The metabolic fate of the coronary vasodilator 4-(3,4,5-Trimethoxycinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine (cinepazide) in the rat, dog and man

1. An oral dose of the coronary vasodilator 4-(3,4,5-trimethoxy[14C]cinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine was well absorbed and more than 60% of the dose was excreted within 24 h. In 5 days, rats, dogs, and man excreted in the urine and faeces respectively 36.7% and 58.3%, 33.4% and 68.6%, and 61.3% and 38.1% dose. Faecal radioactivity was probably excreted via the bile. 2. Plasma concentrations of radioactivity reached a maximum within about 1 h in all three species and declined fairly rapidly (t0.5 less than 3 h). For several hours, more than 50% of the plasma radioactivity was due to unchanged drug. After correction for dose and body weight (normalization), peak plasma concentrations of unchanged drug in man, rat and dog were in the approximate ratio 100 :30:1. 3. Similar metabolites were excreted by the three species, but the relative proportions differed. Rats and man excreted 17.2% and 15.9% respectively as unchanged drug in the urine whereas dogs excreted only 3.6%. Rat bile and urine contained 4.3% and 9.8% dose respectively as glucuronides of the mono-O-demethylated compounds and dog and human urine contained 9.0% and 2.6% respectively of these metabolites. The corresponding pyrrolidone accounted for 2.5%, 5.5% and 5.1% respectively in rat, dog and human urine. Complete O-demethylation also occurred since 4-(3,4,5-trihydroxycinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine was present in rat faeces (22.1% dose).     

Excretion of DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline, PhIP-dG, PhIP-DNA and DiMeIQx-DNA from the rat

The heterocyclic aromatic amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx) are formed during frying of meat. PhIP and 4,8-DiMeIQx have, after metabolic activation, been shown to form adducts with DNA at the C8 of guanine both in vitro and in vivo. In order to investigate possible urinary biomarkers for estimation of the genotoxic dose of PhIP and 4,8-DiMeIQx, [3H]PhIP-dG, [3H]PhIP-DNA and [14C]4,8-DiMeIQx-DNA were injected i.p. to rats and the excretion of radioactivity in urine and faeces were measured. For all three [3H]PhIP-dG, [3H]PhIP-DNA and [14C]4,8-DiMeIQx-DNA 15-20% of the dose were excreted in the urine and 80-85% of the dose were excreted in the faeces. Urinary excretion showed maximum to 24 h (90%) with a rapid decline, 10% to 48 h and 0% to 72 h. Faecal excretion also showed maximum to 24 h (60%) with a slower decline, 30% to 48 h and 10% to 72 h. HPLC analysis of samples of urine and extracts from faeces, from rats dosed with [3H]PhIP-dG, showed that approximately 90% of the radioactivity co-eluted with PhIP-dG, indicating that PhIP-dG is excreted unmetabolized. HPLC analysis of samples of urine and extracts from faeces, from rats dosed with [3H]PhIP-DNA, showed that approximately 85% of the radioactivity co-eluted with PhIP-dG, indicating that PhIP-DNA adducts is mainly excreted as nucleoside adducts. Approximately 5% of the radioactivity excreted in the urine co-eluted with PhIP-G, indicating loss of deoxyribose. HPLC analysis of samples of urine and extracts from faeces, from rats dosed with [14C]4,8-DiMeIQx-DNA, showed that approximately 90% of the radioactivity co-eluted with 4,8-DiMeIQx-dG, indicating that 4,8-DiMeIQx-DNA adducts is mainly excreted as nucleoside adducts. Man is able to eliminate compounds of a higher mol. wt in the urine than the rat, the percentage of PhIP-dG and 4,8-DiMeIQx eliminated in the urine of man would therefore be expected to be higher than in the rat. Measurement of urinary nucleoside adducts of PhIP and 4,8-DiMeIQx could therefore provide a basis for the development of a biomonitoring strategy for the genotoxic dose of these food derived HAA.     

The metabolism of the hypolipidaemic drug sultosilic acid in rat, dog and man

1. Single oral doses of the hypolipidaemic drug [35S]sultosilic acid to rats (40 mg/kg), dogs (40 mg/kg) and man (7 mg/kg) were well absorbed. During three days, means of 59.2%, 58.8% and 61.8% in urine and 37.7%, 31.9% and 19.7% in faeces, were excreted by these species respectively. Most of the dose was excreted during the first 24 h. 2. Peak plasma levels of 35S were generally reached during 1-2 h after oral doses in rats (12 micrograms equiv./ml), dogs (45 micrograms equiv./ml) and two human subjects (15.2 and 10.3 micrograms equiv./ml). In humans, peak plasma levels of unchanged drug (at 1-1.5 h) were 10.5 and 6.3 micrograms/ml. Plasma concentrations of 35S increased almost proportionately to dose in rats following oral doses of 400 and 1200 mg/kg, although in dogs, concentrations were similar at these two dose levels but several times higher than at 40 mg/kg. 3. Tissue concn. of 35S were generally higher in rats than in dogs. Highest concn. occurred at 3 h in rats and 1 h in dogs. Apart from those in the liver and kidneys, tissue concn. were appreciably lower than the corresponding plasma levels. 4. The major radioactive component in dog urine was sultosilic acid. Rat and human urine contained sultosilic acid and also two more polar major metabolites. In male and female rat urine, the proportions of these excretory products differed and the proportions in male rat urine were similar to those in human urine. Sultosilic acid was also the only component detected in dog plasma, whereas rat and human plasma also contained the two urine metabolites. Dog bile contained a conjugate of sultosilic acid. 5. The two metabolites have been identified by mass spectrometry and nuclear magnetic resonance spectroscopy as products resulting from oxidation of the methyl in the p-toluenesulphonyl group. The structures assigned are the corresponding carboxylic acid and the hydroxymethyl derivatives.     

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 10 mg/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.     

Metabolic fate of a new dihydropyridine calcium antagonist, CD-349, in rat and dog

1. The metabolic fate of 14C-CD-349, a new calcium antagonist, was studied in rat and dog. 2. After oral administration of 14C-labelled drug in both species, the plasma levels of radioactivity reached maxima at 1-2 h and declined with elimination half-lives of 6-7 h. In both species, 71-85% of radioactivity was excreted in faeces and 17-27% in urine in 120 h. Biliary excretion in rat after oral doses amounted to 33%. 3. The low ratio of unchanged drug to total radioactivity in plasma suggested that CD-349 underwent rapid metabolism in both species. 4. Twenty-two metabolites were isolated and identified from dog urine and an incubation mixture with 9000 g rat liver supernatant. Principal routes of biotransformation of CD-349 were similar in both species, and involved: (1) oxidation of the dihydropyridine ring to the corresponding pyridine ring; (2) denitration of the nitrate ester; (3) hydrolysis of the carboxy ester to the carboxylic acid; and/or (4) oxidation of the side chain, although quantitative interspecies differences were observed.     

In vivo dexamethasone effects on neutrophil effector functions in a rat model of acute lung injury

1. In healthy male volunteers, the absorption, metabolite profiles and excretion of 14C-benidipine hydrochloride, a new Ca antagonist, were investigated after oral administration at a dose of 8 mg. 2. 14C-benidipine hydrochloride was rapidly absorbed, and the plasma concentration of radioactivity and unchanged drug reached a maximum of 71.2 ng eq./ml at 1.1 h and 2.56 ng/ml at 0.6 h respectively, and then declined bi-exponentially. The half-life in the elimination phase was 14.7 and 5.3 h respectively, AUC of unchanged drug was low, about 1% of that of radioactivity. 3. Five days after administration, 36.4% of the administered radioactivity was excreted in urine and 58.9% in faeces. 4. The metabolite profiles in plasma, urine and faeces were analysed by hplc. At 1 h after administration the predominant metabolites in plasma were M9 and M2, which accounted for 13.8 and 8.2% of the radioactivity respectively, whereas unchanged drug represented 1.2%. Predominant metabolites in urine 12 h after administration were M3 and M8, which accounted for 2.22 and 2.21% of the administered radioactivity respectively. Metabolites excreted in faeces 120 h after administration were very complex and poorly separated by hplc and could not be characterized: unchanged drug was not detected in the faeces.     

Metabolism of linoleamides. I. Absorption, excretion and metabolism of N-(alpha-methylbenzyl)linoleamide in rat and man

1. In urine of rats dosed with N-(alpha-methylbenzyl)linoleamide (MBLA), three dicarboxylic acid monoamides, N-(alpha-methylbenzyl)succinic acid monoamide, N-(alpha-methylbenzyl)glutaric acid monoamide and N-(alpha-methylbenzyl)adipic acid monoamide, were identified. Conjugated alpha-methylbenzylamine, hippuric acid and conjugates of the dicarboxylic acid monoamides were also found in the urine. N-(alpha-Methylbenzyl)succinic acid monoamide was the main metabolite in rats. 2. Biliary excretion of radioactivity was studied in rats, cannulated for collection of bile and duodenal infusion, after oral administration of N-(alpha-methylbenzyl)[1-14C]linoleamide. With constant duodenal infusion of bile, about 7% of the dose was excreted in the bile, while excretion of radioactivity was negligible without bile infusion. 3. The g.l.c. analysis of human urine after oral administration of MBLA revealed that two dicarboxylic acid monoamides were present and N-(alpha-methylbenzyl)succinic acid monoamide was the main metabolite. 4. MBLA was excreted unchanged in the faeces of men who received MBLA to the extent of about 53% dose in 3 days. 5. MBLA was not detected (less than 1 mug/ml) in the serum of a volunteer who had been taking an oral daily dose of 1500 mg of MBLA for 3 months.     

Biotransformation of 2-chloroaniline in the Fischer 344 rat: identification of urinary metabolites

1. The biotransformation of a single i.p. dose of [14C]2-chloroaniline (1.0 mmol/kg, approximately 60 microCi/rat) was investigated in the urine and faeces of the male Fischer 344 rat. 2. During 24 h, 53.1% of the administered radioactivity was eliminated into the urine, while < 1% of the radioactivity appeared in the faeces. 3. The major biotransformation pathways were para-hydroxylation and sulphate conjugation. 4-Amino-3-chlorophenyl sulphate was the major urinary metabolite comprising 31.6% of total urinary radioactivity. The para-hydroxylated metabolite, 4-amino-3-chlorophenol (10.8%), and its O-glucuronide conjugate (3.7%) were also urinary metabolites. The formation of direct conjugates of 2-chloroaniline, the N-sulphate and N-glucuronide, was significant with as much as 18.6 and 8.6%, respectively, of these metabolites excreted in the urine. The parent compound, 2-chloroaniline, accounted for 16.9% of urinary radioactivity. 4. N-Acetylated products were minor metabolites present in urine as 2-chloro-4-hydroxyacetanilide and its sulphate or glucuronide conjugate. Neither 2-chloroacetanilide nor its oxidation products, 2-chloroglycolanilide and 2-chlorooxanilic acid, were urinary metabolites.     

Hyperglycemia delays terminal depolarization and enhances repolarization after peri-infarct spreading depression as measured by serial diffusion MR mapping

The absorption, distribution, and excretion of GT31-104, a novel bile acid sequestrant, was studied in rats and dogs after both acute and subchronic oral administration. The polyallylamine backbone of GT31-104 was labeled with tritium and one of the alkyl side chains was labeled with 14C. The mean blood and plasma concentration of [3H, 14C]GT31-104 in rats, in both treatment regimens, was negligible at all time points, with the highest amount observed being 0.69 microgram eq/g blood; in dogs the mean blood and plasma concentration of [3H, 14C]GT31-104 was below the limit of quantitation (< 0.001% total dose) at all time points. In both rats and dogs, the mean total urinary excretion of [3H, 14C]GT31-104 was approximately 0.06% of the total dose. The fecal excretion data indicates that both 3H- and 14C-derived radioactivity was excreted entirely in the feces. Mean total radioactivity excreted in the feces ranged from approximately 95 to 105% in the rats and 92 to 102% in the dogs. Across the different treatment regimens, in both species, tissue concentrations were negligible (< 0.01% total dose) and no differences in tissue profile were noted, indicating that there was no effect of pretreatment on [3H, 14C]GT31-104 absorption. GT31-104 was extracted with water, and the water-soluble portion contained radioactivity that would correlate to approximately 0.19% of the 3H dose and 0.41% of the 14C dose; this portion probably accounted for the negligible radioactivity observed systemically. Analysis of gastrointestinal (GI) tract tissues with contents indicated that GT31-104 is rapidly cleared from the GI tract. These data indicate that GT31-104 is not absorbed from the GI tract in rats and dogs.     

Disposition and metabolism of [3H]cocaine in acutely and chronically treated dogs

1. Beagle dogs were chronically treated with cocaine, 5 mg/kg subcutaneously twice daily for 6 weeks, followed by same dose of [3H]cocaine given intravenously. 2. The t1/2 values of cocaine in plasma, liver, spleen and heart, in acutely and chronically treated dogs, were: 1-2, 1-1; 2-2, 1-8; 1-8, 1-3; 2-0, 1-2 h, respectively. In both groups, cocaine disappeared from all areas of the central nervous system 12-24 h after injection but significant amounts of radioactivity due to benzoylnorecgonine and benzoylecgonine persisted in the CNS even 1 week after administration of cocaine. Brain-to-plasma ratios of cocaine were lower in chronically-treated than in acutely-treated dogs 2 and 4 h after injection. 3. Norcocaine, benzoylnorecgonine, benzoylecgonine and ecgonine were metabolites of cocaine in dog brain in both groups. Norcocaine and benzoylnorecgonine were present in higher amounts in brains of chronically treated dogs. Rate of disappearance of norcocaine was similar to cocaine in both groups. 4. The amounts of cocaine excreted in urine and faeces as percentage of dose were 0-9-5-0, 1-1-6 in the acute and 2-2-3-3 and 0-2-0-3 in the chronically treated dogs. Major excretion of radiactivity occurred in urine within 24 h in both groups. Total radioactivity (65% of dose) in urine plus faeces was similar in both groups. 5. Norcocaine, benzoylnorecgonine, benzoylecgonine, ecgonine, norecgonine, ecgonine methyl ester and unidentified compounds were urinary metabolites of cocaine in both groups. Benzoylnorecgonine and ecgonine were excreted in higher amounts and benzoylecgonine and norecgonine in lower amounts in the acute than in the chronically treated dogs. 6. The possible role of persistence of benzoylnorecgonine and benzoylecgonine (which possessed potent stimulant activity intracisternally) in the CNS is discussed.     

Absorption, pharmacokinetics and metabolism of 14C-sumatriptan following intranasal administration to the rat

1. Studies have been carried out to investigate the absorption of sumatriptan after intranasal administration to rats. The pharmacokinetics, metabolism and excretion of 14C-sumatriptan were compared following intranasal and intravenous dosing to male and female albino rats using an aqueous buffered formulation at pH 5.5. 2. Following intravenous administration sumatriptan was eliminated from plasma with a half-life of about 1.1 h. After intranasal administration there was rapid absorption of part of the dose and two peak plasma concentrations were observed, initially at 0.5 and then at 1.5-2 h. The elimination half-life after the second peak was estimated as being about 4 h. 3. Radioactivity was largely excreted in urine (up to 89% of dose in 168 h) after both intravenous and intranasal administration, with a faster rate of excretion after intravenous dosage (73% males, 64% females within 6 h) than after intranasal dosage (37% males, 40% females within 6 h). 4. 14C-sumatriptan was the major component in urine and in extracts of faeces after both intravenous and intranasal administration. The major metabolite excreted in urine and faeces was GR49336, the indole acetic acid analogue. 5. The results of this in vivo rat study suggest that absorption of the dose via the nasal mucosa is incomplete after intranasal administration and that there is a secondary absorption phase probably reflecting oral absorption of part of the dose. The bioavailability is estimated as about 30%, for the period 0-6 h.     

Metabolism of linoleamides. II. Absorption, distribution, excretion and metabolism of N-[alpha-phenyl-beta-(p-tolyl)ethyl]linoleamide

1. Absorption, distribution, excretion and metabolism of (-)N-[alpha-phenyl-beta-(p-tolyl)ethyl][14C]linoleamide (14C-PTLA) were studied in rats and dogs. Faecal excretion of PTLA was studied in dogs and men by g.l.c. 2. 14C-PTLA (10 mg/kg) given orally to rats resulted in urinary and faecal excretion of radioactivity of 2 and 93%, respectively, by male rats and 8 and 87% by female rats in 48 h. Faecal excretion of PTLA in men was similar to that in rats. 3. Distribution of radioactivity in rats and dogs after oral administration of 14C-PTLA showed that a major part of the dose was not absorbed. 4. N-[alpha-phenyl-beta-(p-tolyl)ethyl]glutaric acid monoamide were detected in the urine of rats dosed orally with 14C-PTLA.     

Distribution and excretion of radiolabelled tert-butylhydroquinone in Fischer 344 rats

Uniformly 14C-ring-labelled tert-butylhydroquinone (TBHQ) was diluted with non-radioactive TBHQ and administered orally (for excretion studies) to Fischer 344 rats. An average of 72.9% and 10.6% of the administered radioactivity was recovered in the urine and faeces, respectively, of male rats, and 77.3% and 8.2% in the urine and faeces, respectively, of female rats in 4 days. No significant sex-related differences were found in either excretion, tissue distribution or urinary metabolites of TBHQ-derived radiolabel. For distribution studies, intraperitoneal doses were administered to female rats, and tissue levels of radiolabel were determined at various times after dosing. The parent compound quickly disappeared from tissue in vivo. The highest concentrations of radiolabel were found in the liver and kidneys. The urinary metabolites consisted of conjugated TBHQ and unidentified polar substance(s).     

Pharmacokinetics, disposition and metabolism of 546C88 (L-NG-methylarginine hydrochloride) in rat and dog

1. 14C-546C88 (14C-L-NG-methylarginine hydrochloride) was administered to rat and dog as a single 5-min intravenous infusion at 1.7 mg/kg (20 mg/kg/h) to aid in the preclinical safety evaluation of the compound. 2. The distribution and elimination of parent compound from plasma was rapid in both species. 3. Drug-derived radioactivity was eliminated slowly. There was up to 39% of the dose retained in the carcasses at the end of the 7-day collection periods. The main route of elimination was as 14CO2 in the expired air. Less than 8% of the dose was excreted in the urine, and < 5% in the faeces. 4. Drug derived radioactivity was widely distributed throughout the body with highest concentrations in tissues with a high protein turnover, such as glandular tissue and liver. 5. 14C-546C88 appeared to be eliminated primarily by metabolism and subsequent putative amino acid catabolism, resulting in retention of drug-derived radioactivity in tissues, and ultimate elimination as 14CO2 in the expired air. Potential routes of metabolism of 546C88 have been identified.     

Metabolism and excretion of oestradiol-17beta and progesterone in the Sumatran rhinoceros (Dicerorhinus sumatrensis)

3H-labelled oestradiol-17beta and 14C-progesterone were injected i.v. into an adult female Sumatran rhinoceros (Dicerorhinus sumatrensis) and all urine and faeces collected over 4 days. Of the injected steroid, 68% of 3H-oestradiol and 89% of 14C-progesterone were recovered. Peak excretion in urine occurred on day 1 for both steroids, and for faeces on day 2 for 14C-progesterone, and between days 2 and 3 for 3H-oestradiol. Oestradiol metabolites were predominantly (nearly 70%) excreted into the urine, while progesterone metabolites were almost exclusively (> 99%) excreted into the faeces. The majority (> 70%) of urinary excreted oestrogens consisted of water-soluble (i.e., conjugated) forms, with > 90% of these being glucuronides. In contrast, > 75% of faecal oestrogen and progesterone metabolites were excreted as ether-soluble (i.e., unconjugated) forms. HPLC co-chromatography of oestrogens in hydrolysed urine indicated only one peak of radioactivity, co-eluting with authentic oestradiol-17beta, whereas two peaks of radioactivity were found after HPLC of faecal oestrogens, the major one co-eluting with oestrone and the less prominent one with oestradiol-17beta. Progesterone was excreted as numerous metabolites into the faeces. The three most abundant of these were identified using HPLC and gas chromatography mass spectrometry (GCMS) as 5beta-pregnane-3alpha,20alpha-diol, 5beta-pregnane-3alpha-ol-20-one, and a second pregnanediol, the exact structure of which could not be deduced. Measurement of urinary oestradiol-17beta and faecal immunoreactive pregnanediol and 5alpha-pregnane-3alpha-ol-20-one in daily samples enabled the first endocrine characterization of the ovarian cycle and indicated a cycle length of approximately 25 days.     

Disposition of [14C]avitriptan in rats and humans

Avitriptan is a new 5-HT1-like agonist with abortive antimigraine properties. The study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of avitriptan after intravenous (iv) and oral administrations of [14C]avitriptan in rats and oral administration of [14C]avitriptan in humans. The doses used were 20 mg/kg iv and oral in the rat, 10 mg iv in humans, and 50 mg oral in humans. The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring at 0.5 hr postdose. Absolute bioavailability was 19.3% in rats and 17.2% in humans. Renal excretion was a minor route of elimination in both species, with the majority of the dose being excreted in the feces. After a single oral dose, urinary excretion accounted for 10% of the administered dose in rats and 18% of the administered dose in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats. Avitriptan was extensively metabolized after oral administration, with the unchanged drug accounting for 32% and 22% of the total radioactivity in plasma in rats and humans, respectively. Plasma terminal elimination half-life was approximately 1 hr in rats and approximately 5 hr in humans. The drug was extensively distributed in rat tissues, with a tendency to accumulate in the pigmented tissues of the eye.     

Pharmacokinetics of cyproterone acetate in normal subjects after i.m. and oral application (author's transl)

Sixteen volunteers were given cyproterone acetate-2'-14C (6-chloro-17-hydroxy-1alpha,2alpha-methylene-pregna-4,6-diene-3,20-dione acetate; Androcur?) in single doses of between 2 and 12 mg i.m. and p.o. in 19 investigations. The plasma radioactivity was then determined at suitable intervals. Urine and faeces were collected quantitatively for 12 days. After oral administration the highest concentrations in plasma were found 1--4 h after administration. The mean amounts were 2--3% of the administered dose in the plasma volume. Plasma concentrations of more than half the highest values were measured for a period of 2--8 h. Cyproterone acetate was eliminated from the body with a half-life of about 1 1/2 days for men and about 2 days for women. After oral administration in single doses of 2--12 mg the compound was almost completely absorbed.     

Synthesis and excretion profile of 1,4-[14C]phenylenebis(methylene)selenocyanate in the rat

1,4-Phenylenebis(methylene)selenocyanate (p-XSC) inhibits chemically induced tumors in several laboratory animal models. To understand its mode of action, we synthesized p-[14C]XSC, examined its excretion pattern in female CD rats and also the nature of its metabolites. p-[14C]XSC was synthesized from alpha,alpha-dibromo-p-[ring-14C]xylene in 80% yield. The excretion profile of p-[14C]XSC (15.8 mg/kg body wt, 200 microCi/rat, oral administration, in 1 ml corn oil) in vivo was monitored by measuring radioactivity and selenium content. On the basis of radioactivity, approximately 20% of the dose was excreted in the urine and 68% in the feces over 3 days. The cumulative percentages of the dose excreted over 7 days were 24% in urine and 75% in feces, similar to excretion rates of selenium. According to selenium measurement, <1% of the dose was detected in exhaled air; radioactivity was not detected. Only 15% of the dose was extractable from the feces with EtOAc and was identified as tetraselenocyclophane (TSC). Most of the radioactivity remained tightly bound to the feces. Approximately 10% of this bound material converted to TSC on reduction with NaBH4. Organic soluble metabolites in urine did not exceed 2% of the dose; sulfate (9 % of urinary metabolites) and glucuronic acid (19.5% of urinary metabolites) conjugates were observed but their structural identification is still underway. Co-chromatography with a synthetic standard led to the detection of terephthalic acid (1,4-benzenedicarboxylic acid) as a minor metabolite. The major urinary conjugates contained selenium. Despite the low levels of selenium in the exhaled air, the reductive metabolism of p-XSC to H2Se cannot be ruled out. Identification of TSC in vivo indicates that a selenol may be a key intermediate responsible for the chemopreventive action of p-XSC.     

Integrated physical and transcript map of 5q31.3-qter

The disposition of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (CAS 155680-07-2, S-MTPPA, code: M-5011) was studied after oral administration to rats, dogs and monkeys using the 14C-labeled drug. After oral dosing, S-MTPPA was well absorbed from the gastrointestinal tract, to the extent of 97.7% in rats. The concentration of S-MTPPA in rat plasma reached a peak (Cmax: 13.07 micrograms/ml) at 15 min (tmax) after dosing and declined with a half-life (t1/2) of 2.5 h. The values of the parameters tmax, Cmax and t1/2 for dogs were 30 min, 26.2 micrograms/ml and 7.0 h, and those for monkeys were 15 min, 12.8 micrograms/ml and 3.0 h, respectively. The radioactivity was widely distributed in tissues and almost completely excreted in urine and feces within 48 h after oral administration to rats. The excretion of radioactivity in bile, urine and feces within 48 h after oral administration of 14C-S-MTPPA to bile duct-cannulated rats amounted to 75.0, 18.6 and 1.4% of the dose, respectively. The drug was metabolized mainly by oxidation of the thiophenyl moiety and by glucuronidation of the carboxyl group in rats and monkeys. The major urinary and fecal metabolite in dogs was identified as the taurine conjugate of MTPPA.     

Biotransformation, excretion, and nephrotoxicity of the hexachlorobutadiene metabolite (E)-N-acetyl-S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine sulfoxide

The disposition of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4- triazol-1-ylmethyl) quinoline-3-carboxylate (CAS 158146-85-1, TAK-603) after single oral dosing of 14C-labeled TAK-603 ([14C]TAK-603) at 10 mg/kg to rats and dogs was studied. In rats, the concentration of unchanged drug in plasma reached a peak (Cmax, 0.31 microgram/ml) 2 h (Tmax) after dosing of TAK-603 and declined biphasically with apparent half-lives (t 1/2 alpha, t 1/2 beta) of 1.5 and 3.6 h. In dogs, Tmax, Cmax, T 1/2 alpha, and t 1/2 beta were 1.7 h, 0.36 microgram/ml, 1.2, and 10.8 h, respectively. [14C]TAK-603 dosed orally was absorbed quantitatively in rats, while the extent of absorption in dogs was 54%. The bioavailability of TAK-603 was 53% and 42% in rats and dogs, respectively. In rats, 14C was distributed widely in various tissues, with relatively high concentrations in the liver, adrenal gland, and gut. The elimination of 14C from the thyroid was slower than that from other tissues. Unchanged TAK-603 and its pharmacologically active metabolite, M-I, which has the same potency as TAK-603, were distributed in articular soft tissues and synovial fluids, as target tissues, in rats and dogs, respectively. After oral administration of [14C]TAK-603, most of the 14C dosed was excreted within 48 h in rats and within 96 h in dogs. In both animals, a greater amount of the 14C dosed was excreted in feces than in urine. In biliary duct cannulated rats given [14C]TAK-603 intraduodenally, 69% of the dose was excreted in bile, and biliary 14C in part underwent enterohepatic circulation.