Metabolism of promethazine in vitro. Identification of N-oxidized products

1. Incubation of promethazine (Ia) and desmethylpromethazine (Ib) with 9000g supernatant fractions of rabbit liver homogenate resulted in formation of N-dealkylated, N-oxygenated and ring-hydroxylated products.

2. The N-oxidation products identified by t.l.c. and mass spectra using synthetic reference products are promethazine-N-oxide (IX) and the nitrone (VIII), which is believed to be formed chemically and metabolically from the metabolite N-hydroxydesmethylpromethazine (VII).     

Identification of the in vitro N-oxidized metabolites of (+)- and (-)-N-benzylamphetamine.

This study has identified (+)- and (-)-N-benzyl-N-hydroxyamphetamine as metabolites after incubation of both (+)- and (-)-N-benzylamphetamine with fortified rabbit liver homogenates. The isomeric hydroxylamine metabolites were identified using the techniques of g.l.c., t.l.c. and combined g.l.c.-mass spectrometry (ms) and by comparison with results from reference samples. An additional novel metabolic product was identified after incubation of N-benzylamphetamine which had properties consistent with that of N-benzyl-amphetamine nitrone.     

Identification of the in vitro N-oxidized metabolites of (+)- and (−)-N-benzylamphetamine

This study has identified (+)- and (-)-N-benzyl-N-hydroxyamphetamine as metabolites after incubation of both (+)- and (-)-N-benzylamphetamine with fortified rabbit liver homogenates. The isomeric hydroxylamine metabolites were identified using the techniques of g.l.c., t.l.c. and combined g.l.c.-mass spectrometry (ms) and by comparison with results from reference samples. An additional novel metabolic product was identified after incubation of N-benzylamphetamine which had properties consistent with that of N-benzyl-amphetamine nitrone.     

The disposition of phentermine and its N-oxidized metabolic products in the rabbit.

1. When phentermine was injected intraperitoneally to rabbits, 77% of the dose was excreted in the urine within 2 days; N-oxidized metabolic products accounted for 62% dose. Major excretion products were N-hydroxyphentermine (28% dose), conjugated N-hydroxyphentermine (32% dose) and unchanged phentermine (16% dose). 2. Similarly injected N-hydroxyphentermine was excreted (62% dose) in the urine in 2 days; only 4% dose was recovered unchanged. Major routes of metabolism of N-hydroxyphentermine was conjugation (36% dose) and reduction to the parent amine (15% dose). Conditions for hydrolysis of urine to liberate N-hydroxyphentermine from its conjugates were studied; N-hydroxyphentermide decomposes in strong acid. 3. Only 10% of injected alpha, alpha-dimethyl-alpha-nitroso-beta-phenylethane was excreted in the urine in 2 days. 4. N-Oxidations is the major pathway of metabolism of phentermine in rabbits; the present results suggest that some biological activity may be mediated by the pharmacologically active N-hydroxyphentermine.     

Metabolism of benzothiazole. I. Identification of ring-cleavage products

1. The metabolic fate of benzothiazole in guinea pig has been investigated following i.p. administration at a dose of 30mg/kg.

2. Five ring-cleavage products were identified in urinary extracts by g.l.c.-mass spectra. By reference to authentic compounds the three major metabolites were shown to be 2-methylmercaptoaniline (I), 2-methylsulphinylaniline (II) and 2-methylsulphonylaniline (III). On the basis of the mass spectrometric evidence the remaining two metabolites were postulated to be 2-methylsulphinylphenylhydroxylamine (IV) and 2-methylsulphonyl-phenylhydroxylamine (V).

3. I, II and III were present in conjugated and unconjugated forms; IV and V were identified only after hydrolysis with sulphatase.     

Metabolism of benzothiazole. I. Identification of ring-cleavage products.

1. The metabolic fate of benzothiazole in guinea pig has been investigated following i.p. administration at a dose of 30 mg/kg. 2. Five ring-cleavage products were identified in urinary extracts by g.l.c.-mass spectra. By reference to authentic compounds the three major metabolites were shown to be 2-methylmercaptoaniline (I), 2-methylsulphinylaniline (II) and 2-methylsulphonylaniline (III). On the basis of the mass spectrometric evidence the remaining two metabolites were postulated to be 2-methylsulphinylphenylhydroxylamine (IV) and 2-methylsulphonylphenylhydroxylamine (V). 3. I, II and III were present in conjugated and unconjugated forms; IV and V were identified only after hydrolysis with sulphatase.     

Metabolism of chlorpromazine and promazine in vitro: isolation and characterization of N-oxidation products

1. The syntheses of the secondary hydroxylamines of nor1chlorpromazine and nor1promazine via their corresponding primary hydroxylamines and oximes are described. 2. The N-oxidation products are unstable to analysis by g.l.c. without prior derivatization; the decomposition products and the structures of the trimethylsilyl (TMS) and trifluoroacetyl (TFA) derivatives were characterized by g.l.c.-mass spectrometry. 3. Chlorpromazine, promazine and their demethylated products were shown to undergo metabolic N- and alpha-C-oxidation, to yield hydroxylamines and carboxylic acids, on incubation with fortified 9000 g liver homogenates of male New Zealand white rabbits. 4. A condensation product, an artifact formed by reaction of the metabolically derived primary hydroxylamines with acetaldehyde, an impurity in the extraction solvent, diethyl ether, was identified. 5. N-hydroxynor1- and N-hydroxynor2chlorpromazine undergo metabolic reduction to the parent amines, and the secondary hydroxylamine undergoes N-demethylation to yield the corresponding primary hydroxylamine.     

Metabolism of amphetamines. Identification of N-oxygenated products by gas chromatography and mass spectrometry

A sensitive method for the isolation and identification of N-oxygenated metabolites and metabonates of medicinal amines is described. A combination of gas chromatography and mass spectrometry is effective in separating and identifying secondary hydroxylamines, oximes and nitrones, all of which are N-oxygenated products of secondary amines. These products give mass spectra containing diagnostic fragment ions which are of great value in identification. Primary hydroxylamines are oxidized on column to oximes and can be separated and identified as such. This oxidation is avoided if the primary hydroxylamine is introduced by direct inlet into the mass spectrometer. Secondary hydroxylamines are more stable during gas chromatographic examination although some decomposition to nitrone and secondary amine does occur. In contrast, oximes and nitrones show no tendency to decompose when gas chromatographed.     

Metabolism of strychnine in vitro

The in vitro metabolism of strychnine was studied in the 9000g supernatant fractions from rat and rabbit livers. The metabolism was markedly inhibited by cytochrome P-450 inhibitors, SKF-525A and n-octylamine, but only slightly by a microsomal FAD-containing monooxygenase inhibitor, methimazole. Five metabolites formed in vitro with rabbit liver were isolated and purified by Sep-Pak C18 cartridge chromatography and preparative TLC. Three of them were identified as 2-hydroxystrychnine, strychnine N-oxide, and 21 alpha, 22 alpha-dihydroxy-22-hydrostrychnine by comparison with their authentic samples by means of UV, NMR, and mass spectrometries. An additional two metabolites were tentatively identified as strychnine 21,22-epoxide and 11,12-dehydrostrychnine by spectral measurements. Four of these metabolites, with the exception of 2-hydroxystrychnine, were novel metabolites of strychnine. The in vitro formation of these metabolites by rabbit liver was determined by HPLC after partial purification. The major identified metabolite was strychnine N-oxide, which accounted for approximately 15% of the metabolized strychnine. All the other metabolites accounted for less than 1%. The presence of a larger quantity of other metabolites which have been neither isolated nor identified was also suggested.     

Antinociceptive effects of clebopride in the mouse

• 1.1. The effects of the substituted benzamide clebopride, an orthopramide, on nociception of chemical and thermal stimuli were investigated.
• 2.2. Clebopride (0.5, 1.0 and 2.0 mg/kg) promoted significant analgesia in the tail-flick and hot-plate tests and against abdominal constrictions produced by acetic acid or acetylcholine.
• 3.3. The analgesic effects of clebopride were not influenced by pretreatment with naltrexone (1-3 mg/kg).
• 4.4. These results suggest that clebopride induces analgesia against both thermal and chemical nociceptive stimuli, which is not mediated via opioid mechanisms.

     

氯波必利致焦虑抑郁症

患者女,50岁。因间歇性上腹部胀痛20年,今年初再次发作,服用多种胃病药治疗无效,于2003年3月1日来我院就诊。患者9年前因心动过缓在某医院安装了心脏起搏器,既往无精神病史,有双黄连过敏史。查体:T36.5℃,P80次·min-1,BP120/76mmHg(1mmHg=0.133kPa)。血常规:WBC5.9×109·L-1,RBC4.4×1012·L-1,HGB120g·L-1,经胃B超及钡餐检查,确诊为慢性浅表性胃炎。给予氯波必利片0.68mg,3次/d,口服,上腹部胀痛缓解。服药第8天,患者出现坐立不安、意识不清、易怒、情绪低落等精神症状,且日渐加重。至4月2日,上述症状更为明显。转院至湖南省脑科…     

In vitro Metabolism of Bumetanide

A new metabolite of the diuretic drug bumetanide, the 4-[(4-hydroxy)-phenoxy] analog (7), was identified in incubation mixtures of rat liver microsomes. Phenobarbital and clofibrate pretreatment to induce microsomal enzymes changed the relative amounts of the six metabolites formed. Compound 7was the most prevalent metabolite after clofibrate pretreatment.     

肠道细菌对天然药物代谢的研究进展Ⅰ

目的：介绍肠道细菌对天然药物代谢的最新研究进展。方法：综述近年来国内外相关文献,对黄酮、皂甙、木脂素、环烯醚萜苷类等天然产物在肠道细菌作用下的代谢情况进行总结归纳。结果：天然产物经肠道细菌代谢后,转化为具有病理或毒理活性的新化合物。结论：许多天然药物以前药形式存在,肠道细菌在其代谢中发挥着至关重要的作用。     

Metabolism of pentachlorophenol in vivo and in vitro

Pentachlorophenol has earlier been shown to be metabolized in mammals to tetrachloro-p-hydroquinone. The metabolite possesses pronounced inhibitory activity on bacterial -glucuronidase but not on -glucuronidase from liver. Indirect evidence for the occurrence of both pentachlorophenol and tetrachloro-p-hydroquinone as conjugates with glucuronic acid in the urine from pentachlorophenol-treated rats is now presented. Bovine liver -glucuronidase has been utilized to split the conjugates present.The in vivo metabolism of pentachlorophenol has also been studied in rats treated with phenobarbital and -diethylaminoethyldiphenyl propylacetate (SKF 525-A). In vitro metabolism has been studied using liver microsomes from rats pretreated with phenobarbital. Quantitative analysis of the compounds occurring in extracts of urine or extracts from the microsomal incubates was performed by means of mass fragmentography. Pretreatment with phenobarbital increased the metabolism of pentachlorophenol to tetrachloro-p-hydroquinone both in vivo and in vitro. SKF 525-A, however, inhibited the metabolism in vitro but enhanced the metabolism in vivo when given less frequently than every 6th h. Dechlorination of pentachlorophenol is mediated by microsomal enzymes that can be induced by phenobarbital. SKF 525-A does not inhibit the dechlorination in vivo but does so in vitro.

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Zusammenfassung Wie in früheren Versuchen gezeigt worden ist, wird Pentachlorphenol bei Säugern zu Tetrachlor-p-Hydrochinon metabolisiert. Dieser Metabolit wirkt ausgeprägt hemmend auf Bakterien--Glucuronidase, aber nicht auf Leber--Glucuronidase. Ein indirekter Beweis für das Vorkommen von sowohl Pentachlorphenol als auch Tetrachlor-p-Hydrochinon als Konjugate mit Glucuronsäure im Harn von pentachlorphenolbehandelten Ratten wird nun vorgelegt. Zur Spaltung der gegenwärtigen Konjugate wurde Rinderleber--Glucuronidase benutzt.Der in vivo-Abbau von Pentachlorphenol wurde auch an mit phenobarbital und mit -Diäthylaminoäthyl-Diphenyl-Propylacetat (SKF 525-A) behandelten Ratten untersucht.Beim Studium des in vitro-Abbaus wurden Lebermikrosomen von mit Phenobarbital behandelten Ratten benutzt. Phenobarbital steigerte die Umwandlung in Tetrachlor-p-Hydrochinon sowohl in vivo als auch in vitro. SKF 525-A verzögerte indessen den in vitro-Umsatz, steigerte ihn jedoch in vivo, wenn weniger oft als alle 6 Std gegeben. Die Untersuchung zeigt also, daß die Entchlorung von Pentachlorphenol durch Mikrosomenenzyme vermittelt wird, die durch phenobarbital angeregt werden können. SKF 525-A hemmt die Entchlorung nicht in vivo, wohl aber in vitro.