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RISS 인기검색어
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- 저자 : Flockhart, David A. (검색결과 3 건)
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<i>CYP2D6</i> Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations
Province, M A,Goetz, M P,Brauch, H,Flockhart, D A,Hebert, J M,Whaley, R,Suman, V J,Schroth, W,Winter, S,Zembutsu, H,Mushiroda, T,Newman, W G,Lee, M-T M,Ambrosone, C B,Beckmann, M W,Choi, J-Y,Dieudonn& C. V. Mosby 2014 Clinical Pharmacology & Therapeutics Vol. No.
<P>The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (<I>CYP2D6</I>) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor–positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease–free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; <I>P</I> = 0.009). However, <I>CYP2D6</I> status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, <I>n</I> = 2,443; <I>P</I> = 0.25) or when no exclusions were applied (criterion 3, <I>n</I> = 4,935; <I>P</I> = 0.38). Although <I>CYP2D6</I> is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined <I>a priori</I>), prospective studies are necessary to fully establish the value of <I>CYP2D6</I> genotyping in tamoxifen therapy.</P>
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Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers
Cho, D.Y.,Shen, J.H.Q.,Lemler, S.M.,Skaar, T.C.,Li, L.,Blievernicht, J.,Zanger, U.M.,Kim, K.B.,Shin, J.G.,Flockhart, D.A.,Desta, Z. 日本藥物動態學會 2016 DRUG METABOLISM AND PHARMACOKINETICS Vol.31 No.2
The effect of rifampin on the in vivo metabolism of the antiretroviral drug efavirenz was evaluated in healthy volunteers. In a cross-over placebo control trial, healthy subjects (n = 20) were administered a single 600 mg oral dose of efavirenz after pretreatment with placebo or rifampin (600 mg/day for 10 days). Plasma and urine concentrations of efavirenz, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz were measured by LC-MS/MS. Compared to placebo treatment, rifampin increased the oral clearance (by ~2.5-fold) and decreased maximum plasma concentration (C<SUB>max</SUB>) and area under the plasma concentration-time curve (AUC<SUB>0-~</SUB>) of efavirenz (by ~1.6- and ~2.5-fold respectively) (p < 0.001). Rifampin treatment substantially increased the C<SUB>max</SUB> and AUC<SUB>0-12h</SUB> of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz, metabolic ratio (AUC<SUB>0-72h</SUB> of metabolites to AUC<SUB>0-72h</SUB> efavirenz) and the amount of metabolites excreted in urine (Ae<SUB>0-12hr</SUB>) (all, p < 0.01). Female subjects had longer elimination half-life (1.6-2.2-fold) and larger weight-adjusted distribution volume (1.6-1.9-fold) of efavirenz than male subjects (p < 0.05) in placebo and rifampin treated groups respectively. In conclusion, rifampin enhances CYP2B6-mediated efavirenz 8-hydroxylation in vivo. The metabolism of a single oral dose of efavirenz may be a suitable in vivo marker of CYP2B6 activity to evaluate induction drug interactions involving this enzyme.
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Jiang, Fen,Desta, Zeruesenay,Shon, Ji‐,Hong,Yeo, Chang‐,Woo,Kim, Ho‐,Sook,Liu, Kwang‐,Hyeon,Bae, Soo‐,Kyung,Lee, Sang‐,Seop,Flockhart, David A.,Shin, Jae‐,Goo Blackwell Publishing Ltd 2013 British journal of clinical pharmacology Vol.75 No.1
<P><B>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT</B></P><P>• Cytochrome P450 (CYP) 2B6 is the enzyme primarily responsible for the metabolism of many clinically important drugs, including efavirenz, which it converts to 8‐hydroxyefavirenz and then to 8,14‐hydroxyefavirenz.</P><P>• The CYP2B6*6 polymorphism influences efavirenz pharmacokinetics, but a validated phenotyping method for predicting CYP2B6 activity in human subjects is not yet available.</P><P>• The disposition of 8,14‐dihydroxyefavirenz in humans <I>in vivo</I> is unknown.</P><P><B>WHAT THIS STUDY ADDS</B></P><P>• This study is the first quantitative examination of 8,14‐dihydroxyefavirenz pharmacokinetics in human subjects.</P><P>• The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio correlates with efavirenz oral clearance and is sensitive and specific to CYP2B6 activity alterations.</P><P>• The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio may be a useful phenotyping index for CYP2B6 activity <I>in vivo</I>.</P><P><B>AIMS</B> To evaluate the effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites in relation to the <I>CYP2B6</I>*<I>6</I> genotype and explore potential phenotyping indices for CYP2B6 activity <I>in vivo</I> using a low dose of oral efavirenz.</P><P><B>METHODS</B> We conducted a randomized three phase crossover study in 17 healthy Korean subjects pre‐genotyped for the <I>CYP2B6</I>*<I>6</I> allele (<I>CYP2B6</I>*<I>1</I>/*<I>1</I>, <I>n</I>= 6; *<I>1</I>/*<I>6</I>, <I>n</I>= 6; *<I>6</I>/*<I>6</I>, <I>n</I>= 5). Subjects were pretreated with clopidogrel (75 mg day<SUP>−1</SUP> for 4 days), itraconazole (200 mg day<SUP>−1</SUP> for 6 days), or placebo and then given a single dose of efavirenz (200 mg). The plasma (0–120 h) and urine (0–24 h) concentrations of efavirenz and its metabolites (7‐ and 8‐hydroxyefavirenz and 8,14‐dihydroxyefavirenz) were determined by LC/MS/MS.</P><P><B>RESULTS</B> This study is the first to delineate quantitatively the full (phase I and II) metabolic profile of efavirenz and its three hydroxyl metabolites in humans. Clopidogrel pretreatment markedly decreased AUC(0,48 h), <I>C</I><SUB>max</SUB> and Ae(0,24 h) for 8,14‐dihydroxyefavirenz, compared with placebo; 95% CI of the ratios were 0.55, 0.73, 0.30, 0.45 and 0.25, 0.47, respectively. The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio was significantly correlated with the weight‐adjusted CL/<I>F</I> of efavirenz (<I>r</I><SUP>2</SUP>≈ 0.4, <I>P</I> < 0.05), differed with <I>CYP2B6</I>*<I>6</I> genotype and was affected by clopidogrel pretreatment (<I>P</I> < 0.05) but not by itraconazole pretreatment.</P><P><B>CONCLUSIONS</B> The disposition of 8,14‐dihydroxy‐EFV appears to be sensitive to CYP2B6 activity alterations in human subjects. The 8,14‐dihydroxyefaviremz : efavirenz AUC(0,120 h) ratio is attractive as a candidate phenotyping index for CYP2B6 activity <I>in vivo</I>.</P>
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