납의 생체내 세포독성 연구: 랫드에서 혈장 DNA와 혈액화학치 변화

조준형(Joon-Hyoung Cho),정상희(Sang-Hee Jeong),강환구(Hwan-Goo Kang),윤효인(Hyo-In Yun) 한국독성학회 2003 Toxicological Research Vol.19 No.3

Changes of plasma DNA contents and serum biochemical values were measured in rats administered with lead acetate to investigate the in vivo cytotoxic effects of lead and examine the usefulness of these in vivo cytotoxicity changes as indicators of lead exposure and diagnosis of lead poisoning. Rats were given once intraperitonealy with lead acetate (1.6, 8, 40 and 200 mg/kg b.w)<br/> and the changes of plasma DNA contents and serum biochemical values were measured at the time of 2, 4, 8, 24, 48 and 72 hours after the administration of lead acetate. Plasma DNA contents began to increase at 2 hours after the administration of lead acetate in the treatment groups of 8, 40 and 200 mg/kg b.w dose-dependently and significantly compared with control group. These DNA increases of each dosage group were continued until 24, 48 and 72 hours and the maximum levels of DNA (4.02, 10.67 and 14.10 times of control) were arrived at 8, 8 and 4 hours after the each treatment, respectively. Among 10 serum biochemical indicators, the activities of creatine kinase were increased to maximum level (6.55 times of control) at 2 hours after the administration and remained to be significantly higher than that of control by 8 hours in the treatment group of 200 mg, however, after 48 hours, the levels in the treatment groups of 40 mg above were lower than that of control. The values<br/> of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase were higher than that of control from 2 to 24 hours in the treatment group of 200 mg. Maximum levels of these enzymes were 3.34, 3.00 and 3.19 times of control, respectively. Both of alkaline phosphatase and triglyceride values in the treatment groups were decreased compared with control. In the case of alkaline phosphatse, the values were significanly decreased from 24 hours and more severely decreased until 72 hours in the treatment groups of 40 mg above (p<0.01). The minimum value was 0.36 times<br/> of control in the 200 mg group. The values of triglyceride were significantly decreased in the tratment groups of 40 mg above (p<0.01), but the values were not different significantly among the treatment groups. This study demonstrates that plasma DNA content and serum biochemical values such as aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase and triglyceride are valuable as biomarkers for exposure assessment and diagnosis of lead poisoning.

한국재래산양에서 Enrofloxacin의 혈청내 항균효과와 체내동태

윤효인,김무열,박승춘,Yun, Hyo-in,Kim, Moo-youl,Park, Seung-chun 대한수의학회 1997 大韓獸醫學會誌 Vol.37 No.2

Enrofloxacin is one of the second-generation quinolones which have been widely used to treat bacterial infections in various species including chicken, pig, horse and cattle. The objective of the present study was to describe the serum bactericidal activity(SBA) of enrofloxacin, its pharmacokinetic behaviors after intramuscular or intravenous administration to Korean native goats in the dose rate of 5mg/kg b.w. The results obtained through this study were as follows : 1. Sera collected from both sexes of Korean native goats administered 5mg/kg i.v. or i.m. showed potent antibacterial activities up to the 12 hours by way of the serum bactericidal activity. 2. Concentrations of enrofloxacin in the biological samples were measured by high-performance liquid chromatography(HPLC) so as to study pharmacokinetic characteristics. For detection of enrofloxacin, 10% TCA was optimal for protein precipitation and the mobile phase was 0.01M citric acid/methanol/acetonitrile(7/2/1, pH 3.5) with solid phase being the $C_{18}$ reversephase column and detection wavelength being 278nm. The limit of detection of enrofloxacin on HPLC was $0.05{\mu}g/ml$. 3. Pharmacokinetic profile of enrofloxacin administered 5mg/kg i.v. in Korean native goats was best described by two-compartment open model and that administered i.m. the same rate by one-compartment model. There were no sex differences in pharmacokineticl parameters. In conclusion, enrofloxacin showed potent in vivo antibacterial activity and excellent pharmacokinetic properties in Korean native goats, hence it may be used as a potential antibacterial in the veterinary clinical settings.

돼지와 랫트에서 sulfamethazine의 약물동태학 및 조직분포

윤효인,박승춘,오태광,조준형,박종명,Yun, Hyo-in,Park, Seung-chun,Oh, Tae-kwang,Cho, Joon-hyoung,Park, Jong-myeong 대한수의학회 1997 大韓獸醫學會誌 Vol.37 No.2

In order to establish optimal dosage schedules and withdrawal times for sulfamethazine(SMZ) in pigs, pharmacokinetic and tissue distribution experiments were conducted in pigs. For comparative purposes, tissue depletion kinetics are also studied in rats. From three pigs administered with SMZ i.v., the pharmacokinetic profile of SMZ in two pigs was adequately described by a one-compartment open model whereas that in one pig was patterned after a two-compartment open model. Volume of distribution(Vd) was 0.48~0.57 L/kg and biological half-life($t_{1/2}$) was 11.8-16.8 h. From three pigs dosed with SMZ p.o., pharmacokinetic profile was explainable with a one-compartment open model. Time to reach maximum SMZ concentration in serum (Tmax) was 2.8 h, 3.2 h and 7.5 h. Elimination half-life was 2.8-7.5 h. The descending order in concentration of SMZ was plsama > kidney > liver > lung > heart > pancreas > spleen > duodenum > ileum > brain > adipsoe tissue from three pigs sacrificed at 5h, 29h and 54h after the administration of SMZ, p.o.. The protein binding of SMZ in pigs was 55.2%($2.5{\mu}g/ml$), 71.5% ($5{\mu}g/kg$) and 71.5%($10{\mu}g/ml$). The mean systemic bioavailability (F) of SMZ p.o. was 49.1 %. Meanwhile the pharmacokinetic profile of SMZ in rats was adequately described by a one-compartment open model. Absorption of SMZ p.o. in the rat was very rapid. In conclusion, the oral optimal dosage regimen of SMZ for pigs was the initial dose of 45.7 mg/kg followed by the maintenance dose of 30.2 mg/kg for high specific pathogens to SMZ. The time to reach below the stipulated residual allowable concentration (0.1 ppm) was calculated 93 h after oral administration of 200 mg/kg recommended by manufactureres.

이스라엘잉어 장관 수축에 관여하는 약물수용체에 관한 연구

윤효인,한경호,박승춘,조준형,오태광,Yun, Hyo-in,Han, Kyong-oh,Park, Seung-chun,Cho, Joon-hyoung,Oh, Tae-kwang 대한수의학회 1994 大韓獸醫學會誌 Vol.34 No.3

In order to elucidate the characterization of receptors involved in inestinal motility of Israeli carp, spontaneously contracting Israeli carp intestinal preperations were prepared and mounted in the organ chambers for contraction traicings using a polygraph. Various contractile agonists were treated and their dose-response curves were constructed. $EC_{50}$ values$(pD_2)$ of each agonist on specific receptors, $pA_2$ values of competitive antagonists against some agonists, and $K_1$, values of noncompetitive antagonists against some agonists were analyzed for characterization of receptors related with the intestinal contraction. Results obtained through the experiments were summarized as follows: 1. Acetylcholine(ACh) exhibited biphasic dose-response curves: initial ACh-induced dose dependent contractions were observed in pM levels but followed by decreased response in in-between concentration levels. Dose dependent contractions reappeared in ${\mu}M$ level. The peaks in pM and ${\mu}M$ levels appeared in $10^{-13}M$ and $3{\times}10^{-5}M$, respectvely. 2. Carbachol(CaCh) exhibited dose dependent contractions from $10^{-9}M$ to $10^{-5}M$, and its $pD_2$ values were higher than those of ACh($5.60{\pm}0.11$). ACh and CaCh exhibited equiactive contractions. Nicotine had no effects on contractile responses of Israeli carp intestine. 3. ACh-induced responses were inhibited by atropine($K_1:7{\times}10^{-8}M$), a muscarinic antagonist, in a non-competitive manner. But CaCh-induced responses were inhibited by both antimuscarinic atropine($pA_2:9.52{\pm}0.14$) and selective $M_2$ antagonistic 4-DAMP($pA_2:8.16{\pm}0.09$), in competitive manners. Nicotine receptor antagonistic decamethonium and hexamethonium had no effects on ACh-and CaCh-induced contractions. Therefore, the cholinergic receptor related to intestinal motility of Israeli carp was assumed as $M_2$ type. 4. In Israeli carp intestine, 5-HT (serotonin) exhibited dose dependent contractions in concentration range from $10^{-8}M$ to $10^{-5}M$. The maximal responses, however, were corresponded to about 50% of those of ACh or CaCh. 5-HT induced contractions were inhibited by $5-HT_2$ antagonistic ketanserin ($K_1: 7.8{\times}10^{-4}M$) in a non-competitive manner, but not by both of anti $5-HT_1$, spiperone and anti $5-HT_3$, MDL-72222. Hence, $5-HT_2$ receptors are suggested to be existed in Isreli carp intestine.

Effect of gender on the pharmacokinetics and metabolite formation of sulfamethazine in the rabbit

윤효인,박일현,Yun, Hyo-in,Park, Il-hyun The Korean Society of Veterinary Science 1992 大韓獸醫學會誌 Vol.32 No.1

Sulfamethazine(SMZ)은 수의임상에서 감염증 치료 및 예방목적으로 많이 사용되고 있을 뿐 아니라 가축의 생산성 향상을 위해 남용되고 있는 주요한 항균제의 하나이다. SMZ의 생체내 대사 및 약물동태학적 특성은 동물의 종차에 따라 상이함이 잘 알려져 있으나 주요 실험동물 및 경제동물인 토끼에서 조사된 바는 매우 드물다. 한편 성차에 따른 약물대사의 차이는 rat를 비롯한 여러 동물에서 인정되고 있는데 대체로 숫컷이 암컷에 비해 대사능이 활발한 것으로 알려져 있다. 그러나 산양에서의 SMZ의 대사는 오히려 암컷이 더 활발하다는 보고도 있어, 여러 동물종에서 일률적으로 성차에 따른 약물대사를 설명할 수가 없다. 초식성의 습성을 가지고 있는 토끼에 있어 성차에 따른 SMZ의 대사 및 약물동태학적 특성이 다른 초식성 동물인 산양의 경우와 동일한 경향을 보이는지는 매우 흥미 있다할 것이다. New Zealand White 토끼에 SMZ을 이정맥에 35mg/kg를 주사한 후 미리 정해진 시간에 수거된 혈장 및 뇨(24시간)를 HPLC를 이용하여 분석하여 아래와 같은 약물동태학 및 대사적 특성을 얻었다. 1. 토끼에서의 SMZ의 주요 대사경로는 아세틸화$(N_4AcSMZ)$이었다. 두개의 수산화 대사산물(50HSMZ, $6CH_2OHSMZ$)도 생성되어 수산화 경로가 있음을 확인하였으나 양적인 관심에서 주요하지 않았다. 2. 토끼에서의 SMZ의 각 대사산물의 생성은 암수간의 성차에 따른 차이가 인정되지 않았다. 3. SMZ을 토끼의 이정맥에 투여(35mg/kg)하였을 때의 약물동태학적 특성은 1구1차 지수형 배설형태로 설명이 가능하였으며 암수에 따른 성차가 인정되지 않았다. 4. SMZ는 신속하게 $N_4AcSMZ$로 대사되었으며, $N_4AcSMZ$의 체외배설은 SMZ에 비해 매우 느렸으며 성차에 따른 배설속도의 차이를 인정할 수 없었다. SMZ is one of the most widely used antibacterial agents in veterinary medicine. It is also used as a growth promotant in many species of domestic animals There are marked species differences in its metabolism and pharmacokinetics. However, its pharmacokinetic and metabolism in rabbits. which are ragarded not only as good laboratorty animals hut also as good economical animals in its own, are lacking. Sex-differences in drug metabolism are well recognized in wide range of animal species including rats. Males are known to he more active than females. It is also know that there are Significant differences in the direction of metabolic pathways. But recently, female goats are reported to be more active in the metabolie capacity of SMZ than the other sex by Dutch researchers at Utrecht. Therefore, it is not easy to make general conclusicn of having higher SMZ metal-die capacity in the male compared to the opposite sex in every animal species. In this regard, the study on metabolic pattern of SMZ in rabbits, which are regarded as hervivorous, is of interest because the dietary habbits of rabbit are comparable to thai of goal, NEW Zealand White rabbits of each sex were given SMZ(35mg/kg) as a bolus injection into the marginalean, vein in order to study its pharmacokinetic profiles(using plasma) anc metabolic pattem(24h urine) as specified in the methods anc materials. 1. In the rabbit, the major metabolic pathway of SMZ was the acetylation(the formation of $N_4AcSMZ$). There were hydroxylation pathways(50HSMZ, $6CH_2OHSMZ$) as well, in the metabolism of SMZ in the rabbit, but minor pathways. 2. No sex differences in the metabolic direction of SMZ and its metabolites formation were found from the urinary excreted metabolites of SMZ out of 24h collected urine. 3. The concentration-time curves of SMZ(35mg/kg, iv) in the plasma compartment were fitted to a one-compartment open model when using a computer program(NONLIN). There was also no difference in the pharmacokinetic pattem of SMZ between two sexes. 4. The emergence of $N_4AcSMZ$ metabolized from SMZ was very fast in the plasma of the rabbit The elimination of $N_4AcSMZ$ was prolonged as compared to that of the parent drug Vie found no sex difference in the elimination pattern of $N_4AcSMZ$ in the rabbit.

아드레날린성 β-수용체에 대한 higemamine의 약리학적 특성

윤효인,장기철,이창업,Yun, Hyo-in,Chang, Ki-churl,Lee, Chang-eop 대한수의학회 1992 大韓獸醫學會誌 Vol.32 No.1

Higenamine is an Aconiti tuber derived compound whose chemical structure is 1-(4'-hydroxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline containing catechol ring and tetrahydroisoquinoline nucleus in its own structure, both of which are well known to have agonistic effects on adrenergic receptors. Using guinea-pig atria(rich in ${\beta}_1$-receptor) and treachea(rich in ${\beta}_2$-receptor), we studied pharmacological actions of higenamine on these organs with special interest of its relevancy of ${\beta}$-receptor selectivity. In order to further clarify its pharmacological characteristics, the influncences of pretreatment of reserpine or cocaine were also investigated. The results were summarized as follows : 1. Higenamine had remarkable chronotropic, inotropic and bronchodilator effects in guinea-pig spontaneously beating right atria, left atria and trachea, in dose-dependent manners. 2. All of above actions were blocked competitively by propranolol, which shows nonselectivity of higenamine on ${\beta}$-receptor. $pA_2$ values of propranolol against higenamine were 7.93, 7.76 and 8.46 in guinea-pig right atria, left atria and treachea, respectively. 3. Reserpine pretreatment(5mg/kg, ip, 24h) did not show my decrease in pharmacological actions of higenamine, which suggests higenamine has direct action on ${\beta}$-receptor not via catecholamine release. 4. Cocaine pretreatment$(1{\mu}M)$ had no influence on pharmacological actions of higenamine in contrast with nor epinephrine, which suggests there is no neuronal uptake mechanism of higenamine in the studied organ preparations.

Higenamine의 Guinea pig 기관 평활근 이완작용

윤효인,장기철,홍성근,이창업,Yun, Hyo-in,Chang, Ki-chorl,Hong, Seong-geun,Lee, Chang-eop 대한수의학회 1987 大韓獸醫學會誌 Vol.27 No.1

Higenamine, a benzyltetrahydroisopuinoline analog isolated from aconite tuber, has potent isotropic action. Recent studies suggest it may have beta receptor agonistic property in that its inotropic action is blocked by propranolol in isolated rabbit heart. However, no study has been carried out on other organs than heart. Higenamine is expected to have pharmacological actions on smooth muscle on the ground that it has catecholamine moiety and tetrahydrosioquinoline nucleus in its chemical structure, both of which are well known to have smooth muscle relaxation effects. Therefore present study was aimed at determining whether higenamine has bronchodilating effect in isolated guinea pig trachea smooth muscle rich in adrenergic beta receptor and if any, it has agonistic effect on beta receptor. The results were summarized as follows : 1. Higenamine had remarkable bronchodilating effect in guinea pig tracheal smooth muscle in a dose-dependent manner. 2. Bronchodilator effect of higenamine in isolated guinea pig tracheal smooth muscle was blocked competitively by propranolol. The $pD_2$ value of higenamine in isolated guinea pig tracheal smooth muscle was 5.65 and the $pA_2$ value of propranolol against higenamine in the same preparation was 7.97.

Rat에서 설파메타진의 대사 및 약물동태학

윤효인,박승춘,박종명,조준형,이문한,Yun, Hyo-in,Park, Seung-chun,Park, Jong-myung,Cho, Joon-hyoung,Lee, Mun-han 대한수의학회 1995 大韓獸醫學會誌 Vol.35 No.4

We used rats as the experimental animal for the elucidation of metabolic patterns and pharmacokinetic profiles of SMZ in the rat, by use of the urine and plasma from predetermined intervals, respectively. Information herefrom would give some insight into species differences and sex differences in the metabolism and pharamcokinetics of drugs, at least SMZ in particular. Results would be summarized as follows: 1. There were two hydorxy metabolites(5-hydroxysulfamethazine and 6-hydroxyethylsulfamethazine) and an acetyl derivative($N_4$-acetyl sulfamethazine) in the 24h-collected urine, on confirmation with each standard materials. There were also two unknown metabolites therein. 2. In the viewpoint of quantitative aspect, $N_4$-acetylsulfamethazine was the largest, hence it is assumed that the acetyl pathway is the major one in the metabolism of SMZ in the rat. 3. As regards sex difference in the rat, the male had more metabolic capacity than the female in metabolism of SMZ. 4. The concenteration-time curves of sulfamethazine(20mg/kg, po) in the plasma compartment were fitted to a one-compartment open model by use of a computer program(NONLIN). 5. There were significant differences(P<0.05) in the pharmacokinetics of sulfamethazine between two sexes in the rat, with higher disposition rate in the male. 6. The emergence of $N_4AcSMZ$ metabolized from SMZ was fast in the plasma of the rat. Half-life of $N_4AcSMZ$ was also. significantly different(P<0.05) between two sexes, suggesting differences in the eliminatory capacity of $N_4AcSMZ$.

주거재료용 왕겨보드의 생물학적 평가

윤효인(Hyo In Yun),장범수(Beon Su Jang),임종환(Jong Hwan Lim),이화형(Hwa Hyoung Lee),한기선(Kie Sun Han) 한국가구학회 1999 한국가구학회지 Vol.10 No.2

As a countermeasure to reach self-sufficiency for wood supply and demand, we have to develop wood substitutes. Rice hull is the cheapest fiber material we can get in Korea, What is better the yield of rice hull amounts to 1 million tons per year.<br/> Before carrying out this study, new ecomaterial rice hull board for housing materials was developed successfully.<br/> In order to evaluate whether the rice hull board with or without bioceramic treatment is suitable for housing materials, we studied the environmental effects of the above materials in comparison with the polycarbonate, stainless, or concrete on the adaptation (body weight, water/ feed consumption, general signs, urinalysis, autopsy, etc.) and the reproduction (litter size, newborn adaptation, etc.) of mice.<br/> In conclusion, the concrete cage was the worst in the adaptation and so was the stainless steel cage in the reproduction. The rice hull board cage with or without bioceramic treatment was superior or equivalent to other material cages from the standpoints of the adaptation and reproduction.<br/> Key words: rice hull board, environmental effect valuation<br/>

돼지에서 근육주사한 Abamectin에 대한 HPTLC 분석 및 약물동태학

박승춘,윤효인,Park, Seung-chun,Yun, Hyo-in 대한수의학회 2000 大韓獸醫學會誌 Vol.40 No.1

We established a new method to analyze abamectin using HPTLC (high performance thin layer chromatography) in order to obtain its pharmacokinetic profiles in pigs. Recovery of abamectin in pig serum after fluorescence derivatization was $80.01{\pm}3.82%$ at 0.1ppm and $83.67{\pm}3.63%$ at 10ppm, respectively. Detection reproducibility in terms of coefficient variation (c.v.) was 3.09% and 2.74% (intra-day), and 3.71% and 51.7%(inter-day), for 0.1 and 10ppm, respectively. Pharmacokinetics of abamectin was studied in five Yorkshire-Landrace mixed bred male pigs ($35.0{\pm}2.7kg$) administered intramuscularly 0.3mg/kg b.w. Pharmacokinetic profiles of abamectin in pigs were described by the 1-compartment open model with first-order absorption and first-order elimination. AUC (area under the curve) was $262.65{\pm}16.44ng{\cdot}day/ml$ and the biological elimination half-life ($t_{1/2},\;k_e$) was $5.28{\pm}0.84$ days, indicating somewhat high bioavailability and long half-life by the intramuscular route. We suggest intramucular injection of abamectin could be also used in place of the recommended route of its subcutaneous administration so far.