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.     

7-Bromo-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (I), a new tranquillizing agent: metabolism in rats.

1. After intraperitoneal injection of rats with the new benzodiazepine (compound I), four metabolites (compounds II, III, IV and V) were found in the urine. 2. Compound II was identified as 7-bromo-5-(2'-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one by comparison of g.l.c. and mass spectral properties of the metabolite and synthetic compound. 3. Mass spectra of compound III and its acid hydrolysis products indicate that compound III contains a hydroxyl group in the C(5)-phenyl ring. 4. Compounds IV and V were identified by mass spectrometry as products of simultaneous aromatic hydroxylation and methoxylation of the diazepine I. 5. The major urinary excretion products are compounds III, IV and V. Only very small amounts of compounds I and II were detected.     

Metabolism of thymoxamine. I. Studies with 14C-thymoxamine in rats

Thymoxamine is rapidly and completely absorbed in rats. It is a prodrug which does not enter the systemic circulation in its unchanged form. After either oral or intravenous administration it undergoes rapid and intense metabolism involving four biotransformation reactions: Enzymatic hydrolysis to the corresponding phenol (metabolite I), Monodemethylation to metabolite II, Sulfate conjugation of I and II (metabolites III and IV) and Conjugation of I and II with glucuronic acid (metabolites V and VI). With these 6 metabolites identified approximately 95% of the radioactivity can be accounted for in plasma, urine and bile. Whereas the systemic availability of I and II is low, III and IV show high bioavailability. Metabolites I to IV are pharmacologically active, while III and IV are less potent than I and II. The radioactivity distribution in tissues is different after oral and intravenous administration consistent with the higher portion of unconjugated metabolites in the body after administration by parenteral route. Although 60% of the labelled compounds is eliminated via bile, the radioactive compounds are almost completely excreted in the urine after both routes of administration. This demonstrates complete reabsorption of the biliary metabolites. Secondary peaks of radioactivity in plasma and organs at 4 hours are explained by the participation of the metabolites in the enterohepatic circulation.     

Metabolism of a monoterpene ketone, R-(+)-pulegone--a hepatotoxin in rat

1. R-(+)-Pulegone was administered orally to rats and the urinary metabolites were investigated. Six metabolites were isolated and purified using column and thin layer chromatographic techniques. Metabolites were identified by i.r., n.m.r. and mass spectral analyses. 2. The neutral metabolites isolated from urine of rats treated with pulegone (I) were: pulegone (II), 2-hydroxy-2(1'-hydroxy-1'-methylethyl)-5-methylcyclohexanone (III), 3,6-dimethyl-7a-hydroxy-5,6,7,7a-tetrahydro-2(4H)-benzofuranone (V) and menthofuran (VII). Metabolites II and III were also excreted in conjugated form. 3. Acidic metabolites isolated from urine of rats treated with pulegone (I) were: 5-methyl-2(1'-methyl-1'-carboxyethylidene)cyclohexanone (IV) and 5-methyl-5-hydroxy-2(1'hydroxy-1'-carboxyethyl)cyclohexanone (VI).     

Identification of new sulfur-containing metabolites of naphthalene in mouse urine

Seven acidic sulfur-containing metabolites were isolated from mouse urine following administration of naphthalene. The metabolites have been identified as (1-hydroxy-1,2-dihydro-2-naphthalenylthio)acetic acid (I), 2-hydroxy-3-(1-hydroxy-1,2-dihydro-2-naphthalenylthio)propanoic acid (II), (1,2,3-trihydroxy-1,2,3,4-tetrahydro-4-naphthalenylthio)acetic acid (III), and N-acetyl-S-(1-hydroxy-1,2-dihydro-2-naphthalenyl)-L-cysteine (IV). The dehydration products of I, II, and IV, namely 1-(naphthalenylthio)acetic acid (V), 2-hydroxy-3-(1-naphthalenylthio)propanoic acid (VI), and N-acetyl-S-(1-naphthalenyl)-L-cysteine (VII), respectively, were also present in several urinary extracts. Nine methylthio derivatives were identified in the neutral extract of urine. These metabolites were the following: 1-methylthionaphthalene, trans-1-hydroxy-2-methylthio-1,2-dihydronaphthalene, two stereoisomeric 1,2,3-trihydroxy-4-methylthio-1,2,3,4-tetrahydronaphthalenes, 1,3-di(methylthio)-2,4-dihydroxy-1,2,3,4-tetrahydronaphthalene, 1,4-di(methylthio)-2,3-dihydroxy-1,2,3,4-tetrahydronaphthalene, two methylthiohydroxy-naphthalenes, and a methylthiodihydroxydihydronaphthalene. Following intraperitoneal administration of N-acetyl-S-(1-hydroxy-1,2-dihydro-2-naphthalenyl)-L-cysteine to mice, the acidic metabolites I, II, and unchanged IV were found. The gas-chromatographic and gas chromatographic-mass spectral properties of the methyl ester-trimethylsilyl derivatives of the acidic sulfur metabolites of naphthalene are presented.     

铁刀木中一个新的色酮苷

目的 研究铁刀木的化学成分。方法 利用硅胶柱色谱和薄层色谱分离铁刀木的化学成分,通过理化常数测定和波谱分析等鉴定化合物的结构。结果从铁刀木树干中分离并鉴定了5个化合物,其结构分别鉴定为:β-谷甾醇(I),蔗糖(II),正二十八醇(III),2-甲基-5-(2′-羟丙基)-7-羟基色酮-2′-O-β-D-吡喃葡糖苷(IV),3,3′,4,5′-四羟基二苯乙烯(V)。结论化合物II,III,V为首次从该植物中分得,化合物IV为新化合物。     

Metabolism of chlorpheniramine in rat and human by use of stable isotopes

1. The metabolism of chlorpheniramine (I) was examined in vivo in rats and a human volunteer; in the rats a stable isotope was used. 2. In addition to the unchanged drug (I) and the N-demethylated metabolites (II and III), nine further metabolites were identified in rat urine, four of which were also found in human urine. Chlorpheniramine N-oxide (IV), 3-(p-chlorophenyl)-3-(2-pyridyl) propanol (V), 3-(p-chlorophenyl)-3-(2-pyridyl)-N-acetylaminopropane (VII) and 3-(p-chlorophenyl)-3-(2-pyridyl)-propionic acid (XIII) were identified in rat and human urine. 3. The hydroxylated metabolites of the pyridyl ring of the unchanged drug, II, V and VII, and the glucuronide of XIII were identified only in rat urine. XIII was found in rat urine as long as 6 days after the last dose.     

Konstitutionsbeweis für 1,2-Bis(1-hydroxy-2-oxo-cyclohexyl)-äthan durch unabhängige Synthesen. 3. Mitt.: Zur Frage der oxydativen Ringverengung von Cyclohexanderivaten

Syntheses of 1,2-Bis(1-hydroxy-2-oxo-cyclohexyl)-aethane The title compound (I) is reduced to the tetrol II. The diacetate III, the tetraacetate IV and the tetramethylether V of II are formed. Reduction of the dimethylketal of I yields the dimethylether of II (VI). II, III, IV, V and VI are independently synthesized.     

Identification and measurement of urinary metabolites of afloqualone in man

Major urinary metabolites in man of 6-amino-2-fluoromethyl-3-(o-tolyl)-4-(3H)-quinazolinone (afloqualone, I), a new centrally acting muscle relaxant, were identified by GC/MS. Simultaneous quantitative determination of the metabolites was made by mass chromatography using deuterium-labeled internal standards. Approximately 4% of the dose was excreted as unchanged I within 32 hr after oral administration. The major metabolites identified in the neutral and basic fractions of the urine were N-acetylafloqualone (II, 0.3% of the dose), N-acetyl-2'-hydroxymethylafloqualone (III, 5.5%), N-glycolylafloqualone (IV, 0.9%), and N-glycolyl-2'-hydroxy-methylafloqualone (V, 1.3%). I and IV were also excreted in conjugated form as N-glucuronide (VI, 8.0%) and O-glucuronide and/or sulfate (VII, 0.4%), respectively. Other phenolic and sulfur-containing metabolites of I, which have previously been identified in the urine of rats, dogs, or monkeys, were not detected in the human urine. Thus, the main routes of metabolism of I in man consist of N-acetylation followed by hydroxylation at the 2'-methyl and acetylmethyl carbons, and glucuronidation of the aromatic amino group. This pattern of metabolism of I in man was in part similar to that observed in rats and monkeys, but drastically different from that in dogs.     

红凤菜黄酮类化学成分的研究

目的对菊科三七草属植物红凤菜（Gynura bicolor DC.）的黄酮类化学成分进行研究。方法采用硅胶、聚酰胺、SephadexLH-20柱层析等手段分离化合物,根据理化性质和波谱数据鉴定化合物结构。结果分离得到5个黄酮类化合物,分别为槲皮素（Ⅰ）、山柰酚（Ⅱ）、槲皮苷（Ⅲ）、异槲皮苷（Ⅳ）、芦丁（Ⅴ）。结论化合物Ⅰ、Ⅲ、Ⅳ为首次从该植物中分离得到。     

素馨花中一个新的环烯醚萜苷

为研究木犀科植物素馨花干燥花蕾的化学成分， 通过硅胶柱色谱、 Sephadex LH-20柱色谱、 HPLC和重结晶等方法进行分离纯化， 根据化合物的理化性质和波谱数据鉴定结构， 从素馨花干燥花蕾70%乙醇提取物中分离得到6个环烯醚萜苷类化合物， 分别鉴定为素馨花苷(I)、 jaspolyoside (II)、 8-epi-kingiside (III)、 10-羟基橄榄苦苷(IV)、 10-羟基女贞苷(V)、 oleoside-7,11-dimethyl ester (VI)。化合物I为新化合物，其余为首次从本植物中分离得到。     

Studies on drug metabolism by use of isotopes XXVII: urinary metabolites of rutin in rats and the role of intestinal microflora in the metabolism of rutin

Analysis of urinary metabolites of orally administered rutin (I) labeled with deuterium [( 2',5',6'-2H]rutin, rutin-d) was carried out by GLC-MS. In rat urine, 3-hydroxyphenylacetic acid (III), 3-methoxy-4-hydroxyphenylacetic acid (IV), 3,4-dihydroxyphenylacetic acid (V), 3,4-dihydroxytoluene (VI), and 3-(m-hydroxyphenyl)propionic acid (VIII) were identified as rutin metabolites and were differentiated from the corresponding endogeneous compounds. Unchanged I and quercetin (II) were not present in the urine. Rutin-d was injected intraperitoneally in rats, administered orally to neomycin-treated rats, and incubated in vitro with the intestinal contents of rats. The experiments suggested the involvement of intestinal microflora in the metabolism of orally administered I.     

Isolation, synthesis and characterization of impurities in celecoxib, a COX-2 inhibitor

During the impurity profile of Celecoxib, four polar impurities (impurity I, II, III and IV) and one non-polar impurity (impurity V) with respect to Celecoxib were detected by HPLC. LC-MS has been employed in this impurity profile study. The three polar impurities (I, II and III) were found to be process related while impurities (IV and V) turned out to be isomers. The impurities III, IV and V were isolated with the help of preparative HPLC. The structure of impurities III, IV (ortho-isomer) and V (regio-isomer) were confirmed as [5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole], 4-[5-(2'-methyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide, and 4-[4-(4'-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide, respectively. The structures of impurities I, II, III and IV were confirmed by synthesis and structural characterization using spectral data. However, the impurity V was not synthesized.     

Metabolism of thymoxamine. II. Studies with 14C-thymoxamine in man

Thymoxamine is rapidly and completely absorbed in man. Rapid biotransformation is observed after intravenous and oral administration of 40 mg 14C-thymoxamine HCl. No unchanged compound is found in the body. More than 90% of plasma and urine radioactivity could be ascribed to six metabolites: the desacetyl compound (metabolite I), the monodemethylated metabolite I (metabolite II), the sulfate conjugates of I and II (metabolites III and IV) and the glucuronides of I and II (metabolites V and VI). The unconjugated metabolites are observed in plasma only after intravenous administration. Similar patterns for polar metabolites are found in plasma and urine for both routes of administration. The sulfate fraction amounts to about 50-60% and the glucuronide fraction to about 30-40% of the radioactivity, the conjugates of metabolite I being more abundant than those of metabolite II. The elimination of the metabolites is rapid, the half-life of radioactivity elimination being 1.5 h during the first 12 hours and 12 h thereafter. 80% of the radioactivity dose is recovered in the urine within 4 hours. Recovery after four days amounts to 99.8% (i.v.) and 97.7% (oral). The results are discussed with regard to the application of the drug in man, taking into account that not only the unconjugated metabolites but also the sulfate conjugates are pharmacologically active.     

Lidocaine metabolism by rabbit-liver homogenate and detection of a new metabolite

Metabolism of lidocaine in rabbit liver 9000 g supernatant fraction was examined. A capillary g.l.c. assay was developed to separate seven known metabolites of lidocaine, and all seven metabolites were identified in extracts of incubations of lidocaine with rabbit-liver fractions. These metabolites were monoethylglycinexylidide(I), glycinexylidide(II), 3-hydroxymonoethylglycinexylidide(III), 3-hydroxylidocaine(IV), 4-hydroxylidocaine(V), xylidine(VI) and 4-hydroxyxylidine(VII). A new metabolite, 2-amino-3-methylbenzoic acid(VIII), was identified in extracts of incubations of lidocaine with rabbit-liver fractions, by comparison of the mass-spectral fragmentation patterns and g.l.c. retention time with those of the authentic compound. The formation of VIII is dependent on protein, NADPH, time, O2, and the presence of soluble enzymes. Quantitative analysis of metabolites I-VIII after a two hour incubation accounts for 89% of the metabolized lidocaine.     

白花丹参化学成分的研究

从白花丹参(Salvia miltiorrhiza f.alba)中分离出14个二萜醌类化合物,其中2个为新化合物,由光谱分析推定为1,2,15,16-四氢丹参醌(Ⅰ)和丹参醛(Ⅱ);另一个化合物Ⅲ与R₀-090680的结构相同。化合物Ⅰ和Ⅲ对淋巴白血病细胞P₃₈₈均有较强的抑制作用。     

鼓槌石斛化学成分的研究

自中药鼓槌石斛(Dendrobium chrysotoxum Lindl.)茎中分离到5个化合物,经光谱(UV,IR,MS,¹HNMR,DIFNOE和¹³CNMR)分析,分别鉴定为β-谷甾醇(I)、鼓槌菲(chrysotoxene,II)、毛兰素(erianin,III)、毛兰菲(confusarin,IV)和鼓槌联苄(chrysotobibenzyl,V)。II是新化合物,V是新天然产物。     

素馨花糖苷类化学成分研究

为了研究木犀科植物素馨花干燥花蕾的化学成分，应用硅胶柱色谱、Sephadex LH-20柱色谱和重结晶等方法进行分离纯化，根据化合物的理化性质和波谱数据鉴定结构。从素馨花干燥花蕾70%乙醇提取物中分离得到7个糖苷类化合物，分别鉴定为山柰酚-3-O-α-L-吡喃鼠李糖基(1→3)-［α-L-吡喃鼠李糖基(1→6)］-β-D-吡喃半乳糖苷(I)、山柰酚-3-O-芸香糖苷(II)、7-ketologanin (III)、oleoside-11-methyl ester (IV)、7-glucosyl-11-methyl oleoside (V)、ligstroside (VI)、橄榄苦苷(VII)。化合物I为新化合物，化合物III、V为首次从本属植物中分离得到，化合物II、IV、VI为首次从本植物中分离得到。     

Thiolated polymers: evaluation of the influence of the amount of covalently attached L-cysteine to poly(acrylic acid).

It was the aim of this study to investigate the influence of the amount of thiol groups being covalently attached to poly(acrylic acid) 450 kDa on its properties. Five different PAA(450)-L-cysteine conjugates (PAA(450)-Cys) were synthesized bearing 53.0 (PAA I), 113.4 (PAA II), 288.8 (PAA III), 549.1 (PAA IV) and 767.0 (PAA V) micromol immobilized thiol groups per gram polymer. Mucoadhesion studies utilizing the rotating cylinder method, tensile studies and disintegration studies were performed. Self-crosslinking properties were measured by the increase in viscosity. Permeation studies were performed on rat small intestine and Caco-2 monolayers using sodium fluorescein as model drug. Following residence times on the rotating cylinder could be identified: PAA I 3.1; PAA II 5.2; PAA III 22.0; PAA IV 33.8; PAA V 53.7; control 1.3 [h]. The disintegration time of all PAA(450)-Cys tablets was strongly dependent on the degree of thiolation of the polymer. Self-crosslinking studies showed that the different PAA(450)-Cys conjugates (3% m/v) in phosphate buffer, pH 6.8, formed intramolecular disulfide bonds. In case of Caco-2 monolayer transport studies following P(app)-values could be identified: PAA I 9.8; PAA II 10.1; PAA III 11.1; PAA IV 8.9; PAA V 8.2; control 6.4 [P(app)x10(-6), cms(-1)]. Mucoadhesive and self-crosslinking properties are strongly dependent on the degree of thiolation of the polymer and with respect to transport studies, an optimum amount of covalently attached L-cysteine could be identified.     

Structural investigation of the antibiotic ristomycin A. The amino acid constituents.

Hydrolysis of the O-methylated aglycone of ristomycin A by a mixture of KOH and NaBH4 yielded a mixture of aromatic amino acids which, after N-acetylation and O-methylation, were separated by chromatography on silica gel. Compounds III approximately VII were isolated and identified by pmr and mass spectroscopy. Compounds V approximately VII were also oxidatively degraded to the corresponding benzoate esters. Componds III and IV are derived from ristomycinic acid (I) and V from actinoidinic acid (II), both of which had been obtained in earlier acid hydrolyses of the antibiotic. Compounds VI and VII had not been detected previously nor glycine which was also found to be a product of base hydrolysis. It is postulated that the new products arise from bisdechlorovancomycinic acid (X). It is concluded that aglycoristomycin A comprises I, II and X which also constitute the aglycone of ristocetin A.