6－甲氧基正丁苯酞的体内代谢转化研究

大鼠用６－甲氧基正丁苯酞（ＭＢＰ）灌胃，收集０～２４ｈ尿液，经酶水解、提取浓缩、衍生化处理后用ＧＣ／ＭＳ分析。在大鼠０～２４ｈ尿液中，６－甲氧基正丁苯酞原药含量很低，主要以代谢物形式存在，依次为Ｃ－６脱甲基产物、Ｃ３－Ｃα环氧化物、γ－羟化物、β－羟化物以及两个次级代谢产物。６－甲氧基正丁苯酞体内代谢结果与其在肝微粒体中代谢结果基本一致。     

6-甲氧基正丁苯酞在大鼠肝微粒体中的代谢研究

报道了用GC/MS方法及衍生化技术研究6-甲氧基正丁苯酞(MBP)在大鼠肝微粒体中的代谢转化结果。6-甲氧基正丁苯酞在苯巴比妥(PB)诱导的大鼠肝微粒体中主要转化为3-羟基、γ-羟基取代物,6-羟基正丁苯酞与一个环氧化代谢产物。     

LC/DAD/MSD技术研究大鼠胆汁中盐酸非洛普的II相代谢产物

目的研究大鼠服药后胆汁中盐酸非洛普(DDPH)II相代谢产物.方法收集大鼠空白胆汁及给药后12h内的胆汁,以LC/DAD/MSD技术判断II相代谢产物峰位.以HPLC法制备II相代谢产物馏分并以β-葡糖醛酸酶水解,再进行分析;同时将与II相代谢产物相应的I相代谢产物对照品按相同条件进行分析对照.结果大鼠给药后胆汁色谱图中峰M₇,M₈和M₉为DDPH的II相代谢产物,它们的β-葡糖醛酸酶水解产物分别为M₃,M₂和M₁.结论β-1-O-{3,5-二甲基-4-[-2-甲基-2-(3,4-二甲氧基苯乙氨基)-乙氧基]-苯基}-葡糖醛酸(M₇),β-1-O-{2,4-二甲基-3-[2-甲基-2-(3,4-二甲氧基苯乙氨基)-乙氧基]-苯基}-葡糖醛酸(M₈)和β-1-O-{2-甲氧基-4-[1-甲基-2-(2,6-二甲基苯氧基)-乙氨基-乙基]-苯基}-葡糖醛酸(M₉)为大鼠ipDDPH后产生的II相代谢产物.     

拟人参皂苷F11在大鼠体内的药物代谢研究

目的探讨拟人参皂苷F11在大鼠体内的药物代谢产物及其过程.方法ip拟人参皂苷F₁₁后,应用TLC分析排泄物中的代谢产物,并利用制备薄层分离制备代谢产物,通过波谱解析(MS,¹HNMR,¹³CNMR,¹H-¹HCOSY)确定其结构.结果从粪便中分离鉴定了3种代谢产物,分别为拟人参皂苷R_T5,ocotillol和1个新的代谢产物F-3-1,并确定其结构为6-O-α-L-吡喃鼠李糖基(1-2)-β-D-吡喃葡糖基-(20S,23S,24R)-达玛-20(24)-环氧-3β,6α,12β,23,25-五醇(6-O-α-L-rhamnopyranosyl-(1-2)-β-D-glucopyranosyl-(20S,23S,24R)-dammar-20(24)-epoxy-3-β,6α,12β,23,25-pentanol).但在尿液和胆汁中并未发现任何代谢产物.结论拟人参皂苷F₁₁不被肝脏代谢,但胆汁排泄物可在肠道被代谢为水解和氧化产物.     

用固相萃取-核磁共振氢谱法研究大鼠尿液中R-(-)-布洛芬光活代谢产物

目的　用固相萃取-核磁共振氢谱法研究大鼠尿液中R-(-)-布洛芬代谢产物及异构体的转化。方法　将服用R-(-)-布洛芬后0～24 h大鼠尿液经固相萃取柱处理、核磁共振氢谱测定代谢产物的结构。结果　尿液中含有4个主要代谢产物：2＇-羟基-布洛芬及其葡糖苷酸结合物、1＇-羧基-布洛芬葡糖苷酸和布洛芬葡糖苷酸。后两者为非对映异构体混合物。结论　R-(-)-布洛芬在大鼠体内发生了异构体转化,异丁基侧链中末端甲基的氧化代谢具有立体选择性。     

6－甲氧基正丁苯酞在大鼠肝微粒体中的代谢研究

报道了用ＧＣ／ＭＳ方法及衍生化技术研究６甲氧基正丁苯酞（ＭＢＰ）在大鼠肝微粒体中的代谢转化结果。６甲氧基正丁苯酞在苯巴比妥（ＰＢ）诱导的大鼠肝微粒体中主要转化为３羟基、γ羟基取代物，６羟基正丁苯酞与一个环氧化代谢产物     

牡荆素在大鼠体内的代谢研究

目的 研究黄酮碳苷牡荆素在大鼠体内的代谢产物,并推测其代谢途径。方法 SD大鼠灌胃给予5 mg·kg^-1牡荆素,收集0~3 h,3~6 h,6~12 h的尿液,采用UPLC-Q-TOF检测尿样中代谢产物。结果 采用Metabolynx XS代谢物分析软件,根据质谱碎片信息对代谢物进行结构鉴定,最终得到3个代谢产物。结论 牡荆素在大鼠尿液中检测得到1个一相代谢产物,2个二相代谢产物,推测牡荆素在大鼠体内主要发生氧化、甲基化和葡萄糖醛酸结合反应,其中葡萄糖醛酸化反应是较强的代谢种类。     

LC-MS/MS鉴定木兰花碱在大鼠体内外主要代谢产物

目的 研究木兰花碱在大鼠体内外的主要代谢产物及代谢途径。方法 SD大鼠ig木兰花碱（50 mg/kg）,收集0~24 h尿液和粪便,0~6 h胆汁以及1、2、4、6、8 h血浆;体外代谢采用肝微粒体温孵系统和肠菌培养液。利用LC-MS/MS对生物样品中的原型药及代谢产物进行鉴定。采用Agilent TC-C₁₈色谱柱（150 mm×4.6 mm,5 μm）,以乙腈-0.1%甲酸水溶液为流动相梯度洗脱,体积流量1.0 mL/min,柱温30℃。质谱采用电喷雾电离源（ESI）,正离子采集模式;扫描范围m/z100~1 000。根据药物体内代谢规则,结合木兰花碱的色谱保留时间和多级质谱碎片离子特征,推测其代谢产物的结构。结果 给药后生物样品中共鉴定出12个代谢产物,其中Ⅰ相代谢产物8个,Ⅱ相代谢产物4个。主要的代谢途径为羟基化、去甲基化、脱氢作用、酮基化、葡萄糖化、葡萄糖醛酸化及硫酸酯化。结论 木兰花碱在体内可发生Ⅰ相和Ⅱ相代谢,肠道菌群和肝药酶可催化木兰花碱发生Ⅰ相代谢转化,Ⅱ相代谢存在于肠道以外部位,最有可能的部位是肝脏。     

3种不同材质输液器对丁苯酞氯化钠注射液中丁苯酞的吸附考察

摘 要 目的：考察3种不同材质输液器对丁苯酞氯化钠注射液的吸附性,为临床选择输液器提供参考。方法: 采用HPLC法,色谱柱：Eclipse XDB C₁₈柱（150 mm×4.6 mm,5 μm）;流动相：甲醇-0.05 mol·L^-1磷酸二氢钾溶液（60∶40）;流速：1.0 ml·min^-1;检测波长：280 nm;柱温：30℃;进样量为10 μl。结果: 丁苯酞在60.90～487.20 μg·ml^-1浓度范围内呈良好的线性关系（r=0.999 9）,平均回收率为99.9%（RSD=0.3%,n9）。聚氯乙烯输液器对丁苯酞的吸附最为严重,聚丙烯和聚乙烯输液器对丁苯酞的吸附较少。结论:采用的HPLC法简便、准确、灵敏度高,可用于丁苯酞的含量测定。聚氯乙烯输液器不适用于丁苯酞氯化钠注射液的静脉滴注,建议选择聚丙烯和聚乙烯输液器。     

人参皂甙Rb1的肠内菌代谢

通过离体及整体实验观察了人和大鼠肠内菌对人参皂甙Rb₁（G-Rb₁）的代谢。方法：采用薄层色谱（TLC）和电喷雾质谱（ESI-MS）检测G-Rb₁及其代谢产物。结果：离体实验表明,G-Rb₁容易被大鼠和人消化道菌群代谢,随着代谢时间的延长,相继出现Rd, Rg₃/F₂, Rh₂/C-K和Ppd 4种代谢产物。给大鼠ig G-Rb₁ 500 mg.kg^-1后收集4 h和6 h粪,提取G-Rb₁的代谢产物,证明粪中存在Rd和Rg₃/F₂两种代谢产物。结论：G-Rb₁可被人和大鼠肠内菌代谢,其代谢模式为G-Rb₁→Rd→F₂→compound K（C-K）→20（S）protopanaxadiol（Ppd）。     

海南粗榧新碱衍生物HH07A在大鼠体内的代谢转化研究

用GC-MS联用技术对海南粗榧新碱衍生物HH07A在大鼠体内代谢转化进行了研究。尿样经XAD-2固相提取、酶水解、浓缩并硅烷化,用GC-MS联用仪分离鉴定尿中HH07A及其4个代谢物,推断4个代谢物结构及其体内代谢途经。     

Biochemical studies on phthalic esters. III. Metabolism of dibutyl phthalate (DBP) in animals

The excretion, distribution and metabolism of DBP were studied in rats. More than 90% of the dose was excreted in the urine within 48 h following intravenous or oral administration, but the faecal excretion was low. Biliary excretion was remarkably higher than that in the faeces when DBP was given orally. No significant retention was observed in organs and tissues at 24 h after dosing. In vitro experiments showed that DBP was hydrolysed very rapidly to MBP by the esterase of rat liver microsome. DBP was found to be a strong inhibitor for the succinate dehydrogenase of rat liver. DBP and its metabolites, MBP and phthalic acid, did not produce any striking effect upon hepatic and serum enzyme activities in vitro. Urinary metabolites of orally ingested DBP were investigated in 3 species, namely, rats, hamsters and guinea pigs. MBP was a common major metabolite in all 3 species. A further increment was apparently excreted as the glucuronide in the rat, hamster and guinea pig together with a small amount of phthalic acid and unchanged DBP. Omega- or omega-1 oxidation products of MBP were also detected in the urine.     

Differences in urinary metabolic profile from di-n-butyl phthalate-treated rats and hamsters. A possible explanation for species differences in susceptibility to testicular atrophy

A high-performance liquid chromatographic method for the direct analysis of the urinary metabolites of di-n-butyl phthalate (DBP) is described. In both rats and hamsters the major urinary metabolite found after treatment with either DBP or mono-n-butyl phthalate (MBP) was MBP glucuronide and not MBP as previously reported. The levels of unconjugated MBP in the urine of animals treated with DBP or MBP were three- to fourfold higher in the rat than in the hamster. However, intestinal esterase activities were comparable in the two species, whereas the activities of testicular beta-glucuronidase were significantly higher in rats compared to hamsters. It is possible that the differences in the concentration of free MBP, a substance known to produce testicular damage directly in the rat in vitro, may account for the lack of injury seen in hamsters after oral treatment with either DBP or MBP.     

Comparative embryotoxicities of butyl benzyl phthalate, mono-n-butyl phthalate and mono-benzyl phthalate in mice and rats: in vivo and in vitro observations

The embryotoxic effects of butyl benzyl phthalate (BBP) and its two main metabolites mono-n-butyl (MBP) and mono-benzyl (MBzP) phthalate were evaluated in OF1 mice and Sprague-Dawley rats, in vivo and in whole embryo culture. In vivo, pregnant mice and rats received a single oral dose (0.9-5.4 mmol/kg) of either of these compounds on GD 8 and 10, respectively, and their fetuses were examined externally on GD 18 and 21, respectively. In mice, BBP, MBP and MBzP caused concentration-related embryolethality and malformations. In rats, MBP and MBzP did not show developmental toxicity. Some teratogenicity and a slight increase in post-implantation loss were observed after BBP administration, but mice were more susceptible to its toxic effects than were rats. In vitro, GD 8 mouse embryos and GD 10 rat embryos were cultured for 46 h in the presence of the test compounds (0.5 to 3-5mM). The cultured mouse embryos did not appear intrinsically more sensitive to MBP and MBzP, than the rat embryos. Altogether, these results suggest that the species sensitivity observed in vivo after an oral administration of BBP, MBP or MBzP during early organogenesis, might be due to maternal factors, i.e. toxicity and/or kinetics.     

Screening for detection of new antidepressants, neuroleptics, hypnotics, and their metabolites in urine by GC-MS developed using rat liver microsomes

A gas chromatography-mass spectrometry (GC-MS) procedure for the detection of new antidepressants, neuroleptics, hypnotics, and their metabolites in urine is presented. The metabolites were first identified in rat liver microsome preparations by GC-MS after isolation and derivatization. Using these GC-MS data, a GC-MS screening was developed for urine as part of the authors' modified systematic toxicologic analysis procedure. After acid hydrolysis of a 2.5-mL aliquot of urine, a further aliquot was added. The mixture was then liquid-liquid extracted at pH 8-9, acetylated, and GC separated. Using mass chromatography with the ions m/z 58, 100, 120, 182, 195, 235, 261, 276, 284. and 293, the presence of new antidepressants, neuroleptics, hypnotics, and their metabolites could be indicated. Positive peaks could be identified by library search using the reference mass spectra recorded during the microsome studies. The intake of therapeutic doses of the following drugs could be monitored in urine: dosulepin, mirtazapine, moclobemide, nefazodone, trazodone, venlafaxine, and zolpidem. Olanzapine and zotepine were detectable in human urine only under steady-state conditions, and low-dose zopiclone was detectable only in overdose. The detection limit was less than 100 ng/mL (signal-to-noise ratio = 3) for the parent drugs.     

Further structural analysis of rat liver microsomal metabolites of 2-methylnaphthalene

The oxidative metabolites of 2-methylnaphthalene (2-MN) were extracted from rat liver microsome suspensions. One monohydroxylated and three isomeric dihydrodiol metabolites of 2-MN were isolated and purified by HPLC. The metabolites were characterized by GC-MS together with 1H Fourier transform (1HFT) NMR. The identification of a 2-MN-monohydroxylated product as 2-hydroxymethylnaphthalene was confirmed by comparison of its HPLC retention time and NMR spectrum with that of a synthetic standard. The three isomeric dihydrodiol metabolites had different HPLC retention times, fragmentation patterns, ultraviolet, and 1H NMR spectra. GC-MS of the silylated dihydrodiols revealed the consistent presence of an ion peak at m/z 320, indicative of a disilylated dihydrodiol. Analysis of the 1H FT NMR spectra revealed the metabolites to be the 3,4-dihydrodiol, 5,6-dihydrodiol, and 7,8-dihydrodiol of 2-methylnaphthalene.     

Mass spectrometric identification of urinary and plasma metabolites of 6-(6'-carboxyhexyl)-7-n-hexyl-1,3-diazaspiro-[4-4]-nonan-2,4-dione, a new cytoprotective agent.

The compound IBI-P-01028, or R,S-cis-6-(6'-carboxyhexyl)-7-trans-n-hexyl-1,3-diazaspiro-[4-4]-nona n-2,4- dione, is a new cytoprotective agent under development. To study the metabolites of this compound in laboratory animals, we administered it to dogs and rats, and analyzed extracts from dog and rat urine, and from dog plasma, by GC-MS. The metabolic profiles were different in the rat and dog. In the dog (plasma and urine), one metabolite was found, and in the rat urine two other metabolites were found. The unmetabolized drug was found only in the dog plasma and urine.     

Piperazine-derived designer drug 1-(3-chlorophenyl)piperazine (mCPP): GC-MS studies on its metabolism and its toxicological detection in rat urine including analytical differentiation from its precursor drugs trazodone and nefazodone

Studies on the metabolism and the toxicological analysis of the piperazine-derived designer drug 1-(3-chlorophenyl)piperazine (mCPP) in rat urine using gas chromatography-mass spectrometry (GC-MS) are described. mCPP was extensively metabolized, mainly by hydroxylation of the aromatic ring and by degradation of the piperazine moiety to the following metabolites: two hydroxy-mCPP isomers, N-(3-chlorophenyl)ethylenediamine, 3-chloroaniline, and two hydroxy-3-chloroaniline isomers. The hydroxy-mCPP metabolites were partially excreted as the corresponding glucuronides and/or sulfates, and the aniline derivatives were partially acetylated to N-acetyl-hydroxy-3-chloroaniline isomers and N-acetyl-3-chloroaniline. Our systematic toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction, and microwave-assisted acetylation allowed the detection of mCPP and its previously mentioned metabolites in rat urine after single administration of a dose calculated from the doses commonly taken by drug users. The hydroxy-mCPP metabolites should be used as target analytes being the major metabolites of mCPP. Assuming similar metabolism, our STA procedure should be suitable for detection of an intake of mCPP in human urine. Furthermore, possibilities for differentiating an intake of mCPP from that of its precursor drugs trazodone or nefazodone, two common antidepressants, are described. Within the context of these studies, N-(3-chlorophenyl)ethylenediamine was identified as a new metabolite of these two antidepressants.     

丁基苯酞的体内代谢转化研究

大鼠po丁基苯酞(NBP),定时收集尿液,经酶水解、提取浓缩、衍生化处理后用GC/MS分析。在给药后0～24h及24～48h尿中,NBP原药含量很低,主要以代谢物形式存在,依次为γ-羟基、β-羟基与3-羟基取代物。NBP体内代谢结果与肝微粒体中代谢结果基本一致。