• 생물정신의학
• /
• 제13권3호
• /
• pp.152-161
• /
• 2006

Objective : The relationship between the total daily dose of clozapine given and the plasma concentrations of clozapine and its metabolites(N-desmethylclozapine and clozapine N-oxide) and the effect of Glu158Lys (wild-type : Glu, 'H' ; variant : Lys, 'h') and Glu308Gly(wild-type : Glu, 'D' ; variant : Lys, 'd') variation in FMO3 gene on plasma concentrations of clozapine and its metabolites was studied in schizophrenic patients. Methods : Trough plasma concentrations of clozapine and its metabolites were measured in 34 schizophrenic patients receiving clozapine. The genetic variation of 'h' and 'd' in FMO3 were analyzed in 21 among 34 patients. Results : A linear relationship between the total daily dose of clozapine given(mg/kg body weight per day) and the plasma concentrations(nM) of clozapine was revealed by regression analysis(p<0.001) in the 23 patients receiving a constant daily dose of clozapine for 8 days. The plasma molar concentration ratios of clozapine N-oxide/clozapine in 8 subjects with 'hh' or 'Hh' alleles were not different from those in 6 subjects with 'HH' alleles and the plasma molar concentration ratios in 6 subjects with 'dd' or 'Dd' alleles were not different from those in 8 subjects with 'DD' alleles. Conclusion : The effect of Glu158Lys and Glu308Gly variation in FMO3 gene on clozapine metabolism could not be shown.

• The Korean Journal of Physiology and Pharmacology
• /
• 제16권2호
• /
• pp.113-118
• /
• 2012

Ginsenosides are low molecular weight glycosides found in ginseng that exhibit neuroprotective effects through inhibition of $N$-methyl-D-aspartic acid (NMDA) receptor channel activity. Ginsenosides, like other natural compounds, are metabolized by gastric juices and intestinal microorganisms to produce ginsenoside metabolites. However, little is known about how ginsenoside metabolites regulate NMDA receptor channel activity. In the present study, we investigated the effects of ginsenoside metabolites, such as compound K (CK), protopanaxadiol (PPD), and protopanaxatriol (PPT), on oocytes that heterologously express the rat NMDA receptor. NMDA receptor-mediated ion current ($I_{NMDA}$) was measured using the 2-electrode voltage clamp technique. In oocytes injected with cRNAs encoding NMDA receptor subunits, PPT, but not CK or PPD, reversibly inhibited $I_{NMDA}$ in a concentration-dependent manner. The $IC_{50}$ for PPT on $I_{NMDA}$ was $48.1{\pm}4.6\;{\mu}M$, was non-competitive with NMDA, and was independent of the membrane holding potential. These results demonstrate the possibility that PPT interacts with the NMDA receptor, although not at the NMDA binding site, and that the inhibitory effects of PPT on $I_{NMDA}$ could be related to ginseng-mediated neuroprotection.

• Bulletin of the Korean Chemical Society
• /
• 제32권4호
• /
• pp.1158-1164
• /
• 2011

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), a psychoactive tryptamine derivative, is a hallucinogenic drug of abuse. In this study, 5-OH-DIPT and its metabolites were identified and the quantitative method was developed and validated by using hydrophilic interaction chromatography-tandem mass spectrometry (HILICMS/MS). Chromatographic separation was achieved on an Atlantis HILIC silica column ($5{\mu}m$, $100{\times}2.1\;mm$). The metabolites of 5-MeO-DIPT in rat urine were characterized via Q1 scanning and product ion scanning. As a consequence, 5-MeO-IPT, 5-OH-DIPT, 6-OH-5-MeO-DIPT and their glucuronide conjugates were detected and identified as the metabolites of 5-MeO-DIPT. Subsequently, a quantitative method for 5-MeO-DIPT and its major metabolites, 5-MeO-IPT and 5-OH-DIPT, was developed in multiple reactions monitoring (MRM) mode. The calibration curves for all analytes evidenced good linearity over the concentration range of 1-1000 ng/mL with linear correlation co-efficients ($r^2$) in excess of 0.99. The intra- and inter-day accuracy and precision were 92.2-110.2% and 1.5-9.9%, respectively.

• Journal of Animal Science and Technology
• /
• 제64권2호
• /
• pp.247-261
• /
• 2022

Ketosis is associated with high milk yield during lactating or insufficient feed intake in lactating dairy cows. However, few studies have been conducted on the metabolomics of ketosis in Korean lactating dairy cows. The present study aimed to investigate the serum and urine metabolites profiling of lactating dairy cows through proton nuclear magnetic resonance (¹H-NMR) spectroscopy and comparing those between healthy (CON) and subclinical ketosis (SCK) groups. Six lactating dairy cows were categorized into CON and SCK groups. All experimental Holstein cows were fed total mixed ration. Serum and urine samples were collected from the jugular vein of the neck and by hand sweeping the perineum, respectively. The metabolites in the serum and urine were determined using ¹H-NMR spectroscopy. Identification and quantification of metabolites was performed by Chenomx NMR Suite 8.4 software. Metabolites statistical analysis was performed by Metaboanalyst version 5.0 program. In the serum, the acetoacetate level was significantly (p < 0.05) higher in the SCK group than in the CON group, and whereas acetate, galactose and pyruvate levels tended to be higher. CON group had significantly (p < 0.05) higher levels of 5-aminolevulinate and betaine. Indole-3-acetate, theophylline, p-cresol, 3-hydroxymandelate, gentisate, N-acetylglucosamine, N-nitrosodimethylamine, xanthine and pyridoxine levels were significantly (p < 0.05) higher in the urine of the SCK group than that in the CON group, which had higher levels of homogentisate, ribose, gluconate, ethylene glycol, maltose, 3-methyl-2-oxovalerate and glycocholate. Some significantly (p < 0.05) different metabolites in the serum and urine were associated with ketosis diseases, inflammation, energy balance and body weight. This study will be contributed useful a future ketosis metabolomics studies in Korea.

• 대한약리학회지
• /
• 제28권1호
• /
• pp.1-9
• /
• 1992

최근에 개발된 생체내 미세투석법을 이용하여 정상혈압 흰쥐(WKY)와 자연발생성 고혈압 흰쥐(SHR)의 후 시상하부에서 세포외액의 모노아민과 그 대사체들을 측정하였다. 뇌정위 고정장치에 의해서 미세투석관을 후 시상하부에 위치시킨후 링거액으로 관류하였다. 모노아민과 그 대사체들은 고속액체 크로마토그라피와 전기화학 검출기를 이용하여 정량하였다. 미세투석관의 시험관내 회수율 검사 결과, 관류액의 유속과 신경화학물질의 상대적 회수율 사이에는 역비례 관계가 있음이 확인되었다. 정상 혈압 흰쥐에서 후 사상하부의 관류액으로 부터 축정한 각종 신경화학물질의 세포외액 농도는 도파민 32nM, 노르에피네프린 50nM, 에피네프린 50nM, 세로토닌 73nM, 3.4-dihydroxyphenylacetic acid(DOPAC) 281 nM, homovanillic acid(HVA) 181 nM, 5-hydroxyindoleacetic acid(5HIAA) 3767nM이었다. 후 시상하부에서 측정된 신경전달물질의 기준치는 WHY와 SHR사이에 차이가 없었으나, DOPAC, HVA, 5HIAA의 기준치는 WKY에 비해서 SHR에서 유의하게 높게 나타났다. 본 연구는 중추 신경화학물질들의 생체내 측정에 미세투석법을 이용할 수 있음을 보여주었다.

• 한국식품영양과학회지
• /
• 제27권5호
• /
• pp.1015-1018
• /
• 1998

Capsaicin(8-methyl-N-vanillyl-6-nonenamide: CAP) known well as a major compound of not taste in hot pepper, was investigated for the inhibition effect on in vitro nitrosation. CAP(100$\mu$mol) inhibited the formation of N-nitrosoproline(NPRO) and N-nitrosothioproline(NTPRO) by 56% and 26%, respectively. Vanillyl alcohol inhibited the nitrosation of proline by a concentration-dependent manner, and vanillic acid and vanillin were less effective in blocking the nitrosation of proline compared to CAP and anillyl alcohol. The inhibitory effect of NPRO formation by CAP was evaluated to similar with alpha-tocopherol, and vanillyl alcohol was more effective than alpha-tocopherol in blocking the nitrosation of proline. Our results suggested that CAP and its metabolites such as vanillyl alcohol could inhibit endogenous nitrosation in hydrophobic biological environment.

• 환경분석과 독성보건
• /
• 제21권4호
• /
• pp.243-251
• /
• 2018

Pharmaceuticals in wastewater effluents have been recognized as emerging pollutants threatening freshwater organisms. To extend understanding for bioaccumulation and toxicity in those organisms, information on biotransformation products (or metabolites) and their metabolic pathway are crucial. The aim of the present study is to identify and elucidate metabolites of pharmaceuticals formed in exposed organisms using suspect and nontarget screening approach using LC-HRMS. As the target pharmaceuticals, carbamazepine, ketoprofen, metoprolol, propranolol, and verapamil were selected whereas Daphnia magna and Gammarus pulex were used as test organisms. After 24h exposure, metabolites formed in the organisms were identified using LC-HRMS. The structures of metabolites were elucidated via analysis of MS/MS fragment pattern and the comparison with fragment database. As the results, a total of 10 metabolites were identified for 5 parent compounds (C253/C356 for carbamazepine, K211 for ketoprofen, M256 for metoprolol, P218/P276/P306 for propranolol, V196/V291/V441 for verapamil). Among them, the presence of C253 and V291 was confirmed using standard materials. Most of the identified metabolites were formed through oxidative reactions such as hydroxylation, N-demethylation, and dealkylation. Cysteine conjugation (phase II reaction) metabolite (C356) for carbamazepine was found in daphnia. The metabolic pathway of verapamil showed similar metabolic pathways and metabolic pathways for both species. Although the toxicological information on the identified metabolites could not be confirmed, the molecular structure information of the proposed metabolites can be used for future evaluation and prediction of toxicity.

• 분석과학
• /
• 제23권5호
• /
• pp.437-445
• /
• 2010

본 연구에서는 동물용 의약품으로 널리 사용되고 환경 중 잔류 가능성이 높은 설폰아미드계 항생제 5종 (sulfadiazine, sulfamerazine, sulfamethazine, sulfamethoxazole, sulfathiazole) 및 대사체 5종($N^4$-acetylsulfadiazine, $N^4$-acetylsulfamerazine, $N^4$--acetylsulfamethazine, N4-acetylsulfamethoxazole, sulfamethoxazole-$N^1$-glucuronide)의 분석방법을 연구하였다. 다양한 전처리 조건을 비교 검토하여 최적의 동시 추출방법과 LC/ESI-MS/MS를 이용한 기기분석 조건을 확립하였다. 카트리지별 추출효율은 C18 카트리지에서 12~94%, HLB 카트리지에서 60-95%, MCX 카트리지에서 25-123%였으며, MCX와 HLB 카트리지를 결합한 방법의 회수율은 70-90%이었다. HLB를 선택하여 확립된 분석방법의 회수율은 66~115%, 상대표준편차 5~17%이었으며, 방법검출한계는 0.001~0.187 ng/mL 였다. 이를 실제 환경시료에 적용한 결과 4종의 설폰아미드 항생제가 0.008~2.153 ng/mL 농도범위로 검출되었으며, 대사체의 경우 $N^4$-acetylsulfamethoxazole이 확인되었으나 검출한계 미만으로 관찰되었다.

• 약학회지
• /
• 제36권3호
• /
• pp.230-240
• /
• 1992

The metabolic profile of doxylamine, N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy] ethanamine, was determined in the human urine. The free fractions of extracts were obtained without hydrolysis, and the conjugated fractions of extracts were obtained with enzyme hydrolysis using ${\beta}-glucuronidase/arylsulfatase$ from Helix pomatia. The mixture of acetic anhydride/pyridine (10 : 1, v : v) was used to derivatize the urinary extracts and then analyzed by gas chromatography and mass selective detector. N-desmethyldoxylamine, doxylamine carboxylic acid, desaminohydroxydoxylamine, N, N-didesmethyldoxylamine, N-acetyl conjugates of N-desmethyl and N, N-didesmethyldoxylamine, quarternary ammonium N-glucuronide of doxylamine, N-desmethyldoxylamine N-glucuronide and unchanged doxylamine were detected in the human urine obtained after oral treatment with doxylamine succinate. $N-methyl-{\alpha}-hydroxy-2-[1-phenyl-1-(2-pyridinyl)$ ethoxy] ethanamine, which can be a key intermediate of this metabolism, was tentatively identified by the interpretation of its mass spectrum. In this study, we proposed the metabolic pathway of doxylamine in the human on the basis of our data of the identified metabolites of doxylamine.

• Mass Spectrometry Letters
• /
• 제14권1호
• /
• pp.1-8
• /
• 2023

Eutylone, dibutylone, and dimethylone are potential psychotropic designer drugs. The purpose of this study was to investigate the in vitro metabolic pathways of synthetic cathinones with methylenedioxy groups. The three methylenedioxy derivatives were incubated with human liver microsomes. The metabolites were characterized based on liquid chromatography and quadrupole-time-of-flight mass spectrometry. Eutylone, dibutylone, and dimethylone were metabolized to yield three, six, and four metabolites, respectively. Reduction and demethylenation were the major metabolic pathways for all three drugs tested. However, dibutylone and dimethylone showed an additional metabolite generated via N-oxidation. These results provide evidence for the in vivo metabolism of methylenedioxy synthetic cathinones, and could be applied to the analysis of synthetic cathinones and their relevant metabolites in biological samples.