4-Tert-Octylphenol의 랫드에서의 조직분포 및 독성동태에 관한 연구

강미령(Mi Kyung Kang),안미령(Mee Ryung Ahn),정혜주(Hye Joo Chung),최선옥(Sun Ok Choi),최홍석(Hong Serk Choi),양지선(Ji Sun Yang),이용복(Yong Bok Lee),유태무(Tae Moo Yoo),손수정(Soo Jung Sohn) 한국독성학회 2004 Toxicological Research Vol.20 No.3

4-Tert-octylphenol (OP) is a surfactant additive widely used in the manufacture of a variety<br/> of detergents and plastic products. OP can disrupt endocrine function in humans and animals. This<br/> study was carried out to obtain toxicokinetic parameters of OP in male Sprague-Dawley (SD) rats. Male<br/> rats were administered with OP by single oral application of 200 mg/kg body weight. Blood, urine and tissues<br/> samples were taken at several time intervals after administration. Analysis of samples for OP was<br/> performed by column-switching high performance liquid chromatography (HPLC). In addition, we examined<br/> tissue distribution and accumulation of OP after single oral application of 50, 100, and 200 mg/kg,<br/> single intravenous injection of 1, 5 and 10 mg/kg or daily application of 50 mg/kg for 14 consecutive days.<br/> After single oral administration of 200 mg/kg, Cmax of 213 ± 123 ng/ml was reached within the first 1.3 hr<br/> (Tmax) in the plasma. AUC was calculated for 1,333 ± 484 ng · hr/ml. The final elimination half-life of<br/> plasma was longer than that of urine, but urinary clearance was lower than oral. A very small fraction of<br/> OP (Fe < 0.0017%) was excreted in urine within 24 hr. These results indicated that the major excretion<br/> route of OP was not urine. The mean maximal tissue distribution of OP was obserbed at 6 hr after treatment<br/> and slowly decreased time-dependently. High OP concentrations were detected in fat at 24 hr. The<br/> OP in fat was slowly released with longer elimination half-life and lower clearance than that of other tissues.<br/> OP was not accumulated in the liver following single oral application but 14-day oral treatments<br/> resulted in two-fold accumulation. It was probably due to the saturation of detoxification pathways. On the<br/> other hand, the mRNA expression of cytochrome P450 isoforms except CYP2C11 was not affected by<br/> OP at any dose. The expression of CYP2C11 mRNA decreased in a dose-dependent manner. This result<br/> suggests that OP changes expression of the male-specific cytochrome P450 isoforms in rat liver, and<br/> these changes are closely related to the toxic and estrogenic effect of OP.

위염치료제의 임상시험평가지침 연구

송윤경,진선경,한의식,안미령,정주연,이이다,조일영,김동섭,지은희,박효영,오정미,신원,이선희,김인규,Song, Yun-Kyoung,Jin, Sun-Kyung,Han, Eui-Sik,Ahn, Mee-Ryung,Jung, Ju-Yeon,Lee, Rhee-Da,Cho, Il-Yong,Kim, Dong-Sub,Ji, Eun-Hee,Park, Hyo-Young,Oh, 대한약학회 2011 약학회지 Vol.55 No.4

Gastritis is the most common disease among Korean. The demand for the development of gastritis drugs has been increasing. Currently, however, there is no guideline available for the clinical evaluation of gastritis drugs worldwide. As a consequence, domestic and international pharmaceutical companies make errors in the drug development processes, and it becomes difficult for them to establish the scientific validity and objectivity of newly developed drugs. The objective of this study was to develop the Guideline for Clinical Trials Evaluation of Gastritis which can be used in improving the quality and consistency of clinical trials. First, we collected and reviewed the clinical trials on gastritis drugs that were available from Japan Pharmaceuticals and Medical Devices Agency and Korea Food and Drug Administration (KFDA), and investigated the recent research trends on clinical trials of gastritis drugs. Reviewers from KFDA and National Institute of Food and Drug Safety Evaluation and scientific experts from the pharmaceutical industries developed the guidelines through regularly scheduled meetings. Opinions and consultation from academic fields and industry experts were also obtained. This project will provide the clinical trial practitioners, investigator and reviewers the scientific and rational guidelines for performance and evaluation of clinical trials for gastritis drugs. Furthermore, we hope this guideline contributes to establishing the national competitiveness, improving the quality of clinical trial, and encouraging researches on drug development for gastritis.

오수유가 N-nitro-L-arginine methyl ester로 유발한 고혈압흰쥐의 심혈관계에 미치는 영향

정수연(Soo Youn Chung),이숙영(Sook Young Yi),유태무(Tae Moo Yoo),안미령(Mee Ryung Ahn),최현진(Hyun Jin Choi),정면우(Myeon Woo Chung),류항묵(Hang Mook Rheu),양지선(Ji Sun Yang) 대한약학회 1999 약학회지 Vol.43 No.3

The present study examined the effect of a methanol extract of Evodiae Fructus on the cardiovascular function in N-nitro-L-arginine methyl ester (NAME)-induced hypertensive Wistar rats after treatment over 6 weeks. In rats treated with NAME, blood pressure, weight of heart, aorta media thickness and media/lumen ratio significantly (p<0.05) increased, whereas coronary flow and heart rate of isolated heart significantly (p<0.05) decreased compared with control group at 6 weeks. In rats treated with NAME and Evodiae Fructus, blood pressure, aorta media thickness and media/lumen ratio signiflcantly(p<0.05) decreased compared with NAME treated group at 6 weeks. These results suggest that Evodiae Fructus is applicable to the treatment of hypertension and vascular hypertrophy.

단보 : 서방성 제제의 생물학적동등성시험을 위한 가이드라인

서현옥 ( Hyun Ok Seo ),김소희 ( So Hee Kim ),안미령 ( Mee Ryung Ahn ),안충열 ( Choong Yul Ahn ),박혜진 ( Hye Jin Park ),오은경 ( Eun Kyung Oh ),이은주 ( Eun Ju Lee ),김보연 ( Bo Yeon Kim ),우나리 ( Na Ry Woo ),서희원 ( Hee Won Seo 한국약제학회 2010 Journal of Pharmaceutical Investigation Vol.40 No.1

홍화씨의 경골골절치유에 미치는 영향

정수연(Soo Youn Chung),최현진(Hyun Jin Choi),정면우(Myeon Woo Chung),안미령(Mee Ryung Ahn),유태무(Tae Moo Yoo),류항묵(Hang Mook Rheu),양지선(Ji Sun Yang) 대한약학회 1999 약학회지 Vol.43 No.4

We investigated the effect of safflower-seed on fracture healing of fracture model in rat. Fracture healing was evaluated by examining the degree of wound healing macroscopically, radiography, bone histomorphometry and biochemical examination. After 1,3,5,7 days, the wound healing was accelerate in safflower-seed diet group. Radiography does not reveal the difference in fracture healing between two groups. After 2 weeks, safflower-seed had a significant, stimulatory effect on external callus formation(p<0.05). But after 4,6,8 weeks, no difference was observed between normal and safflower-seed diet group in callus size. Urinary hydroxyproline, osteocalcin and total alkaline phosphatase decreased significantly (p<0.05) in safflower-seed treated group at 2 week after fracture.

적출관류 간에서 대황, 마황 및 황금이 7-에톡시쿠마린의 대사에 미치는 영향

최기환(Ki Hwan Choi),김순선(Soon Sun Kim),박윤주(Youn Joo Park),정혜주(Hye Joo Chung),안미령(Mee Ryung Ahn),서수경(Soo Kyung Suh),신윤용(Yhun Yhong Sheen),김동섭(Dong Sup Kim),장영섭(Young Sup Chang) 대한약학회 1998 약학회지 Vol.42 No.4

In order to study the effects of Rhei rhizoma, Ephedrae herba and Scutellariae radix on hepatic metabolism, we examined the pretreatment effect of those on the metabolism of 7-ethoxycoumarin (EC). Water extracts (1g/kg) of Rhei rhizoma, Ephedrae herba and Scutellariae radix were administered orally to rats for 7 days, respectively. Livers were then isolated and perfused with 100mcM EC for 2 hours. The metabolites of EC, 7-hydroxycoumarin, sulfate conjugate and glucuronide conjugate were measured in the perfusates. The amount of glucuronide conjugates was decreased in Rhei rhizoma pretreated rats (p<0.01), however. 7-hydroxycoumarin was increased in Ephedrae herba pretxeated rats (p<O.OD. We examined whether the change of enzyme activity is related to the change of cytochrome P4501A1 a n d P4502B1 mRNA level in the perfused rat liver, which are responsible for EC metabolism. CYPlAl a n d CYP2B1 mRNA level was increased, which was not statistically significant with rhei rhizoma nor ephedrae herba pretreatment. We also assessed the hepatotoxicity of Rhei rhizoma. Ephedrae herba a n d Scutellariae radix. The activities of ALT and AST were assayed at 24 hours after 7 days administration. Only the ratio of ALT over AST was increased in ephedrae herba pre treated rats (p<0.05). Lipid peroxidation was increased in Rhei rhizoma treatment (p<0.05). while histopathological examination performed after liver perfusion did not show a n y difference compared with vehicle treatment. These results suggest that Ephedrae herba pretreatment increases the o-deethy-lation of 7-ethoxycoumarin in rats, which may be mediated b y CYPlAl mRNA induction.

Rat에서의 Octylphenol의 독성동태 연구

손수정(Soo Jung Sohn),강현구(Hyun Gu Kang),이선우(Sun Woo Yi),서수경(Soo Kyung Suh),박인숙(In Sook Park),안미령(Mee Ryung Ahn),최홍석(Hong Seok Choi),조재민(Jae Min Cho),손동환(Dong Hwan Sohn),유태무(Tae Moo Yoo),양지선(Ji Sun Yang) 한국환경성돌연변이발암원학회 2001 한국환경성돌연변이·발암원학회지 Vol.21 No.2

4-tert-octylphenol (OP) is a surfactant additive widely used in the manufacture of a variety of detergents and plastic products. Also, OP is known to have estrogenic activity by interacting with development and functions of endocrine system. This study was carried out to obtain toxicokinetic parameters of OP in male<br/> Sprague-Dawley rats. Male rats were administered OP, by either single oral (gavage) applications of 50, 100 or 200 mg/kg body weight. or a single intravenous injections of 1, 5 or 10 mg/kg body weight. Blood samples taken at several time intervals after administration were obtained from the femoral artery. Analysis of blood samples for OP was performed by gas chromatography mass spectrometry (GC/MS). The detection limit of OP was 1.9 ng/ml at SIM (selected ion monitoring) mode of GC/MS. Calibration curve for analysis of the concentrations of OP in plasma was (OP/butylphenol peak area ratio) = 0.0294 × (plasma conc.) + 0.028 (r²= 0.9991). The OP plasma concentration was 3921 ng/ml immediately after single intravenous application, decreased rapidly within 45 min, and was detectable at low concentration up to 6 hr after application. When administered orally in rats (50, 100 and 200 mg/kg), OP was detected in the blood early after gavage administration, indicating the rapid initial uptake from gastrointestinal tract, with Tmax obtained from 0.67~0.83 hr. Using the AUC (area under the curve) of plasma concentration vs. time, low oral bioavailabilities of 1.2, 5.0 and 5.3% were calculated for the 50, 100 and 200 mg/kg groups, respectively.

죽염의 약리작용 평가

정수연(Soo Youn Chung),이숙영(Sook Young Yi),류항묵(Hang Mook Rheu),양지선(Ji Sun Yang),유태무(Tae Moo Yoo),김옥희(Ok Hee Kim),노용남(Yong Nam Roh),정면우(Myeon Woo Chung),안미령(Mee Ryung Ahn),최현진(Hyun Jin Choi) 한국응용약물학회 1999 Biomolecules & Therapeutics(구 응용약물학회지) Vol.7 No.2

Bamboo salt has been used for the purpose of precaution and treatment of certain diseases including cancer. Therefore, present study was carried out to ascertain the effects of bamboo salt upon anti-cancer, anti-hypertensive, and anti-diabetic activities as well. To examine the anti-cancer activity of bamboo salt, ICR mice implanted with 1 X 10^6 cells of sarcoma 180 intraperitoneally had been treated daily with bamboo salt A, crude salt, and reagent-grade NaCl (0.2, 1.0, and 2.0 g/kg, p.o.) for 60 days using adriamycin (2 mg/kg) as a positive control. Neither survival rate nor body weight had been significantly influenced by all the treatments indicating that bamboo salt A did not exert the anti-cancer effect on ICR mice. Anti-hypertensive activity was examined in spontaneously hypertensive rats (SHR) which had been administered with bamboo salt A, crude salt, and reagent-grade NaCl (0.1, 0.5, and 1.0 % in drinking water) for 28 days using hydralazin (2 mg/kg) as a positive control. Blood pressure and heart rate were measured at 1, 3, and 4 weeks after the starting date. Significant anti-hypertensive activity was not observed in any treated group compared to the positive control group. In order to determine if bamboo salt had anti-diabetic activity, rats in which diabetes had been induced by streptozotocin (45 mg/kg, i.m.) were treated daily with bamboo salt A, crude salt, and reagent-grade NaCl (0.2, 1.0, and 2.0 g/kg, p.o.) for 28 days using insulin (50 U/kg, s.c.) as a positive control. Blood samples were taken and analyzed at 1, 2, and 4 weeks after the starting date. Bamboo salt did not cause any decreasing effect on the blood glucose levels. These results clearly demonstrated that bamboo salt A did not exert anti-cancer, anti-hypertensive, or anti-diabetic activities in the present experimental animals.

간질환 치료약물의 효력검색에 관한 연구

안미령,유태무,정면우,박창신,양지선 식품의약품안전청 1998 식품의약품안전청 연보 Vol.2 No.-

간질환 치료약물로 민간에서 사용되고 있는 한방제제인 인진호탕의 안전성 및 유효성을 평가하기 위하여 간질환 동물모질을 이용하여 in vivo에서 효력을 검색하고 간대사 효소의 활성도 변화를 측정하였다. 각종 간 질환은 만성적으로 진행되면써 공통적으로 간겪화에 이르게 된다. 파라서, 본 연구에서는 담도결찰 및 사염화탄소 만성투여로 실험적 간경화를 유도하고, 인진호탕(3.7Sg/kg)과 그 구성 약물인 인진호(3.Og/kg), 치자(1.5g/kg), 대환(0.gg/kg)을 각각 깊주간 투여하여 실험하였다. 간조직내의 hydroxyprolin양 및 iNO즐 발현 과 혈청증 ALT · AST · ALP측정하고, 조직검사를 병행하여 유효성을 평가하였고, 약물대사효소인 cytochrome P4SO의 각 isoByue에 대한 mRNA level 및 효소활성을 측정하여 안전성을 평가하였다. 사염화탄노 투여모킬에서는 인진호탕, 치자, 대황이 hydroxyprolin양을 유의적으로 감소시켰으며 혈청 중 ALT, A끌T, JtLP도 감소시켰다. 이러한 효과는 인잔호탕에서 가장 컸다. 담도결찰모텔에서는 민진호탕과 치자가 hydroxyprotine 양을 유의적으로 감소시켰으며, 혈청 중 ALT도 감소시켰다. 그러나, 조직학적 검사에서는 약물투여에 의한 변화가 뚜편하게 나타나지 않았다. iNOS의 발현은 간경화에 의해서 증가되었으나 약물에 대한 반응은 두 모질에서 파르게 나타났다. 즉 사염화탄소 병태유발 ?1변의 경우는 파물투여에 의한 iNOS발현이 관찰되지 쟈았고, 당도결찰모질에서는 인진호탕에 의한 iNOS발현이 앙린채조 군인 silfmarin투여군과 같이 증가되었다. 또한, 간경화에 외하여 전반절으로 강소된 약물대사효소의 mnNA :1!소활성은 각 isozyme마다 약물에 대하여 파르게 반응하였다. 이 결과로부터 인진호탕 및 치자에 패한 효력을 인 확인하였으며, 각 생약의 투여에 치한 대사효소의 변화를 제시함으로서 간애서 cytochrome P450의 각 isoz『nI 확대사되는 약물과의 병용투여시 적정 용량에 대한 근거를 설정하였다. These studies were conducted to evaluate the efficacy and safety of the Yinchinho-Tang, oriental Hledicine used to treat liver diseases. When it comes to the chronic hepatitisT it usually pro-gressed to cirrhosis. We induced the liver cirrhosis model in rat with chronic trreatrnent of carbon tetra-chloride for 12 weeks or the bile duct double-ligation and scission(BBL/S). After the induction of livercirrhosis, Yinchinho-tang(3.75g/kg) and its ingredients, f feruiriae cafiffaris .H☞rSa(3.Og/kg), eBrOeni3efrHcfue(1.5g/kg) & fAei ffiroma(0.9g/kg) were administered daily for 4 weeks per os. In this study,contents of hydroxyproline(HYP), iNOS mRNA expression aBd histology in liver fissile were measuredas well as the activities of ALT · AST · ALP in serum for efffcacy- Also both the ensyme aetivity andmRNA erpression of enzfme which are responsible for drug metabolim such as Cypfsos were measured.According to our results, in case of a cirrhotie model induced by carbon tetrachloride, both the contentsof HYP in liver and the activities of ALT · AST · ALP in serum were significantly decreased(p<0.01)in each treatment group of Yinchinho-tang, eardeHiae frudHs, and fAei ffiroma. In the other cirrhoticmodel induced by BDL/S, also both the contents of HYP in liver and ALT activity in serum were signifi-cantly decreased(p<0.01) in each treatment group of YiBchinho-tang and eardeniae frHdHs, however,the JLLF activity was significantly decreasrdfp<0.01) only in eardeniae frucfHs. MeaBwhile, it wasfound that there was no siginificant changes in histolegy between the treatment groups. iNOS mRNAexpressilf was increased in cirrhosis but was different between two models when it is treated withdrugs. While there was no finding of observations in iNOS mRlfA expression at each treatment group inmodel of carbon tetrachloride, the treatment of Yinchinho-tallg resulted in the inereased iNOS mRNAexpression in BDL/S, likely in silymarin. The activities of 0yp450s were totally decreased in cirrhosisand different activities of isozymes were noted in the drug trtatrRent groups. To taken all together, wefound there were a partial efficacies of Yinchinho-taBg and farcceniae frHdus. Aslo, it can be postulatedthat the changes in Cypaso isozyme's activitles could be the marker of drug interaction.

항암제에 대한 PK/PD 모델 설정 연구

박인숙,안미령,서수경,이선우,최흥석,안은주,진숙,손수정,구효정,양지선,유태무 식품의약품안전청 2000 식품의약품안전청 연보 Vol.4 No.-

약물에 대한 약동학(PK) 및 약력학(PD) 연구는 최적의 약물효과를 얻기 위한 약물툰여계획수립에 대한 기본데이타를 제공하띠 현대 약물요법에서 그 중요성이 더욱 강조되고 있다. PK-PD 모델링은 투여용량-혈중농도-약효간의 관계를 수학적으로 묘사하여 약동학 및 약력학 사이의 정량적이고 구체적인 상관성을 규명하고 이를 이용하여.투여용량으로부터 시간에 따른 약물의 동태 및 효력을 예측할 수 있다. 따라사 신약개발시에도 전임상단계 및 임상시험단계에서 PK-PD에 관한 정보가 제공되면 의다 적절한 약물요법을 결정하여 약물의 효과를 극대화할 수 있으므로 치료률 및 신약개발의 가능성을 높이는데 기여한다. 본 시험에서는 PK-PD 모델링에 대한 기본개념 및 방법을 연구하고자, 국내예서 개발된 캄토테신계 항암제인 CKD-6OB를 이용하여 약물의 약동학 및 약력학적 특성을 HT-29 cell에서 측정하였다. 항암제의 치료는 암세포로의 약물침투 및 효력발현 시점에 따라 투약을 조절함으로써 부작용을 최소화할 수 있다. 따라서 효력검색을 위하여 MTT 측정법을 사용하여 암세포의 증식정도를 측정하였으며, 투여시간에 판른 세포내외의 약물농도 측정을 통하여 약물동태를 연구하였다. 실험결과 CKD-602의 HT-29 cell에 대한 ICD는 250nbt로 나타났으며, 약물투여 24시간 후부터 세포로의 유입이 나타났파. 그러나 CKD-602의 쎄포내외의 농도비율이 거의 변화가 없으며 CKD-602의 려T-29 cell 에 대한 지연효과가 나폭나는 것으로 미루어 CKD-602의 항암효력이 약물농도 주입속도와 상관성이 있을 것으로 사료된다. Pharmacokinetic(PK) and pbarrnacodynamic(PD) information get from the scientific basis of modern iharrnacotheraDy PharrnacoEnetics describes ·the drug concentration- time courfes in body Huids resulting from administration of a cnfain drug dost and pharmacodynamics describes the observed effect resulting from a crrtain drug concentration. A Pf(/PD model is amathematical descfption of these relationships. The rationale for PK#PD-rnodelfng is to linkpharmacokinetics arid pharrnacofynamics In order to establish and evaluate dose-concentration-response relationships and subseauently describe and predict the effect-time courses resultingfrorrl a drug dose. The expanded use cf PK/PD-modeITing is assumed to be highly beneficialfor drug development as well as applied pharrnacotherfpy and will most likely improve thecurrent state of applied therapeutics. The anticancer drug therapy depends on the ability of the drug to penetrate on the solidtumor for the time-and concentraton-dependent drug. The present study examined thedeterminants of Pft/PD modeling of CKD-602 in HT-29 cel.Is. Anticancer effects of CKD-602by MTT assay was dependent on the time and the concentration. The concentration ofCKD-602 in both the cell and the medium was correlated with time and drug concentration.But pharmacodynamics of CKD-602 was not drug uptake limited and the relative importance ofdrug was exposure time. The knowledge of relative importance of a drug. in pbarrnacodynamicstudies will heTp to idendify the optimal dose resimens.