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Shon, Ji-Hong,Yoon, Young-Ran,Kim, Min-Jung,Kim, Kyoung-Ah,Lim, Young-Chae,Liu, Kwang-Hyeon,Shin, Dong-Hoon,Lee, Chung Han,Cha, In-June,Shin, Jae-Gook Blackwell Science Ltd 2005 British journal of clinical pharmacology Vol.59 No.5
<P>Aims</P><P>We evaluated the involvement of cytochrome P450 (CYP) isoforms 2C9 and 2C19 in chlorpropamide 2-hydroxylation <I>in vitro</I> and in chlorpropamide disposition <I>in vivo</I>.</P><P>Methods</P><P>To identify CYP isoforms(s) that catalyse 2-hydroxylation of chlorpropamide, the incubation studies were conducted using human liver microsomes and recombinant CYP isoforms. To evaluate whether genetic polymorphisms of CYP2C9 and/or CYP2C19 influence the disposition of chlorpropamide, a single oral dose of 250 mg chlorpropamide was administered to 21 healthy subjects pregenotyped for CYP2C9 and CYP2C19.</P><P>Results</P><P>In human liver microsomal incubation studies, the formation of 2-hydroxychlorpropamide (2-OH-chlorpropamide), a major chlorpropamide metabolite in human, has been best described by a one-enzyme model with estimated <I>K</I><SUB><I>m</I></SUB> and <I>V</I><SUB>max</SUB> of 121.7 ± 19.9 µ<SMALL>M</SMALL> and 16.1 ± 5.0 pmol min<SUP>−1</SUP> mg<SUP>−1</SUP> protein, respectively. In incubation studies using human recombinant CYP isoforms, however, 2-OH-chlorpropamide was formed by both CYP2C9 and CYP2C19 with similar intrinsic clearances (CYP2C9 <I>vs.</I> CYP2C19: 0.26 <I>vs.</I> 0.22 µl min<SUP>−1</SUP> nmol<SUP>−1</SUP> protein). Formation of 2-OH-chlorpropamide in human liver microsomes was significantly inhibited by sulfaphenazole, but not by <I>S</I>-mephenytoin, ketoconazole, quinidine, or furafylline. In <I>in vivo</I> clinical trials, eight subjects with the <I>CYP2C9</I>*<I>1/</I>*<I>3</I> genotype exhibited significantly lower nonrenal clearance [*<I>1/</I>*<I>3 vs.</I>*<I>1/</I>*<I>1</I>: 1.8 ± 0.2 <I>vs.</I> 2.4 ± 0.1 ml h<SUP>−1</SUP> kg<SUP>−1</SUP>, <I>P</I> < 0.05; 95% confidence interval (CI) on the difference 0.2, 1.0] and higher metabolic ratios (of chlorpropamide/2-OH-chlorpropamide in urine: *<I>1/</I>*<I>3 vs.</I>*<I>1/</I>*<I>1</I>: 1.01 ± 0.19 <I>vs.</I> 0.56 ± 0.08, <I>P</I> < 0.05; 95% CI on the difference − 0.9, − 0.1) than did 13 subjects with <I>CYP2C9</I>*<I>1/</I>*<I>1</I> genotype. In contrast, no differences in chlorpropamide pharmacokinetics were observed for subjects with the <I>CYP2C19</I> extensive metabolizer <I>vs.</I> poor metabolizer genotypes.</P><P>Conclusions</P><P>These results suggest that chlorpropamide disposition is principally determined by CYP2C9 activity <I>in vivo</I>, although both CYP2C9 and CYP2C19 have a catalysing activity of chlorpropamide 2-hydroxylation pathway.</P>
Shon, Ji-Hong,Ku, Hei-Young,Bae, Seol-Youn,Oh, Min-Kyung,Yeo, Chang-Woo,Bae, Soo-Kyung,Shin, Jae-Gook Lippincott Williams Wilkins, Inc. 2011 Pharmacogenetics and genomics Vol.21 No.12
OBJECTIVES: This study was conducted to compare the effect of CYP3A5*3 genotype on the disposition of three phosphodiesterase type 5 inhibitors (PDE5Is), vardenafil, sildenafil, and udenafil, because our previous in-vitro microsomal incubation study showed that the relative contribution of CYP3A5 enzyme to their metabolism was different among these PDE5Is. METHODS: An open-label three-way crossover study was performed with a single oral dose of PDE5Is (20 mg vardenafil, 100 mg sildenafil, or 200 mg udenafil) in 21 healthy men carrying CYP3A5*1/*1, *1/*3, or *3/*3. After each dose, plasma concentrations of the parents and their major metabolites were measured up to 24 or 48 h. RESULTS: The AUC∞ and Cmax of vardenafil were 2.9-fold and 3.1-fold higher in CYP3A5*3/*3 carriers than in individuals with CYP3A5*1/*1 (P=0.003 and 0.002, respectively). The AUC∞ and Cmax of sildenafil were 1.5-fold and 1.7-fold higher in CYP3A5*3/*3 carriers compared with individuals with CYP3A5*1/*1, but the statistical difference of both parameters among genotype groups was not observed. The disposition of udenafil differed little among groups in relation to the CYP3A5*3 allelic variant. CONCLUSION: These results suggest that the disposition of these PDE5Is are differently influenced by the CYP3A5*3 genotype of individual participants. The CYP3A5*3 genotype affects the oral disposition of vardenafil significantly. The pharmacokinetic diversity of PDE5Is in relation to CYP3A5 genotype may lead to the clinical response variation and remains to be evaluated.
Current Status of the Spent Filter Waste and Consideration of Its Treatment Method in KAERI
Young-Yong Ji,Dae-Seok Hong,Il-Sik Kang,Jong-Sik Shon 한국방사성폐기물학회 2007 방사성폐기물학회지 Vol.5 No.3
한국원자력연구원 방사성폐기물 저장시설에는 2006년 기준으로 약 1,000 여개(200L 환산)의 폐필터가 저장중이며, 그 발생량은 계속 증가하는 추세에 있다. 현재 저장시설의 저장 공간 확보뿐만 아니라 폐필터의 효율적인 관리를 위하여 비닐 백에 넣어 저장 및 관리되고 있는 폐필터들을 적절한 압축 처리 과정을 거쳐 최종적으로 규격화된 드럼에 포장하려는 계획을 가지고 있다. 이를 위해, 먼저 과거 발생이력을 조사함으로서 저장중인 폐필터들의 분류를 통한 그룹화를 수행하였다. 또한 드럼포장을 위해서는 사전에 핵종평가가 수행되어야 하며, 그 방법으로는 폐필터의 해체 없이 표면선량률을 측정하여 대표시료를 채취하며, 이 시료에 대하여 방사성폐기물 인도규정에서 요구하는 수준의 핵종분석을 수행할 것이다. 그리고 드럼포장을 위해, 방사성폐기물 처리시설에서 개발된 폐필터 처리장치를 이용하여 직육면체 형의 폐필터를 원주형 성형을 함으로서 드럼에 넣은 후, 최종적으로 수직 압축함으로써 폐필터를 처리하고자 한다. Spent filter wastes of about 1,000 units (200 L) have been stored in the waste storage facility of the Korea Atomic Energy Research Institute since its operation. At the moment, to secure space in a waste storage facility as well as to efficiently manage spent filter wastes, it is necessary to conduct a compaction treatment of these spent filters, and finally, to repack the compacted spent filters into a 200 liter drum. To do that, the spent filter wastes were first classified according to their generation facilities, their generation date and their surface dose rate by investigating the inventory of the spent filters. In order to repack a compacted spent filter in a 200 liter drum, it is first necessary to conduct a radionuclide assessment of a spent filter before compacting it. Therefore, after taking a representative sample from a spent filter without a dismantlement, the nuclide analysis for it will be conducted. And then, after putting a spent filter into a regular drum by conducting the columnar shaping of the hexahedral form of a spent filter, the compaction treatment of the shaped spent filter will be conducted by vertically compacting it.
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>