse transcriptase inhibitor, is mainly cleared by CYP2B6, an enzyme strongly inhibited in vitro by voriconazole. To test efavirenz metabolism as an in vivo probe of CYP2B6 activity, we quantified the inhibition of CYP2B6 activity by voriconazole in sixty-one healthy volunteers administered a single 100 mg oral dose of efavirenz with and without voriconazole administration...
September 6, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27538916/roles-of-residues-f206-and-v367-in-human-cyp2b6-effects-of-mutations-on-androgen-hydroxylation-mechanism-based-inactivation-and-reversible-inhibition
#13
Hsia-Lien Lin, Haoming Zhang, Cesar Kenaan, Paul F Hollenberg
The crystal structures of human CYP2B6 indicate that Phe206 and Val367 are in close proximity to the substrate binding site and suggest that both residues may play important roles in substrate metabolism and inhibitor binding. To test this hypothesis, we investigated the effects of mutating these residues to Ala on the regiospecificity of CYP2B6 for the metabolism of testosterone and androstenedione. For testosterone metabolism, 16β-OH-testosterone formation by the F206A mutant was <5% of the wild type (WT), whereas the V367A mutant exhibited a doubling of 16α-OH-testosterone formation with a 50% decrease in 16β-OH-testosterone formation compared with the WT...
November 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27457783/bioactivation-of-trimethoprim-to-protein-reactive-metabolites-in-human-liver-microsomes
#14
Jennifer L Goldman, Yakov M Koen, Steven A Rogers, Kelin Li, James S Leeder, Robert P Hanzlik
The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP)-sulfamethoxazole (SMX) is a combination antibiotic that commonly causes IADRs. Recent data suggest that the contribution of the TMP component of TMP-SMX to IADRs may be underappreciated. We previously demonstrated that TMP is bioactivated to chemically reactive intermediates that can be trapped in vitro by N-acetyl cysteine (NAC), and we have detected TMP-NAC adducts (i...
October 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27449528/the-uremic-toxin-indoxyl-3-sulfate-induces-cyp1a2-in-primary-human-hepatocytes
#15
Rangaraj Narayanan, Lisa Liu, Matthew Hoffmann, Sekhar Surapaneni
: Chronic kidney disease (CKD) generally impacts clearance of renally eliminated drugs but growing evidence shows that it can influence clearance of hepatically eliminated drugs and a complete mechanistic understanding of this phenomenon is still lacking. CKD leads to accumulation of uremic toxins, including indoxyl-3-sulfate (3-INDS) and indole-3-acetic acid (3-IAA). OBJECTIVE: In this study, we evaluated the potential of 3-INDS and 3-IAA (10, 30 and 100 μM) to induce liver cytochrome P450 (CYP) enzymes CYP1A2, 2B6 and 3A4/5 using cultured primary human hepatocytes following once daily treatment for 3 days...
July 19, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27449409/the-uremic-toxin-indoxyl-3-sulfate-induces-cyp1a2-in-primary-human-hepatocytes
#16
Rangaraj Narayanan, Lisa Liu, Matthew Hoffmann, Sekhar Surapaneni
: Chronic kidney disease (CKD) generally impacts clearance of renally eliminated drugs but growing evidence shows that it can influence clearance of hepatically eliminated drugs and a complete mechanistic understanding of this phenomenon is still lacking. CKD leads to accumulation of uremic toxins, including indoxyl-3-sulfate (3-INDS) and indole-3-acetic acid (3-IAA). OBJECTIVE: In this study, we evaluated the potential of 3-INDS and 3-IAA (10, 30 and 100 μM) to induce liver cytochrome P450 (CYP) enzymes CYP1A2, 2B6 and 3A4/5 using cultured primary human hepatocytes following once daily treatment for 3 days...
July 19, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27439448/the-p450-oxidoreductase-por-rs2868177-and-cytochrome-p450-cyp-2b6-6-polymorphisms-contribute-to-the-interindividual-variability-in-human-cyp2b6-activity
#17
Li-Chen Gao, Fang-Qun Liu, Li Yang, Lin Cheng, Hai-Ying Dai, Ran Tao, Shi-Peng Cao, Di Wang, Jie Tang
AIM: To investigate whether single-nucleotide polymorphisms (SNPs) in the P450 oxidoreductase (POR) gene were correlated with interindividual variations in cytochrome P450 (CYP) 2B6 activity. METHODS: Thirty-six healthy volunteers who tested CYP2B6 and POR polymorphisms were enrolled in the study. CYP2B6 activity was measured by bupropion hydroxylation with LC/MS/MS. The ratio of hydroxybupropion versus bupropion (AUC_hyd/AUC_bup) in terms of area under the time-concentration curve (AUC) was used to represent the CYP2B6 activity...
October 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27437087/inhibition-of-cytochrome-p450-by-propolis-in-human-liver-microsomes
#18
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
https://www.readbyqxmd.com/read/27435752/towards-a-best-practice-approach-in-pbpk-modeling-case-example-of-developing-a-unified-efavirenz-model-accounting-for-induction-of-cyps-3a4-and-2b6
#19
A Ke, Z Barter, K Rowland-Yeo, L Almond
In this study, we present efavirenz physiologically based pharmacokinetic (PBPK) model development as an example of our best practice approach that uses a stepwise approach to verify the different components of the model. First, a PBPK model for efavirenz incorporating in vitro and clinical pharmacokinetic (PK) data was developed to predict exposure following multiple dosing (600 mg q.d.). Alfentanil i.v. and p.o. drug-drug interaction (DDI) studies were utilized to evaluate and refine the CYP3A4 induction component in the liver and gut...
July 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27417918/in-vivo-individual-variations-in-pharmacokinetics-of-efavirenz-in-cynomolgus-monkeys-genotyped-for-cytochrome-p450-2c9
#20
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
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