Cytochrome P450 2B6 catalyzes the formation of pharmacologically active sibutramine (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) metabolites in human liver microsomes.

Bae, Soo Kyung,Cao, Shan,Seo, Kyung-Ah,Kim, Hyunmi,Kim, Min-Jung,Shon, Ji-Hong,Liu, Kwang-Hyeon,Zhou, Hong-Hao,Shin, Jae-Gook American Society for Pharmacology and Experimental 2008 Drug metabolism and disposition: the biological fa Vol.36 No.8

<P>We identified cytochrome P450 (P450) isozymes that are involved in the formation of two active sibutramine (N-{1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) metabolites, M1 (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine) and M2 (1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine), in humans using a combination chemical inhibition, correlation analyses in human liver microsomes (HLMs), and activity assays using recombinant P450s. Mechanism-based CYP2B6 inhibitors (i.e., clopidogrel, ticlopidine, and triethylenethiophoramide) significantly inhibited the formation of M1 from sibutramine and M2 from M1, respectively; in contrast, no effect was observed when using potent inhibitors of eight P450 isozymes (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A). In addition, the formations of M1 from sibutramine (r = 0.694, p = 0.0029) and M2 from M1 (r = 0.834, p < 0.0001) were strongly correlated with CYP2B6-catalyzed bupropion hydroxylation in 16 different HLM panels. Furthermore, recombinant CYP2B6 catalyzed M1 and/or M2 formation at the highest rate among 10 P450s. Although recombinant CYP2C19, 3A4, and 3A5 also catalyzed, to a less extent, M1 formation at high substrate concentrations (>5 microM), those contributions might be minor considering usual concentrations of sibutramine and M1 in the clinical setting. The kinetics of M1 and/or M2 formation from sibutramine in HLMs were fitted by a two-enzyme model, and the mean apparent K(m) value (4.79 microM) for high-affinity component was similar to that observed in recombinant CYP2B6 (8.02 microM). In conclusion, CYP2B6 is the primary catalyst for the formation of sibutramine two active metabolites, which may suggest that pharmacogenetics and drug interactions of sibutramine in relation to CYP2B6 activity should be considered in the pharmacotherapy of sibutramine.</P>

Poster Presentations : DA - 8159 , a Novel Selective PDE 5 Inhibitor , Induces Penile Erection in Rabbits with Acute Spinal Injury

(Kyung Koo Kang),(Gook Jun Ahn),(Dae Hyun Baek),(Yong Sung Sohn),(Dong Hwan Kim),(Byoung Ok Ahn),(Jong Won Kwon),(Won Bae Kim) 서울시립대학교 산업기술연구소 2002 국제학술SYMPOSIUM논문집 Vol.10 No.1

HPLC determination of irbesartan in human plasma: its application to pharmacokinetic studies

Bae, Soo Kyung,Kim, Min-Jung,Shim, Eon-Jeong,Cho, Doo-Yeoun,Shon, Ji-Hong,Liu, Kwang-Hyeon,Kim, Eun-Young,Shin, Jae-Gook John Wiley Sons, Ltd. 2009 Biomedical chromatography Vol.23 No.6

<P>A simple and rapid HPLC method using fluorescence detection was developed for determination of irbesartan in human plasma. Sample preparation was accomplished through a simple deproteinization procedure with 0.4 mL of acetonitrile containing 800 ng/mL of losartan (internal standard), and to a 0.1 mL plasma sample. Chromatographic separation was performed on a Zorbax Xclipse XDB C<SUB>18</SUB> column (150 × 4.6 mm, i.d., 5 µm) at 40°C. An isocratic mobile phase, acetonitrile:0.1% formic acid (37:63, v/v), was run at a flow-rate of 1.0 mL/min, and the column eluent was monitored using a fluorescence detector set at excitation and emission wavelengths of 250 and 370 nm, respectively. The retention times of irbesartan and losartan were 4.4 and 5.9 min, respectively. This assay was linear over a concentration range of 10–5000 ng/mL with a lower limit of quantification of 10 ng/mL. The coefficient of variation for this assay precision was less than 8.48%, and the accuracy exceeded 94.4%. The mean relative recoveries of irbesartan and losartan were 98.4 and 99.1%, respectively. This method was successfully applied for pharmacokinetic study after oral administration of irbesartan (300 mg) to 23 Korean healthy male volunteers. Copyright © 2009 John Wiley & Sons, Ltd.</P>

천공성 십이지장 궤양의 임상적 고찰

박경화(Kyung Hwa Park),김진승(Chin Seung Kim),김호성(Ho Sung Kim),박신희(Sin Hee Park),이광찬(Kwang Chan Lee),최상용(Sang Yong Choi),배국현(Gook Hyun Bae) 대한외과학회 2003 Annals of Surgical Treatment and Research Vol.65 No.5

유비쿼터스 비즈니스 서비스 설계 사례연구

김경규(Kyung Kyu Kim),장항배(Hang Bae Chang),김흥국(Heung Gook Kim),권혁준(Hyuk-Jun Kwon) 한국전자거래학회 2008 한국전자거래학회지 Vol.13 No.2

본 연구에서는 유비쿼터스 컴퓨팅 기술을 활용하여 대형 도서매장에서 적용될 수 있는 수요자 기반의 u 비즈니스 서비스를 설계하였다. 이를 위하여 대형 도서매장의 업무 프로세스를 분석하고, 현재 제공되고 있는 서비스 사용자로부터 충족되지 못하고 있는 요구사항 또는 새로운 서비스 개발 요구사항을 조사한 다음, 이러한 요구사항을 만족시킬 수 있는 u 비즈니스 서비스를 설계하였다. 설계된 서비스들은 평가모형에 따라 통계적 분석을 진행한 다음 킬러 서비스를 도출하고, 이를 지원하기 위한 자원 시스템을 설계하였다. 본 연구의 결과는 향후 전개될 유비쿼터스 컴퓨팅 환경에서 필요로 하는 사용자 요구사항에 근거한 비즈니스 서비스를 제시함으로써, 관련 기술개발을 위한 타당성을 제시함과 동시에 비즈니스 모델개발을 위한 기초자료로 활용될 수 있을 것으로 기대된다. In this study we designed the killer services for the scene of bookstore in ubiquitous computing. To achieve this study, we have explored the unmet needs of employees and users in bookstores and examined whether the unmet needs could be served by the resources and capabilities of ubiquitous computing. Then we have extracted detailed killer services that includes value propositions and resource map by using statistical methodology. Finally, the killer services were designed to serve employees and users in bookstores with the service architecture. The result of this study will be applied to develop new business model in ubiquitous computing as the basic research.

Effect of DA-8159, a Selective Phosphodiesterase Type 5 Inhibitor, on Electroretinogram and Retinal Histology in Rabbits

Kang Kyung Koo,Ahn Gook Jun,Shim Hyun Joo,Kim Won Bae,조호균 대한의학회 2004 Journal of Korean medical science Vol.19 No.4

DA-8159, a Potent cGMP Phosphodiesterase Inhibitor, Attenuates Monocrotaline-Induced Pulmonary Hypertension in Rats

Kang, Kyung-Koo,Ahn, Gook-Jun,Sohn, Yong-Sung,Ahn, Byoung-Ok,Kim, Won-Bae The Pharmaceutical Society of Korea 2003 Archives of Pharmacal Research Vol.26 No.8

In this study, we evaluated the effects of oral administration of DA-8159, a selective phosphodiesterase-5 inhibitor, on the development of pulmonary hypertension (PH) induced by monocrotaline (MCT). Rats were administered either MCT (60 mg/kg) or saline. MCT-treated rats were divided into three groups and received orally administered vehicle, or 1 mg/kg or 5 mg/kg of DA-8159, twice a day for twenty-one days. The MCT group demonstrated increased right ventricular weights, medial wall thickening in the pulmonary arteries, myocardial fibrosis and the level of plasma cyclic guanosine monophosphate (cGMP), along with decreased body weight gains. However, DA-8159 markedly and dose-dependently reduced the development of right ventricular hypertrophy and medial wall thickening. DA-8159 also amplified the increase in plasma cGMP level and significantly increased the level of lung cGMP, compared with the MCT group. Although the body weight gain was still lower from the saline-treated control group, DA-8159 demonstrated a significant increase in body weight gains, in both 1 mg/kg and 5 mg/kg groups, when compared with the MCT group. In myocardial morphology, MCT-induced myocardial fibrosis was markedly prevented by DA-8159. These results suggest that DA-8159 may be a useful oral treatment option for PH.

Ilaprazole, a new proton pump inhibitor, is primarily metabolized to ilaprazole sulfone by CYP3A4 and 3A5

Seo, Kyung-Ah,Lee, So-Jeong,Kim, Kwon-Bok,Bae, Soo Kyung,Liu, Kwang-Hyeon,Kim, Dong-Hyun,Shin, Jae-Gook Informa Healthcare 2012 Xenobiotica Vol.42 No.3

<OL><LI><P>Ilaprazole is a new proton pump inhibitor, designed for treatment of gastric ulcers, and developed by Il-Yang Pharmaceutical Co (Seoul, Korea). It is extensively metabolised to the major metabolite ilaprazole sulfone.</P></LI><LI><P>In the present study, several <I>in vitro</I> approaches were used to identify the cytochrome P450 (CYP) enzymes responsible for ilaprazole sulfone formation. Concentrations of ilaprazole sulfone were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).</P></LI><LI><P>Incubation of ilaprazole with cDNA-expressed recombinant CYPs indicated that CYP3A was the major enzyme that catalyses ilaprozole to ilaprazole sulfone. This reaction was inhibited significantly by ketoconazole, a CYP3A inhibitor, and azamulin, a mechanism-based inhibitor of CYP3A, while no substantial effect was observed using selective inhibitors for eight other P450s (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1).</P></LI><LI><P>In addition, the formation of ilaprazole sulfone correlated well with CYP3A-catalysed testosterone 6β-hydroxylation and midazolam 1′-hydroxylation in 20 different human liver microsome panels. The intrinsic clearance of the formation of ilaprazole sulfone by CYP3A4 was 16-fold higher than that by CYP3A5.</P></LI><LI><P>Collectively, these results indicate that the formation of the major metabolite of ilaprazole, ilaprazole sulfone, is predominantly catalysed by CYP3A4/5.</P></LI></OL>

Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism

Pan, Wei,Bae, Soo-Kyung,Shim, Eon-Jeong,Park, Sung-Eun,Lee, Sang-Seop,Park, Soo-Jin,Yeo, Chang-Woo,Zhou, Hong-Hao,Shon, Ji-Hong,Shin, Jae-Gook Informa Healthcare 2013 Xenobiotica Vol.43 No.2

<OL><LI><P>Plasma concentrations of sibutramine and its two active metabolites after single oral dose of sibutramine were determined in Korean healthy male subjects with different CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and *6/*6), either alone or after four-day pretreatment with clopidogrel or clarithromycin.</P></LI><LI><P>The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration-time curve (AUC) of sibutramine by 163% and 255%, respectively.</P></LI><LI><P>Co-administration of clarithromycin, combined with <I>CYP2B6*6/*6</I> genotype, led to highest concentration of sibutramine.</P></LI><LI><P>The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype.</P></LI><LI><P>The <I>CYP2B6*6/*6</I> subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases.</P></LI><LI><P>The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype.</P></LI><LI><P>The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine.</P></LI><LI><P>These results suggest that the perturbation of CYP2B6 activity may contribute to the inter-individual variation of sibutramine drug responses although the clinical relevance is remained to be established.</P></LI></OL>

Effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, in healthy subjects

Kim, Hyunmi,Bae, Soo Kyung,Park, Soo-Jin,Shim, Eon-Jeong,Kim, Ho-Sook,Shon, Ji-Hong,Liu, Kwang-Hyeon,Shin, Jae-Gook Blackwell Publishing Ltd 2010 British journal of clinical pharmacology Vol.70 No.1

<P><B>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT</B></P><P>• Woohwangcheongsimwon suspension has traditionally been used for the treatment and prevention of stroke, hypertension, palpitations, convulsions and unconsciousness in various Asian countries.</P><P>• Woohwangcheongsimwon suspensions showed an inhibitory effect on CYP2B6 activity <I>in vitro</I>. Two terpenoids, borneol and isoborneol, are major constituents of woohwangcheongsimwon suspension, and show a competitive inhibition of CYP2B6 with <I>K</I><SUB>i</SUB> values of 9.5 and 5.9 µ<SMALL>M</SMALL>, respectively.</P><P>• Bupropion undergoes metabolic transformation to the active metabolite, 4-hydroxybupropion, primarily via CYP2B6 both <I>in vivo</I> and <I>in vitro</I>. It is often used as a CYP2B6 substrate for clinical drug–drug interaction studies.</P><P>• Drug interactions may occur between woohwangcheongsimwon suspension and bupropion.</P><P><B>WHAT THIS STUDY ADDS</B></P><P>• Co-administration with woohwangcheongsimwon suspension did not alter the pharmacokinetics of bupropion or its metabolite, 4-hydroxybupropion.</P><P>• Dosage adjustment of bupropion is unnecessary in patients concomitantly administered the highest recommended daily dose of woohwangcheongsimwon suspension.</P><P>AIMS</P><P>To examine the effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, formed via CYP2B6 <I>in vivo</I>.</P><P>METHODS</P><P>A two-way crossover clinical trial with a 2 week washout period was conducted in 14 healthy volunteers. In phases I and II, subjects received 150 mg bupropion with or without woohwangcheongsimwon suspension four times (at −0.17, 3.5, 23.5 and 47.5 h, with the time of bupropion administration taken as 0 h) in a randomized balanced crossover order. Bupropion and 4-hydroxybupropion plasma concentrations were measured for up to 72 h by LC-MS/MS. Urine was collected up to 24 h to calculate the renal clearance. In addition, the <I>CYP2B6</I>*6 genotype was also analyzed.</P><P>RESULTS</P><P>The geometric mean ratios and 90% confidence interval of bupropion with woohwangcheongsimwon suspension relative to bupropion alone were 0.976 (0.917, 1.04) for AUC(0,∞) and 0.948 (0.830,1.08) for <I>C</I><SUB>max</SUB>, respectively. The corresponding values for 4-hydroxybupropion were 0.856 (0.802, 0.912) and 0.845 (0.782, 0.914), respectively. The <I>t</I><SUB>max</SUB> values of bupropion and 4-hydroxybupropion were not significantly different between the two groups (<I>P</I> > 0.05). The pharmacokinetic parameters of bupropion and 4-hydroxybupropion were unaffected by woohwangcheongsimwon suspension.</P><P>CONCLUSIONS</P><P>These results indicate that woohwangcheongsimwon suspension has a negligible effect on the disposition of a single dose of bupropion <I>in vivo</I>. As a result, temporary co-administration with woohwangcheongsimwon suspension does not seem to require a dosage adjustment of bupropion.</P>