人胆汁中罗红霉素代谢产物的研究

目的：研究人胆汁中罗红霉素的代谢转化产物。方法：采用高效液相色谱-离子阱质谱法,对患者po罗红霉素后的胆汁样品进行了分析。结果：发现了13个代谢产物,分别为罗红霉素的(9Z)-异构体及其(9E)-,(9Z)-N-去甲基和N-双去甲基衍生物和(9E)-及(9Z)-脱克拉定糖衍生物,(9E)-和(9Z)-红霉素肟及其(9E)-和(9Z)-N-去甲基及N-双去甲基衍生物,其中9种为新发现的代谢物。结论：罗红霉素及其代谢物均可在体内发生几何异构化。     

HPLC-MSn法鉴定葫芦巴碱及其在大鼠体内的主要代谢产物

目的建立快速灵敏的LC-MSⁿ检测葫芦巴碱及其在大鼠体内代谢物的分析方法。方法以葫芦巴碱对LC-MS²色谱及质谱条件进行优化，分析其电喷雾质谱的一级电离规律和多级质谱裂解规律，以此作为葫芦巴碱大鼠体内代谢物分析鉴定的依据。健康大鼠尾静脉注射8 mg·kg^-1葫芦巴碱，收集0～48 h的尿样，经C₁₈小柱固相萃取分离纯化后，直接采用LC-MSⁿ方法对尿样进行测定。结果根据生物体内药物代谢转化规律及母体药物的色谱-质谱行为规律，在尿样中鉴定出母药及其N-去甲基、N-去甲基环氧化产物，以及母药及其N-去甲基环氧化物的甘氨酸轭合物。结论本方法灵敏、快速、选择性高、专属性好，可用于葫芦巴碱的代谢产物研究。     

高效液相色谱-电喷雾离子阱串联质谱分析水苏碱及其大鼠体内代谢物

目的鉴定水苏碱在大鼠体内的代谢物。方法应用高效液相色谱-电喷雾离子阱串联质谱(HPLC-ESI/MSⁿ)技术研究水苏碱的一级质谱电离规律、二级质谱裂解规律及其色谱保留，以此作为水苏碱大鼠体内代谢物分析鉴定的依据；再将健康大鼠空腹灌胃25 mg·kg^-1水苏碱，收集0～24 h的尿样，经C₁₈小柱固相萃取分离纯化后，应用HPLC-ESI/MS分析尿样中水苏碱代谢物。结果在大鼠尿样中发现了母药及其N-去甲基、氧化脱氢、环氧化等6种I相代谢产物及两种环氧化物的甘氨酸轭合II相代谢产物。结论HPLC-ESI/MS法灵敏度高，快速，定性能力强，适合于水苏碱大鼠体内代谢物的分析。     

液相色谱-电喷雾离子阱质谱法分析大鼠血浆中的樟柳碱及其代谢物

目的用液相色谱-电喷雾离子阱串联质谱(LC-MS^{n)联用方法鉴定大鼠血浆中的樟柳碱及其主要代谢物。方法取单剂量灌胃樟柳碱20 mg的大鼠血浆，甲醇沉淀蛋白，采用LC-MSn等方法分析血样。与空白血样及樟柳碱对照品相比较，根据血样中代谢物相对分子质量的变化及其多级质谱数据，鉴定并阐述其结构。结果在服药后的大鼠血样中发现4种代谢物， 分别为东莨菪醇、 N-去甲基东莨菪醇、 羟基化樟柳碱以及N-氧化樟柳碱。结论 该方法灵敏、快速、简便，适合于药物及其代谢物的快速鉴定。}     

大鼠粪样中山莨菪碱及其代谢物的串联质谱法检测

目的运用液相色谱-电喷雾串联质谱(LC-MSn)法检测大鼠粪样中山莨菪碱及其代谢物。方法收集灌胃山莨菪碱(25 mg·kg^-1)的大鼠粪样,用水浸泡后,以乙酸乙酯萃取,采用LC-MS及LC-MSn等方法检测原药及其代谢物。根据代谢物相对分子质量的变化(ΔM)及其多级质谱数据,鉴定并阐述其结构,同时与空白粪样及山莨菪碱相比较。结果在服药后的大鼠粪样中发现山莨菪碱及其7种代谢产物, 分别为6β-羟基托品、N-去甲基-6β-羟基托品、N-去甲基脱水山莨菪碱、脱水山莨菪碱、N-去甲基山莨菪碱、羟基山莨菪碱以及托品酸等。结论该方法灵敏、快速、简便、有效,适合于生物样品中的药物及其代谢产物的快速鉴定。     

HPLC-ESI-ITMSn法鉴定麻黄碱及其大鼠体内主要代谢产物

目的建立快速灵敏的LC-ESI-ITMSⁿ分析检测麻黄碱及其大鼠体内代谢物的方法。方法以麻黄碱对照品对LC-ESI-ITMS²色谱及质谱条件进行了优化，分析总结其电喷雾质谱的一级电离规律和多级质谱裂解规律，以此作为麻黄碱大鼠体内代谢物分析鉴定的依据。健康大鼠空腹灌胃麻黄碱10 mg·kg^-1，收集0~48 h的尿样，经C₁₈小柱固相萃取分离纯化后，直接采用LC-ESI-ITMSⁿ方法对尿样进行测定。结果根据生物体内药物代谢转化规律及母体药物的色谱-质谱行为规律，在尿样中鉴定出3个第I相代谢产物，未发现第II相代谢产物。结论本方法灵敏、快速、选择性高、专属性好，可用于麻黄碱的代谢产物研究。     

罗红霉素在苯巴比妥诱导的大鼠肝微粒体中的代谢

目的:研究罗红霉素在大鼠肝微粒体中的代谢,并考察罗红霉素及其代谢物对细胞色素P-450的影响.方法:采用超离心法制备了苯巴比妥诱导的大鼠肝微粒体酶.罗红霉素的体外代谢采用微粒体孵化方法,代谢物经LC-MS方法分离和分析,并通过进一步与合成对照品比较其质谱和色谱行为确定其结构.结果:在微粒体孵化液中发现了N-去甲基,N-双去甲基及O-去烷基三种代谢物.罗红霉素及其代谢物与CYP450 Fe~(2 )形成复合物的能力较弱.结论:罗红霉素在苯巴比妥诱导的大鼠肝微粒体中主要经历N-去甲基化和肟醚侧链O-去烷基化途径,两种转化途径均为NADPH依赖性.罗红霉素及其代谢物对CYP450的抑制作用较弱,     

新型抗炎镇痛剂SFZ-47在家兔体内羟基化及其结合型代谢产物的鉴定

目的：鉴定新型抗炎镇痛剂SFZ-47［3H-1,2-二氢-2-(4-甲基苯胺基)甲基-1-吡咯里嗪酮］在家兔体内的羟基化及其结合型代谢产物。方法：选择4只健康家兔单剂量口服100 mg SFZ-47,收集0～10 h的尿样。将未经或经过β-D-葡萄糖苷酸酶/硫酸酯酶水解的尿样以Sep-Pak C₁₈固相萃取柱纯化后,采用LC/MSn方法对尿中推测的代谢物分别进行选择离子监测(SIM)和多级全扫描质谱(MSⁿ)分析。结果：在尿中首次检测到SFZ-47羟基化及其β-D-葡糖苷酸与硫酸结合型代谢物。结论：SFZ-47在家兔体内主要代谢途径应为苯环上的甲基先氧化成羟甲基和羧基,再分别与β-D-葡糖醛酸或硫酸结合。     

八宝素在Beagle犬体内药代动力学

目的研究八宝素在Beagle犬体内的药代动力学。方法用高效液相色谱法，以蒽为内标，苯甲酰氯为衍生剂，甲醇-水(64∶36)为流动相，测定一次性静脉注射10.6和21.3 mg·kg^-1八宝素后，Beagle犬血液中八宝素的含量。采用3P97程序计算药物代谢动力学参数。结果八宝素iv在Beagle犬体内的药代动力学符合二室开放模型，两剂量组t^1/2α为2.3和2.1 min， t_1/2β分别为1.9和2.0 h， v_s均为0.54 L·kg^-1， AUC分别为1.8和4.1 g·min·L^-1，CL分别为0.004 8和0.005 6 L·kg^-1·min^-1。结论八宝素在Beagle犬体内分布和消除较快,呈一级动力学特征。     

人与大鼠体内罗红霉素去甲基化代谢(英文)

目的:研究罗红霉素在人体和大鼠体内的去甲基化代谢途径,并研究去甲基罗红霉素的体外抗菌活性方法:采用LC-MS方法测定了罗红霉素在人体和大鼠体内的去甲基代谢产物;并用二倍稀释法,选择三种生物检测实验标准菌株,测定了罗红霉素、去甲基代谢产物以及其他几种主要代谢产物的体外抗菌活性。结果:罗红霉素在人体内主要经历O-去甲基化代谢,而在大鼠体内主要经历N-去甲基化代谢。代谢物O-去甲基罗红霉素具有与母体药相当的体外抗菌活性。结论:O-去甲基罗红霉素是罗红霉素在人体内的活性代谢产物,罗红霉素在人与大鼠体内的去甲基化产物具有种属差异。     

pH-dependent geometric isomerization of roxithromycin in simulated gastrointestinal fluids and in rats

The biotransformation of roxithromycin in simulated gastrointestinal fluids at 37 degrees C and in rats was investigated by using liquid chromatography-tandem mass spectrometry. Roxithromycin degraded to its Z-isomer and decladinose derivative in simulated gastrointestinal fluids in vitro at pH 相似文献   

Metabolism and excretion of atorvastatin in rats and dogs.

Atorvastatin (AT) is a second-generation potent inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, clinically approved for lowering plasma cholesterol. Using a mixture of [D(5)/D(0)] AT and/or [(14)C]AT, the metabolic fate and excretion of AT were examined in rats and dogs following single and multiple oral doses. Limited biliary recycling was examined in one dog after a single dose of AT. AT-derived metabolites in bile samples were identified by metabolite screening of the [D(5)/D(0)] AT molecular clusters using tandem mass spectrometry. Bile was a major route of [(14)C] drug-derived excretion, accounting for 73 and 33% of the oral dose in the rat and dog, respectively. The remaining radioactivity was recovered in the feces; only trace amounts were excreted in urine. Radioactive components identified in rat and dog bile were the para- and ortho-hydroxy metabolites, a glucuronide conjugate of ortho-hydroxy AT, and unchanged AT. Two minor radioactive components were identified as beta-oxidation products of AT with one confirmed as a beta-oxidized AT derivative. The reappearance of AT and major metabolites in bile from a dog administered a sample of its previously excreted bile indicated biliary recycling is an important component in AT metabolism. Multiple dose administration in rats did not alter biliary metabolic profiles. Rat and dog plasma profiles after multiple dose administration were similar and showed no additional metabolites not found in bile. Examination of rat and dog bile and plasma indicates that AT primarily undergoes oxidative metabolism.     

Metabolism and disposition of 14C-granisetron in rat,dog and man after intravenous and oral dosing

1. The disposition and metabolic fate of ¹⁴C-granisetron, a novel 5-HT₃ antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration.

2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species.

3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0·25 and 5 mg/kg in rat and 0·25 and 10mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man.

4. In rat and dog, 35–41% of the dose was excreted in urine and 52–62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5–25% of dose).

5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.     

罗红霉素主要代谢产物的体外抗菌活性研究

临床上广泛使用的 (E) -罗红霉素在人体内有多种代谢途径。在鉴别和制备其代谢产物的基础上 ,采用二倍稀释法 ,选用 3种生物检测实验标准菌株 ,测定了母体药物和 6种主要代谢产物的体外抗菌活性(MIC,MBC)。结果表明 ,(E) -罗红霉素经代谢转化后 ,生成的 (Z) -罗红霉素异构体的活性略下降 ,(E) -红霉素肟的活性无明显改变 ,(E) - O-单去甲罗红霉素的 MIC未改变 ,而对芽孢杆菌的 MBC有所降低 ,(E) - N-单去甲罗红霉素的活性显著降低 ,(E) -脱红霉糖罗红霉素则基本失活。被测药物及代谢物在不同菌株之间的MIC和 MBC变化趋势基本相同 ,MBC较相应的 MIC大 10 0～ 10 0 0倍左右。     

Pharmacokinetics and metabolism of lithospermic acid by LC/MS/MS in rats

The pharmacokinetics and metabolism of lithospermic acid (LA), a component isolated from Salvia miltiorrhiza, and its two O-methylated metabolites (3′-monomethyl- and 3′,3″-dimethyl-lithospermic acid), were analyzed by a rapid and specific isocratic liquid chromatography-tandem mass spectrometry (LC/MS/MS) method. Rat serum samples collected after intravenous and oral administration were analyzed for obtaining pharmacokinetic data of LA. Two O-methylated metabolites, namely one 3′-monomethyl- and one 3′,3″-dimethyl-lithospermic acid were detected in rat serum and bile samples after intravenous and oral administration of LA, respectively. An oral bioavailability of 1.15% was found, with the AUC_0–t values of 301.89 and 3.46 mg h/L for intravenous and oral administration, respectively. The total recovery from bile was 75.36% (0.46% for LA, 17.23% for M1, and 57.67% for M2) after intravenous administration, and 4.26% (0.00% for LA, 0.10% for M1, and 4.16% for M2) after oral administration. These results indicate that methylation is the main metabolic pathway of LA, and that LA is excreted into rat bile and finally into feces.     

Structural identification of bitespiramycin metabolites in rat: a single oral dose study

Bitespiramycin is a macrolide antibiotic consisting of a mixture of some nine spiramycin ester derivatives. It has a similar spectrum of antibiotic activity to that of spiramycin but has superior pharmacokinetic properties. In this study, a rapid and facile LC/ESI-MSn method was applied to study the metabolism of bitespiramycin in rat following a single oral dose (80 mg kg-1). Concentrations of parent drug constituents and metabolites were determined in plasma, urine, feces and bile. Concentrations of parent drug constituents and metabolites in plasma were very low. In urine, feces and bile, parent drug constituents and 38 metabolites were identified on the basis of their chromatographic and mass spectrometric properties. The identity of 17 metabolites was confirmed by comparison with reference substances. The principal metabolites were the corresponding spiramycins formed by hydrolysis of the 4'-(3-methylbutanoate) groups. Other important metabolic pathways were: hydrolytic loss of the forosamine and mycarose sugars; aldehyde reduction; cysteine conjugation of the aldehyde group; and hydrolysis of the lactone ring. Products formed by lactone ring opening were found only in urine, and those formed by aldehyde reduction were found only in feces. Aldehyde reduction and hydrolytic loss of forosamine represent novel biotransformation pathways for spiramycin derivatives.     

Structural identification of bitespiramycin metabolites in rat: A single oral dose study

Bitespiramycin is a macrolide antibiotic consisting of a mixture of some nine spiramycin ester derivatives. It has a similar spectrum of antibiotic activity to that of spiramycin but has superior pharmacokinetic properties. In this study, a rapid and facile LC/ESI-MSⁿ method was applied to study the metabolism of bitespiramycin in rat following a single oral dose (80?mg?kg^?1). Concentrations of parent drug constituents and metabolites were determined in plasma, urine, feces and bile. Concentrations of parent drug constituents and metabolites in plasma were very low. In urine, feces and bile, parent drug constituents and 38 metabolites were identified on the basis of their chromatographic and mass spectrometric properties. The identity of 17 metabolites was confirmed by comparison with reference substances. The principal metabolites were the corresponding spiramycins formed by hydrolysis of the 4′′-(3-methylbutanoate) groups. Other important metabolic pathways were: hydrolytic loss of the forosamine and mycarose sugars; aldehyde reduction; cysteine conjugation of the aldehyde group; and hydrolysis of the lactone ring. Products formed by lactone ring opening were found only in urine, and those formed by aldehyde reduction were found only in feces. Aldehyde reduction and hydrolytic loss of forosamine represent novel biotransformation pathways for spiramycin derivatives.     

Characterization of urinary metabolites of a new benzofuroquinoline derivative, 3,9-bis(N,N-dimethylcarbamoyloxy)-5 H-benzofuro[3,2-c]-quinoline-6-one (KCA-098), in dogs.

The metabolism of 3,9-bis(N,N-dimethylcarbamoyloxy)-5 H-benzofuro[3,2-c]-quinoline-6-one (KCA-098), a new inhibitor of bone resorption and stimulator of bone formation, was examined after oral administration to dogs. Nine metabolites and the unchanged KCA-098 were isolated by extraction and HPLC from dog urine. The structures of these metabolites were characterized by LC/MS or LC/MS/MS, and/or were confirmed by comparison with corresponding authentic standards. The presumed main metabolic pathways were hydrolysis, hydroxylation, and N-demethylation of the N,N-dimethyl-carbamate ester group.     

The metabolism of chlorpromazine N-oxide in man and dog

1. The metabolism of chlorpromazine N-oxide was studied in female dogs and adult male humans after a single oral dose. 2. There was extensive metabolism in both species in that between four and seven metabolites were separately identified in urine and faeces. Apart from chlorpromazine N-oxide, chlorpromazine N,S-dioxide was the only isolated metabolite which retained the N-oxide group. The other identified metabolites were chlorpromazine and its 7-hydroxy, sulphoxide, N-desmethyl, 7-hydroxy-N-desmethyl and N-desmethylsulphoxide derivatives. 3. With dog samples, metabolites were separated by h.p.l.c. and individually collected prior to mass spectrometric analysis. With human samples, metabolites were directly subjected to h.p.l.c.-mass spectrometric determination. With all metabolites their structures were confirmed by direct comparison of their mass spectra and chromatographic behaviours with those of authentic samples. 4. The metabolites identified in urine and faeces were for the most part the same in both species, with the exceptions that chlorpromazine N-oxide was identified in the faeces of dog only and 7-hydroxy-N-desmethylchlorpromazine was identified in the urine of man only. 5. The observation of N-oxide compounds in the excreta of both man and dog contrasted with that for the previously studied rat, where no such compounds were detected.