• The Korean Journal of Physiology and Pharmacology
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• 제1권6호
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• pp.759-767
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• 1997

In the present study, we characterized the non-vascular smooth muscle relaxant effects of a novel benzoyran derivative ,SKP-450 (2-[2'(1',3'-dioxolone)-2-methyl-4- (2'-oxo-1'-pyrrolidinyl) -6-nitro-2H-1- benzopyran) and its metabolite, SKP-310, in comparison with levcromakalim (LCRK). In the rat stomach fundus, the spontaneous motility stimulated by $10^{-6.5}\;M$ bethanechol was completely eliminated not only by $10^{-7}\;M$ SKP-450 but also by $10^{-6}\;M$ LCRK, which were blocked by $10^{-6}\;M$ glibenclamide. The inhibitory effect of SKP-450 $pD_2,\;3.94{\pm}0.66)$ was much less than LCRK $(pD2,\;5.73{\pm}0.38,\;p<0.05)$. In the bethanechol $(10{-6.5 }\;M)-stimulated$ urinary bladder, the tonus was decreased in association with elimination of spontaneous motility by $10^{-7}\;M$ M SKP-450 and $10^{-6}\;M\;LCRK\;(pD2,\;6.77{\pm}0.06)\;(P<0.05)$, which were inhibitable by $10^{-6}\;M$ glibenclamide. The inhibitory effect of SKP-450 $(pD2,\;7.66{\pm}0.05)$ was significantly more potent than that of LCRK $(pD2,\;6.77{\pm}0.06,\;p<0.05)$. In the rat uterus stimulated by $PGF_{2\alpha}\;(10^{-7}\;M)$, both increased tonus and spontaneous motility were eliminated by $10^{-6}\;M$ LCRK with slight depression of the tonus, but not by SKP-450 $(10^{-5}\;M)$. The stimulated trachea of guinea-pig by $10^{-6.5}\;M$ bethanechol was moderately suppressed by SKP-450 $(10^{-6}{sim}10^{-5}\;M)$ but little by SKP-310. In association with the relaxant effects, SKP-450 $(10^{-6}\;M)$ and LCRK $(10^{-5}\;M)$ caused a significant stimulation of the $^{86}Rb$ efflux from rat urinary bladder and stomach fundus, which were antagonized by $10^{-5}\;M$ glibenclamide, whereas the $K^+$ channel openers could not exert a stimulation of the $^{86}Rb$ efflux from rat uterus. In conclusion, it is suggested that SKP-450 exerts potent relaxant effects on the urinary bladder detrusor muscle and duodenum, whereas it shows much less effect on stomach fundus and uterus as contrasted to LCRK.

• 대한의생명과학회지
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• 제5권1호
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• pp.59-66
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• 1999

실험동물에 xylene의 반복 투여가 이물질의 대사에 어떠한 영향을 미치는지를 알아보기 위하여 흰쥐에 m-xylene과 olive oil의 동량혼합액을 체중 100 g당 0.25 ml씩 2일 간격으로 1, 4, 8, 12 및 16회 복강으로 투여한 다음 마지막 투여 24시간 후에 처치하여 다음과 같은 결과를 얻었다. 요 중 m-methylhippuric acid함량은 m-xylene 4회 투여군의 경우 1회 투여군에 비하여 약 56%의 유의한 증가를 보였으며 이후 12회 투여까지 유사한 결과를 나타내었으나 m-xylene 16회 투여시에는 xylene 1회 투여군 치와 유사한 치로 감소되었다. 그리고 간조직의 microsomal aniline hydroxylase와 alcohol dehydrogenase 활성은 m-xylene 12회 투여시 까지는 대체적으로 점진적인 증가를 보였으나 이후 16회 투여시에는 12회 투여군에 비하여 유의한 감소를 보였다. 또한 aldehyde dehydrogenase 활성은 m-xylene투여 회수에 비례해서 전 실험기간 동안 감소되었으며 특히 16회 투여군에서 본 효소활성의 현저한 감소를 보였다. 한편 본 실험조건에서 투여기간에 따른 전자현미경적 미세구조의 변화는 초기에 활면소포체의 증식이 보이다가 16회 투여군에서는 활면소포체가 감소되고 조면소포체가 증가되었다. 이상 실험결과는 흰쥐에 있어서 xylene투여 회수에 따라서 요 중 m-methylhippuric acid의 농도 변동이 초래되며 이는 효소단백 유도에 따른 xylene 대사효소 활성 변동에 기인된 결과로 생각된다.

• 분석과학
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• 제11권5호
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• pp.353-359
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• 1998

국제 올림픽 위원회에서 금지하고 있는 합성 동화성 스테로이드로서 다양한 생물학적 효과를 나타내고 있는 danazol을 대상으로 androgenic 효과를 확인하기 위해 성인 남자 3명에게 100 mg씩 복용하게 한 후 그들의 소변을 채취하였다. 인체내 대사과정에서 생성되는 주요 대사체인 ethisterone의 배설에 따른 8가지의 내인성 스테로이드들의 배설정도를 GC/MS의 selected ion monitoring(SIM) 방법으로 동시분석 하였다. 그 결과 본실험방법에서 내인성 스테로이드들에 대한 회수율은 71.59%~93.56% 이었으며, within-a day 및 day-to-day 분석에서의 RSD 값은 각각 1.87%~10.48%와 1.32~11.25%이었다. 이때의 검출한계는 $0.01{\sim}0.05{\mu}g/mL$ 이었다. 각각의 내인성 스테로이드들과 ethisterone의 표준물질을 뇨시료에 0.1, 0.5, 1.0, 10, 20 그리고 $50{\mu}g/mL$를 첨가하여 작성한 검정곡선은 전체적으로 상관계수 0.963~0.991의 직선성을 보였다. 따라서 본 실험은 내인성 스테로이드들의 변화를 관찰함으로서 간접적으로 스테로이드 계열의 금지약물 복용여부를 판단할 수 있는 방법으로 매우 유용함을 알 수 있었다.

• Journal of Pharmaceutical Investigation
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• 제31권4호
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• pp.265-271
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• 2001

In order to elucidate the influence of intestinal and hepatic first-pass effect on the pharmacokinetics of triflusal, the biotransformation of triflusal in the gastrointestinal tract and liver was designed. Moreover, we tried to establish an HPLC method applicable for bioassay and available to pharmacokinetics, not only with the simultaneous determination of triflusal and its active metabolite, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), but also with improving sensitivity. After the administration of triflusal (10 mg/kg) and HTB (10 mg/kg) into femoral vein, portal vein (only triflusal) and oral route (only triflusal), pharmacokinetic parameters were investigated from the plasma concentration-time profiles of triflusal and HTB in rats. An HPLC method was developed for the simultaneous determination of triflusal and HTB in rat plasma, urine and bile. The HPLC analysis was carried out using a C18 column and acetonitrile-methanol-water (25:10:65, v/v/v) as the mobile phase and UV detection at 234 nm. Furosemide was used as the internal standard. The calibration curves were linear over the concentration range $0.05-5.0\;{\mu}g/ml$ for triflusal and $0.2-200.0\;{\mu}g/ml$ for HTB with correlation coefficients greater than 0.999 and with intra-day or inter-day coefficients of variation not exceeding 10.0%. This assay procedure was applied to the study of metabolite pharmacokinetics of triflusal and HTB in rats. It was supposed that triflusal was almost metabolized in vivo because urinary and biliary excreted amounts of triflusal could be ignored as it was lower than 1.2% of the administered dose. According to the gastrointestinal and hepatic biotransformation pathways of triflusal, it was found that triflusal was hydrolyzed by about 5% in intestine and metabolized by about 53% in liver, and that the bioavailability of triflusal after oral administration of triflusal was 0.44, and also that the fraction of total elimination rate of triflusal which formed HTB in liver $(F_{mi},\;%)$ was about 98%. These results showed that triflusal was almost metabolized in liver, and the total elimination of triflusal in the body was dependent to the formation rate of HTB from triflusal in liver.

• 한국산업보건학회지
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• 제19권1호
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• pp.73-79
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• 2009

This study was undertaken to investigate the effects of single and combined exposure of toluene (T) and xylene (X) on the cytochrome-450(CYP)-mediated metabolizing capacity, induction of CYP isozymes and the excretion of their metabolites in urine. Animal were adults male Sprague-Dawley (SD) rats and divided into 4 groups such as control, T (treated with 63.7 mg/body kg), X (treated with 65.9 mg/body kg) and TX(T=X). Organic solvents was administrated by intraperitoneal injection for 3 days. The contents of protein and CYP in liver microsomes of control group were $16.48{\pm}0.56 mg/m{\ell}$ and $0.744{\pm}0.025$ nmol/mg protein, respectively, and they contents were significantly lower than in derived from treated groups (p<0.01). The activities of PROD and ${\rho}NPH$ were significantly higher in single treated groups than in control and combined group (TX). When Western immunoblotting were carried out with two monoclonal antibodies (MAb 1-98-1 and MAb 2-66-3) which were specific against CYP2B1/2 and CYP2E1, respectively, a strong signal corresponding to CYP2B1/2 was observed in microsomes obtained from rats treated with X and TX. The color density against CYP2E1 was slightly increased in T and TX groups compared with C and X groups. The amounts of urinary hippuric acid in T single treated group was $3.29{\pm}1.97$ g/g creatinine and TX combined group was $2.91{\pm}1.76$ g/g creatinine, but was not significant. However, amount of urinary methy hippuric acid in X single treated group ($1.62{\pm}0.72$ g/g creatinine) was significantly higher than TX combined group ($0.93{\pm} 0.63$ g/g creatinine)(p<0.01). These results suggested that CYP2E1 isozyme might be responsible for the metabolism of T, and CYP2B1/2 isozyme is for X. And also, difference of metabolites level between single and combined group may be speculated that the intermediates of T and X interacted each other in the process of their metabolite formation reaction.

• Journal of Preventive Medicine and Public Health
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• 제31권4호
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• pp.680-691
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• 1998

본 연구는 흰쥐와 마우스에서 TCE 경구투여 후 주대사산물인 TCE-OH와 TCA의 요중 배설량과 시간에 따른 배설량의 변화와 이에 대한 ethanol의 영향 및 종간의 차이를 조사하여 다음과 같은 결과를 얻었다. 1. TCE 경구 투여 후 요중 TTC 배설양상은 실험동물의 종간에 현저한 차이가 있었으며, 흰쥐에서는 TTC 배설량이 투여량에 따라 증가하다가 체중 kg당 1,000 mg 용량 이상에서 포화되는 양상을 나타내었으나, 마우스에서는 2,000 mg까지 거의 선형적으로 증가하였다. 투여용량에 따른 TTC 배설 량은 흰쥐보다 마우스에서 유의하게 높았다(p<0.01). 2. TCE 투여 후 경과시간에 따른 대사산물 배설양상은 종이나 투여용량에 관계없이 비슷한 양상을 나타내었다. TCE-OH는 12시간에서 거의 대부분$(82.8\sim87.6%)$이 배설되었으며, TCA는 12 시간 $(39.2\sim41.6%)$과 24시간$(33.4\sim36.6%)$에 최고치를 보였고 그 후 서서히 배설되었다. 3. Ethanol 전처치시 횐쥐에서는 TTC와 TCE-OH 배설량이 유의하게 증가하였으나(p<0.01), TCA 배설량은 증가하지 않았다. 마우스에서는 TTC, TCE-OH 및 TCA 배설량 모두 ethanol 군과 대조군 사이에 유의한 차이가 없었다.

• 한국환경보건학회지
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• 제50권1호
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• pp.25-35
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• 2024

Background: There are concerns about the health effects of various environmental pollution exposures among residents living near coal-fired power plants (CFPP). Objectives: This study attempted to compare the concentrations of heavy metals in blood and urine and those of urinary volatile organic compound (VOC) metabolites according to the residential separation distance. Methods: Participants in the study totaled 334 people who have lived for more than 10 years in areas within 10 km of a CFPP. The separation distance was analyzed in quartiles by dividing it into Q1 (88 people), Q2 (89 people), Q3 (89 people), and Q4 (68 people). We explained the purpose of this study to the participants and collected blood and urine after obtaining signatures on a participation agreement. Results: The study participants were 102 males (30.5%) and 232 females (69.5%), with an average age of 71. The average length of residence and distance were 43.8 years and 4,800 meters. The geometric mean concentrations of Pb, Cd, and Hg in blood and As and Cd in urine were respective 1.35 ㎍/dL, 1.43 ㎍/L, 3.16 ㎍/L. They were 167.88 ㎍/g for creatinine and 1.58 ㎍/g creatinine. The metabolite concentrations of VOCs were 50.67 ㎍/g creatinine in t, t-muconic acid (t, t-MA), 10.73 ㎍/g creatinine in benzyl mercapturic acid, 317.05 ㎍/g creatinine in phenylglyoxylic acid, 123.55 ㎍/g creatinine in methylhippuric acid, and 190.82 ㎍/g creatinine in mandelic acid. The concentration of Pb in the blood and Cd and t, t-MA in the urine of residents within affected area of the CFPP showed statistically significant differences among distance groups. Conclusions: The concentration of urinary VOCs metabolites, especially t, t-MA, differed according to the distance groups of residents within the affected area of CFPP (p<0.05).

• Biomolecules & Therapeutics
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• 제5권1호
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• pp.82-86
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• 1997

Pharmacokinetics of a new capsaicin analog, DA-5018 were evaluated after a subcutaneous injection or topical application of $[^{14}C]$--labelled or unlabelled DA-5018 to rats and rabbits. After subcutaneous injection of $_{14}$c-labelled or unlabelled DA-5018, 0.5 mg/kg (equivalent to DA-5018) to rats, the plasma total activity peaked at 2 hr with the terminal half life of 5.34 hr, however, unlabelled-DA-5018 peaked at 1 hr with the terminal half life of 1.26 hr. Moreover, the AUC (0.726 versus 0.2337g hr/ml) and MRT (7.82 versus 3.55 hr) increased significantly based on total radioactivity compared with intact DA-5018. Above data indicated that DA-5018 is extensively metabolized in rats and the terminal half- life of the metabolite(5) had a longer half-life than that of DA-5018. The cumulative percentages of biliary excretion of dose after subcutaneous injection of $[^{14}C]$DA-5018 was 40.2%, however, the value was only 2.14% when unlabelled DA-5018 was injected. After topical application of 0.1% or 0.3% $_{14}$C-labelled or unlabelled DA-5018 cream, 500 mg/kg to rats, the plasma and tissue concentrations except applied skin were under the detection limit. After consecutive 7 days topical application of unlabelled DA-5018, 0.1% and 0.3% cream to rats, the plasma concentrations were also under the detection limit. But the urinary excretion of DA-5018 was significantly increased by repeated topical administration. After topical application of unlabelled DA-5018, 0.1% and 0.3% cream to rabbits, the plasma and urine concentrations were under the detection limit. Above data indicated that the skin permeation of DA-5018 was lower and the metabolism of DA-5018 was higher in rabbits than that in rats.

• Journal of Preventive Medicine and Public Health
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• 제37권2호
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• pp.127-132
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• 2004

Objectives : Cotinine, the major metabolite of nicotine, is a useful marker of exposure to tobacco smoke and self-reporting of smoking status is thought not to be reliable. This study aimed to evaluate the agreement between the smoking self-report among adolescents and the urinary cotinine test. Methods : The study subjects were 1226 middle and high school students in Hanam city, who were selected by stratified random sampling. The self-report about smoking behavior was compared with urine cotinine value measured with PBM $AccuSign^{\circledR}fi$ Nicotine(Princeton BioMeditech Corporation, USA). The percentage agreement, kappa and 95% confidence interval(CI) were calculated. Results : The overall percentage agreement was 88.6%, and those for boys, girls, middle school, general school and vocational school students were 87.3%, 90.1%, 93.7%, 85,5%, 90.7%, and 78.4%, respectively. The overall kappa index was 0.46(95% CI=0.39-0.54)for overall, .and those for boys, girls, middle school, general school and vocational school students were 0.56(95% CI=0.48-0.65), 0.20(95% CI=0.07-0.32), 0.21(95% CI=0.09-0.34), 0.55(95% CI=0.47-0.64), 0.42(95% CI=0.33-0.52), and 0.48(95% CI=0.36-0.60), respectively. Conclusion : The percentage agreement was relatively high but the kappa values very low for girls, and middle school students. Though the prevalence bias can be influenced by these results, the self-report was not a sufficient tool for the evaluation of adolescents' smoking status, especially in girls or middle school students.

• The Korean Journal of Physiology and Pharmacology
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• 제1권5호
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• pp.597-602
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• 1997

Cytochrome P450 2E1 (CYP2E1) is involved in the toxicity and carcinogenicity of a number of solvents and xenobiotics. Like the various types of oxidation pharmacogenetics, the activity of the enzyme shows a discernible interindividual and interethnic variation. However, no pharmacogenetic information on CYP2E1 polymorphism has been available from a Korean population. The aim of this study was to explore the pharmacogenetics of CYP2E1 polymorphism in a native Koreans after an oral 400 mg dose of chlorzoxazone administered to 128 subjects. Urine samples were collected during the subsequent 8-hour period and urinary concentrations of chlorzoxazone and 6-hydroxychlorzoxazone were determined by a high performance liquid chromatography with an ultraviolet detector. The limit of detection in the samples was found to be $0.5\;{\mu}g/ml$. The mean value of the 6-hydroxychlorzoxazone excreted in 8 hr urine expressed as the percentage was 48.2 13.8%. The frequency distribution of percentage of the administered dose excreted as the 6-hydroxy metabolite was unimodally distributed in the subjects studied. However, the values showed wide (7-fold) interindividual difference, ranged from 11.6% to 79.8% of the dose of chlorzoxazone. Thus, it was considered that the pharmacogenetic characteristics of CYP2E1 in a Korean population did not represent multimodal distribution in the 6-hydroxychlorzoxazone excreted in 8-hr urine expressed as the percentage. And the activity of the CYP2E1 in a Korean population seemed to be less compared with that of the Caucasian subjects.