Metabolism and urinary excretion of chlormethiazole in humans.

1. Chlormethiazole and five of its metabolites excreted in urine in man have been investigated by g.l.c.-mass spectrometry. 2. Four metabolites have been identified by comparison with authentic compounds as 5-acetyl-4-methylthiazole, 5-(1-hydroxyethyl)-4-methylthiazole, 5-(2-hydroxyethyl)-4-methylthiazole and 4-methyl-5-thiazoleacetic acid; 4-methyl-5-thiazoleacetaldehyde is proposed for the other metabolite. 3. The amounts of chlormethiazole and its identified metabolites excreted in urine have been quantitatively determined after a single oral dose in three healthy adults. Approximately 16% of the dose was excreted as chlormethiazole, 5-acetyl-4-methylthiazole, 5-(1-hydroxyethyx)-4-methylthiazole and 4-methyl-5-thiazoleacetic acid.     

The plasma levels of chlormethiazole and two of its metabolites in elderly subjects after single and multiple dosing

Plasma levels of chlormethiazole and two of its metabolites have been estimated in elderly subjects both after single and repeated oral dosage and on withdrawal. A sensitive analytical method was developed to permit the quantitation of chlormethiazole and its two major metabolites in plasma. The two major metabolites were positively identified against authentic standards as 5-acetyl-4-methylthiazole and 5-(1-hydroxyethyl)-4-methylthiazole. Chlormethiazole and its metabolites were shown to have accumulated to varying extents after seven nightly doses. On withdrawal of the drug, the plasma was free of chlormethiazole within 44 h and free of all traces of its metabolites within 84 h. The accumulation was not accompanied by any undue clinical effect and was not in itself considered to be detrimental to the normal use of chlormethiazole in the treatment of sleep disturbances in the elderly.     

Urinary metabolites of clomethiazole. Detection and structural analysis by gas chromatography-mass spectrometry

As the result of a renewed extensive investigation of clomethiazole (Distraneurin) metabolism five previously unknown metabolites could be isolated from human urine. Their structures were elucidated by mass spectrometry. Whereas previous investigations on the metabolism of clomethiazole had demonstrated changes only of the ethyl group, we now found metabolites attached to the methyl group, too. The newly isolated compounds 5-(1-hydroxy-2-chloroethyl)-4-methylthiazole (9) and 5-(2-hydroxyethyl)-4-thiazole carboxylic acid lactone (5) were found to be more abundant in human urine than 4-methyl-5-thiazole acetic acid previously considered as the main metabolite.     

Disposition of 3H-enisoprost,a gastric antisecretory prostaglandin,in healthy humans

1. After oral administration of ³H-enisoprost (450 μg) to five healthy men, as a solution in capsules, peak ³H levels of 5624 ± 566 pg equiv./ml (mean ± S.E.M.) were reached within one hour. No unchanged drug was detected in plasma.

2. Enisoprost was rapidly de-esterified to SC-36067 [(±)11α, 16ζ-dihydroxy-16-methyl-9-oxoprost-4Z, 13E-dien-1-oic acid], a pharmacologically active analogue, which reached peak concentrations of 651±200 pg/ml within 20 min of dosing. SC-36067 was eliminated metabolically, with a half-life of 1.61 h, by a combination of β-oxidation, β-oxidation and 9-keto-reduction.

3. After nine days 59.0±2.98% and 17.4±1.57% of the dose was excreted in urine and faeces respectively. The majority of this excretion was complete in two days.

4. Five urinary metabolites were identified by GC-MS. These were (±)3-[2β-(4-hydroxy-4-methyl-1E-octenyl)-3α-hydroxy-5-oxo-1α-cyclopentanyl]propanoic acid (SC-41411; 3.6% dose), (±)3-[3α,5-dihydroxy-2β-(4-hydroxy-4-methyl-1E-octenyl)-1α-cyclopentanyl]propanoic acid (SC-41411 PGF analogue; 4.8% dose), (±)3-[2β-(8-carboxy-4-hydroxy-4-methyl-1E-octenyl)-3α-hydroxy-5-oxo-1α-cyclopentanyl] propanoic acid (SC-41411-16-carboxylic acid; 22% dose), (±)3-[2β-(8-carboxy-4-hydroxy-4-methyl-1E-octenyl)-3α,5-dihydroxy-1α-cylopentanyl]propanoic acid (SC-41411 PGF analogue-16-carboxylic acid; 8.5% dose) and its γ lactone (2.6% dose).

5. These metabolites were also identified chromatographically in plasma, as were SC-36067, (±)3-[2β-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-1α-cyclopent-3-enyl]propaloic acid and (±)3-[2β-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-cyclopent-1-enyl]propanoic acid.

6. Some 5-10% of the dose was excreted in urine as tritiated water, indicating that oxidation of the 11α-hydroxy group in SC-36067 or its metabolites also occurred.     

In vivo metabolism of the anti-inflammatory agent 2-(5-ethylpyridin-2-yl)benzimidazole

The metabolic fate of anti-inflammatory agent 2-(5-ethylpyridin-2-yl)benzimidazole (KB-1043) was studied in rats after oral administration. An average of 12.2 +/- 1.5% of the dose was excreted in the urine in the course of 0-48 h; 56.7 +/- 2.6% with feces. Two metabolites were also detected in the urine and isolated by reverse phase HPLC. Structures have been given after identification by comparison with authentic samples. The more abundant metabolite proved to be 2-(5-(1-hydroxyethyl)pyridin-2-yl)benzimidazole, a benzylic oxidation product, which was also excreted as glucuronic acid conjugate; the other metabolite was confirmed to be 2-(5-acetylpyridin-2-yl)benzimidazole. Carrageenin edema and gastric ulcerogenic activity were also tested for the two identified metabolites.     

Disposition of 3H-enisoprost, a gastric antisecretory prostaglandin, in healthy humans

1. After oral administration of 3H-enisoprost (450 micrograms) to five healthy men, as a solution in capsules, peak 3H levels of 5624 +/- 566 pg equiv./ml (mean +/- S.E.M.) were reached within one hour. No unchanged drug was detected in plasma. 2. Enisoprost was rapidly de-esterified to SC-36067 [(+/-)11 alpha, 16 zeta-dihydroxy-16-methyl-9-oxoprost-4Z, 13E-dien-1-oic acid], a pharmacologically active analogue, which reached peak concentrations of 651 +/- 200 pg/ml within 20 min of dosing. SC-36067 was eliminated metabolically, with a half-life of 1.61 h, by a combination of beta-oxidation, omega-oxidation and 9-keto-reduction. 3. After nine days 59.0 +/- 2.98% and 17.4 +/- 1.57% of the dose was excreted in urine and faeces respectively. The majority of this excretion was complete in two days. 4. Five urinary metabolites were identified by GC-MS. These were (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-3 alpha-hydroxy-5-oxo-1 alpha-cyclopentanyl]propanoic acid (SC-41411; 3.6% dose), (+/-)3-[3 alpha,5-dihydroxy-2 beta-(4-hydroxy-4-methyl-1E-octenyl)-1 alpha-cyclopentanyl]propanoic acid (SC-41411 PGF analogue; 4.8% dose), (+/-)3-[2 beta-(8-carboxy-4-hydroxy- 4-methyl-1E-octenyl)-3 alpha-hydroxy-5-oxo-1 alpha-cyclopentanyl] propanoic acid (SC-41411-16-carboxylic acid; 22% dose), (+/-)3-[2 beta-(8-carboxy-4- hydroxy-4-methyl-1E-octenyl)-3 alpha,5-dihydroxy-1 alpha-cyclopentanyl] propanoic acid (SC-41411 PGF analogue-16-carboxylic acid; 8.5% dose) and its gamma lactone (2.6% dose). 5. These metabolites were also identified chromatographically in plasma, as were SC-36067, (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-1 alpha- cyclopent-3-enyl]propanoic acid and (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-cyclopent-1- propanoic acid. 6. Some 5-10% of the dose was excreted in urine as tritiated water, indicating that oxidation of the 11 alpha-hydroxy group in SC-36067 or its metabolites also occurred.     

Biotransformation of diethenylbenzenes. I. Identification of the main urinary metabolites of 1,4-diethenylbenzene in the rat

1. Biotransformation of 1,4-diethenylbenzene (1) in rat was studied. Six urinary metabolites, namely, N-acetyl-S-[2-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine (3), N-acetyl-S-[1-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine (4), N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine (5), 1-(4-ethenylphenyl)ethane-1,2-diol (6), 4-ethenylbenzoic acid (9) and 4-ethenylbenzoyl-glycine (12) were isolated and identified by n.m.r. and mass spectrometry. 2. G.l.c.-mass spectral analysis of the methylated urine extract allowed the identification of four other metabolites, as 4-ethenylphenylacetic acid (11), 4-ethenylphenylacetylglycine (13), 4-ethenylmandelic acid (7), and 4-ethenylphenylglyoxylic acid (8). 3. The structures of the identified metabolites indicate that the main reactive intermediate in the metabolism of 1 is 4-ethenylphenyloxirane (2). The first step in the biotransformation of 1, formation of an oxirane, is very similar to the metabolic activation of styrene. However, subsequent steps lead not only to analogues of styrene metabolites but also to oxidation of the second ethenyl group leading to compound(s) which may contribute to the toxicity of 1, e.g. to the aldehyde 5. 4. Rats dosed with a single i.p. dose of 1 excreted nearly 5.6% of the dose as the glycine conjugate 12, irrespective of the dose. 5. In contrast, the total thioether fraction decreased significantly with increasing dose, being 23 +/- 3, 17 +/- 5 and 12 +/- 1% of dose at 100, 200 and 300 mg/kg, respectively (mean +/- SD).     

Metabolism of proxyphylline in man. Isolation and identification of metabolites in urine

The urinary excretion of radioactivity has been measured in man following intravenous injection of 400 mg of [8-14C]proxyphylline. Of the radioactive dose, 95% was recovered in urine 3 days after drug administration. Proxyphylline metabolites were isolated from the urine excreted between 8 and 19.5 hr after drug administration and separated into four different fractions. Unmetabolized proxyphylline accounted for 22% of the excreted radioactivity. The main metabolite was identified as 1-methyl-7-(beta-hydroxypropyl)xanthine, which accounted for 60--65% of the excreted radioactivity. About 1% was excreted as the corresponding 1-methyl-7-(beta-hydroxypropyl)uric acid. Nine percent of the dose was excreted as glucuronic acid conjugates, mainly as proxyphylline glucuronide, but 0.5--1% of 1-methyl-7-(beta-hydroxypropyl)xanthine glucuronide, was also found. The previously postulated metabolite, theophylline, was not excreted in detectable amounts.     

Biotransformation of diethenylbenzenes. III: Identification of metabolites of 1,3-diethenylbenzene in rat.

1. Biotransformation of 1,3-diethenylbenzene (1) in rat gave four major metabolites, namely, 3-ethenylphenylglyoxylic acid (2), 3-ethenylmandelic acid (3), N-acetyl-S-[2-(3-ethenylphenyl)-2-hydroxyethyl]-L-cysteine (4) and N-acetyl-S-[1-(3-ethenylphenyl)-2-hydroxyethyl]-L-cysteine (5) were isolated from urine and identified by n.m.r. and mass spectrometry. 2. Four minor metabolites, 3-ethenylbenzoic acid (6), 3-ethenylphenylacetic acid (7), 3-ethenylbenzoylglycine (8) and 2-(3-ethenylphenyl)ethanol (9) were identified by g.l.c.-mass spectrometric analysis of urine extract derivatized in two different ways. 3. All identified metabolites are derived from 3-ethenylphenyloxirane (10), a reactive metabolic intermediate. No product of any metabolic transformation of second ethenyl group has been identified. However, several minor unidentified metabolites were detected by g.l.c.-mass spectrometry. 4. Total thioether excretion in 24 h urine after a single i.p. dose of 1 amounted to 28.3 +/- 3.5 dose (mean +/- SD). No significant differences in the thioether fraction were observed in the dose range 100-300 mg/kg. 5. Thioether metabolites consisted mainly of mercapturic acids 4 and 5. The ratio of metabolites 5 to 4 was 62:38. Each mercapturic acid consisted of two diastereomers. Their ratio, as determined by quantitative 13C-n.m.r. measurement was 95:5 and 79:21 for mercapturic acids 4 and 5, respectively.     

Studies on the Metabolism of Sympathomimetic Amines. The Metabolism of (±)-[14C]Noradrenaline in the Horse

Abstract

1. The metabolism of (±)-[¹⁴C]noradrenaline in horses has been studied. The plasma half-life of radioactivity following intravenous injection was 95 min.

2. Two horses each excreted about 80–85% of the radioactivity in the urine in 15 h after rapid intravenous injection and about 75% of the excreted radioactivity has been identified.

3. The unchanged drug in the urine accounted for less than 1% of the dose and 3-methoxynoradrenaline for about 7%. The main metabolites were 4-hydroxy-3-methoxymandelic acid (22%), 4-hydroxy-3-methoxybenzoic acid (13%) and 4-hydroxy-3-methoxyphenylglycol (11%). 3,4-Dihydroxyphenylglycol was a minor metabolite (5%).     

Metabolism and kinetics of amlodipine in man

1. The disposition of amlodipine, R,S,2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine has been studied in two human volunteers using single oral and intravenous doses of ¹⁴C-amlodipine. The drug was well absorbed by the oral route while the mean oral bioavailability for unchanged drug was 62˙5%.

2. Renal elimination was the major route of excretion with about 60% of the dosed radioactivity recovered in urine. Mean total recovered radioactivity in urine and faeces amounted to 84% for both the oral and intravenous routes.

3. Apart from a small amount of unchanged amlodipine (10% of urine ¹⁴C), only pyridine metabolites of amlodipine were excreted in urine. The majority (<95%) of the metabolites excreted in the 0-72h post-dose period were identified; the major metabolite was 2-([4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-pyridyl]methoxy) acetic acid and this represented 33% of urinary radioactivity. The data indicate that oxidation of amlodipine to its pyridine analogue is the principal route of metabolism with subsequent metabolism by oxidative deamination, de-esterification and aliphatic hydroxylation.

4. For the two volunteers, amlodipine concentrations in plasma declined with a mean half-life of 33 h, while slower elimination of total drug-related material from plasma was observed, consistent with prolonged excretion (up to 12 days) of metabolites in urine and faeces. Only amlodipine and pyridine metabolites were found in the circulation. As these pyridine derivatives have minimal calcium antagonist activity the efficacy of amlodipine in man can most probably be attributed to the parent drug.     

Biotransformation of diethenylbenzenes. III: Identification of metabolites of 1,3-diethenylbenzene in rat

1. Biotransformation of 1,3-diethenylbenzene (1) in rat gave four major metabolites, namely, 3-ethenylphenylglyoxylic acid (2), 3-ethenylmandelic acid (3), N-acetyl-S-[2-(3-ethenylphenyl)-2-hydroxyethyl]-L-cysteine (4) and N-acetyl-S-[1-(3-ethenylphenyl)-2-hydroxyethyl]-L-cysteine (5) were isolated from urine and identified by n.m.r. and mass spectrometry.

2. Four minor metabolites, 3-ethenylbenzoic acid (6), 3-ethenylphenylacetic acid (7), 3-ethenylbenzoylglycine (8) and 2-(3-ethenylphenyl)ethanol (9) were identified by g.l.c.-mass spectrometric analysis of urine extract derivatized in two different ways.

3. All identified metabolites are derived from 3-ethenylphenyloxirane (10), a reactive metabolic intermediate. No product of any metabolic transformation of second ethenyl group has been identified. However, several minor unidentified metabolites were detected by g.l.c.-mass spectrometry.

4. Total thioether excretion in 24h urine after a single i.p. dose of 1 amounted to 28·3±3·5 dose (mean±SD). No significant differences in the thioether fraction were observed in the dose range 100-300mg/kg.

5. Thioether metabolites consisted mainly of mercapturic acids 4 and 5. The ratio of metabolites 5 to 4 was 62:38. Each mercapturic acid consisted of two diastereomers. Their ratio, as determined by quantitative ¹³C-n.m.r. measurement was 95:5 and 79:21 for mercapturic acids 4 and 5, respectively.     

Metabolism of the Hydroxyethylrutosides III. The Fate of Orally Administered Hydroxyethylrutosides in Laboratory Animals; Metabolism by Rat Intestinal Microflora in vitro

1. The absorption, metabolism and excretion of hydroxyethylrutosides in rat and other mammals have been studied. Following oral administration to rats of 3′,4′,7-tri-O-(β-hydroxyethyl)rutoside, 4′,7-di-O-(β-hydroxyethyl)ruto-side and 7-O-(β-hydroxyethyl)rutoside, significant levels of the administered compounds and their conjugates in bile were observed, but 3′,4′,5,7-tetra-O-(β-hydroxyethyl)rutoside was poorly absorbed. The major portion of the dose of each rutoside was excreted as the aglycone in faeces. Urinary excretion of all rutosides was low.

2. Levels of excretion of ¹⁴C in the urine of rabbits and rhesus monkeys given 3′,4′,7-tri-O-(β-hydroxy[¹⁴C₂]ethyl)rutoside and 3′,4′,5,7-tetra-O-(β-hydroxy[¹⁴C₂]ethyl)rutoside were similar (<2.5% of dose) to those observed in the rat.

3. The hydroxyethylrutosides and rutin are degraded to their aglycones by the rat intestinal microflora both in vivo and in vitro. The B rings of rutin and 7-O-(β-hydroxyethyl)rutoside give rise to the same phenolic acid metabolites. Mono-O-(β-hydroxyethyl)phloroglucinol is formed from the A ring of 7-O-(β-hydroxyethyl)rutoside. Excretion of these metabolites in urine is suppressed by concurrent administration of neomycin.

4. 3′,4′,7-Tri-O-(β-hydrcxyethyl)rutoside did not undergo cleavage to metabolites other than the aglycone after continuous administration to rats for periods of up to 5 months.     

Comparative metabolism of the renal carcinogen 1,4-dichlorobenzene in rat: Identification and quantitation of novel metabolites

1. The metabolism of 1,4-dichlorobenzene has been studied in the male and female Fisher 344 rat over 72 h after oral administration of ¹⁴C-1,4-dichlorobenzene (900 mg = 96.8 μCi/kg). No covalent binding of radioactivity could be detected in samples of liver, kidney, lung and spleen. The major route of excretion was with urine accounting for 41.3% of the dose for male and 37.8% of the dose for female rat within 72 h after dosing.

2. Urinary metabolites of 1,4-dichlorobenzene were identified and quantified. The major metabolites identified in the urine of both the male and female rat, were the sulphate and glucuronide of 2,5-dichlorophenol. Minor amounts of 2,5-dichlorohydroquinone were excreted as an unidentified conjugate.

3. 2-(N-acetyl-cysteine-S-yl)- 1,4-dichlorobenzene and 2-(N-acetyl-cysteine-S-yl)-2,3-dihydro-3-hydroxy-1,3-hydroxy-1,4-dichlorobenzene were minor metabolites excreted in the urine of both sexes.

4. A novel biotransformation pathway for 1,4-dichlorobenzene may be postulated, leading to the urinary excretion of a mercapturic acid of chlorophenol.

5. No marked differences in the distribution and excretion of metabolites of 1,4-dichlorobenzene were observed between the male and female Fisher 344 rat.     

Species differences in the metabolism and excretion of fenclofenac

1. The excretion and metabolism of radiolabelled fenclofenac (2-(2, 4-dichlorophenoxy)phenylacetic acid, Flenac^R) has been studied in five species.

2. In the rat, absorption of oral doses of fenclofenac was virtually complete and elimination occurred mainly by the bile and faeces. The guinea-pig excreted equal amounts of radioactivity in urine and faeces, while in rabbit, baboon and man renal excretion was the more important route.

3. In all species the majority of excreted radioactivity was present as fenclofenac ester glucuronide. Amino acid conjunction with fenclofenac was minimal in all species studied.

4. Mono- and di-hydroxylated metabolites have been detected in urine from guineapig, baboon and man. The major hydroxylated metabolite in baboon urine has been identified as 2-(2,4-dichlorophenoxy)-5′-hydroxyphenylacetic acid.     

The metabolism of clomethiazole in gerbils and the neuroprotective and sedative activity of the metabolites

A single dose of clomethiazole (600 micromol kg(-1) i.p.) has previously been shown to be neuroprotective in the gerbil model of global ischaemia. In gerbils, clomethiazole (600 micromol kg(-1)) injection produced a rapid appearance (peak within 5 min) of drug in plasma and brain and similar clearance (plasma t(1/2): 40 min) from both tissues. The peak brain concentration (226+/-56 nmol g(-1)) was 40% higher than plasma. One major metabolite, 5-(1-hydroxyethyl-2-chloro)-4-methylthiazole (NLA-715) and two minor metabolites 5-(1-hydroxyethyl)-4-methylthiazole (NLA-272) and 5-acetyl-4-methylthiazole (NLA-511) were detected in plasma and brain. Evidence suggested that clomethiazole is metabolized directly to both NLA-715 and NLA-272. Injection of NLA-715, NLA-272 or NLA-511 (each at 600 micromol kg(-1)) produced brain concentrations respectively 2.2, 38 and 92 times greater than seen after clomethiazole (600 micromol kg(-1)). Clomethiazole (600 micromol kg(-1)) injected 60 min after a 5 min bilateral carotid artery occlusion in gerbils attenuated the ischaemia-induced degeneration of the hippocampus by approximately 70%. The metabolites were not neuroprotective at this dose. In mice, clomethiazole (600 micromol kg(-1)) produced peak plasma and brain concentrations approximately 100% higher than in gerbils, drug concentrations in several brain regions were similar but 35% higher than plasma. Clomethiazole (ED(50): 180 micromol kg(-1)) and NLA-715 (ED(50): 240 micromol kg(-1)) inhibited spontaneous locomotor activity. The other metabolites were not sedative (ED(50) >600 micromol kg(-1)). These data suggest that the neuroprotective action of clomethiazole results from an action of the parent compound and that NLA-715 contributes to the sedative activity of the drug. British Journal of Pharmacology (2000) 129, 95 - 100     

Identification of three sulphur-containing urinary metabolites of styrene in the rat

1. After administration of styrene (1) to rat, three sulphur-containing urinary metabolites were isolated in the molar ratio of III : IV : V equal to 65 : 34 : 1. 2. These metabolites were identified as N-acetyl-S-(1-phenyl-2-hydroxyethyl)cysteine (III), N-acetyl-S-(2-phenyl-2-hydroxyethyl)cysteine (IV) and N-acetyl-S-(phenacyl)cysteine (V). 3. After a single dose (250 mg/kg, 2.4 mmol/kg) styrene, the totally excreted mercapturic acids in the urine amounted to 10.7 +/- 1.0% (n = 5) of the dose.     

Identification of ginkgolic acid (15:1) metabolites in rats following oral administration by high-performance liquid chromatography coupled to tandem mass spectrometry

1.?In this article, metabolites of ginkgolic acid (GA) (15:1) in rats plasma, bile, urine and faeces after oral administration have been investigated for the first time by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) with the aid of on-line hydrogen/deuterium (H/D) exchange technique and β-glucuronidase hydrolysis experiments.

2.?After oral administration of GA (15:1, M0) to rats at a dose of 10?mg/kg, it was found that metabolites M1-M5 together with parent compound (M0) existed in rat plasma; parent compound (M0) and metabolites M2–M5 were observed in rat bile, and parent compound (M0) with metabolites M1 and M2 were discovered in rat faeces, and there was no parent compound and metabolite detectable in rat urine.

3.?Two oxidative metabolites of GA (15:1, M0) were identified as 2-hydroxy-6-(pentadec-8-enyl-10-hydroxy) benzoic acid (M1) and 2-hydroxy-6-(pentadec-8-enyl-11-hydroxy-13-carbonyl) benzoic acid (M2), respectively. Metabolites M3, M4 and M5 were identified as the mono-glucuronic acid conjugates of parent compound (M0), M1 and M2, respectively.

4.?The results indicated that M1 and M2 with parent compound (M0) were mainly eliminated in faeces and three glucuronide metabolites (M3, M4 and M5) excreted in bile as the predominant forms after oral administration of GA (15:1) to rats.     

Metabolism and disposition of the dopaminergic agonist 5-hydroxy-6-methyl-2-di-n-propylaminotetralin in the rat

As part of a program to investigate the metabolism and disposition of putative dopamine receptor agonists, DK-118 (5-hydroxy-6-methyl-2-di-n-propylaminotetralin) was chosen for study in the rat. Following a 3.85 mg/kg (ip) dose of 5-hydroxy[6-14C]methyl-2-di-n-propylaminotetralin, an average (+/- SD) of 100.3 +/- 12.2% was recovered in 67 hr: 77.2 +/- 7.9% in urine and 23.1 +/- 6.2% in feces. No excretion of 14CO2 was observed. In bile duct-cannulated animals, an average of 31.6% of the dose was recovered in the bile within 6 hr. After injection of bile containing radiolabeled drug/metabolites into the lumen of the duodenum, 30.2 +/- 1.7% of the injected radioactivity was recovered in the urine, suggesting enterohepatic circulation of some of the drug/metabolites excreted in bile. Highest concentrations of tissue radioactivity, 0.5 hr after ip injection of 14C-DK-118, were found in lung, kidney, and liver. Only a small amount of unchanged DK-118 is excreted into urine and bile; HPLC radiochromatography separated five metabolites in urine and at least eight metabolites in bile. The three major metabolites in urine (70% of urinary radioactivity) have been identified as 5-hydroxy-6-carboxy-2-di-n-propylaminotetralin, 5-hydroxy-6-carboxy-2-n-propylaminotetralin, and 5-hydroxy-6-methyl-2-n-propylaminotetralin-O-sulfate. The two major biliary metabolites have been identified as 5-hydroxy-6-carboxy-2-n-propylaminotetralin and an acid-labile conjugate of DK-118. Together, these data indicate that DK-118 is metabolized in the rat by a combination of N-dealkylation, oxidation of the 6-methyl carbon, and conjugation with sulfate.     

Some Metabolites of S-Pentyl-L-cysteine in the Rabbit and Other Species

Abstract

1. The metabolism of S-pentyl-L-cysteine has been investigated in the guinea pig, hamster, mouse, rabbit and rat and in vitro by liver slices of these animals and of the pigeon and by kidney slices of mouse, rabbit and rat.

2. The amounts of pentylmercapturic acid, 3-(pentylthio)lactic acid and 3-(pentylthio)pyruvic acid excreted have been measured.

3. All the species examined excreted pentylmercapturic acid, the amount varying from 2% of the dose by the guinea pig to 73% by the hamster. 3-(Pentylthio)pyruvic and 3-(pentylthio)lactic acids were not detected in the urine of the hamster or rat but were excreted by the other species in amounts approximately the same as those of pentylmercapturic acid.

4. ‘Hydroxypentylmercapturic’ acids were excreted by mouse, rabbit and rat and were identified in the case of the rabbit and rat.

5. 4-Carboxybutylmercapturic acid was identified in the urine of dosed mice, rabbits and rats. A further metabolite in rat urine was tentatively identified as 3-(4-carboxybutylthio)lactic acid.

6. Pentylmercapturic acid sulphoxide was detected in the urine of dosed guinea pigs and mice.

7. All tissue preparations examined converted pentyl-L-cysteine to pentylmercapturic acid. 3-(Pentylthio)lactic acid and 3-(pentylthio)pyruvic acid were formed by all tissues examined although only in trace amounts by hamster liver and rat kidney slices. All tissues examined formed hydroxymercapturic acids' although only traces were detected in digests containing hamster liver slices. 4-Carboxybutylmercapturic acid was formed in rabbit liver digests. With rabbit kidney a metabolite thought to be 3-(4-carboxybutylthio)lactic acid was produced.