Percutaneous absorption of triclocarban in rat and man

The route and rate of excretion by rats of the germicide [¹⁴C] Triclocarban formerly called trichlorocarbanilide, given by parenteral injection has been investigated. Blood levels based radioactivity and by chemical determination after parenteral injection have been compared with those obtained after topical application of [¹⁴C] Triclocarban in acetone.Absorption of [¹⁴C] Triclocarban in soaps and in dimethylformamide (DMF) through occluded rat skin has been studied. Other soaps and a hand cleanser containing [¹⁴C] Triclocarban have been applied to rat skin without occlucion and the effects of duration of contract, concentration and the use of a solubilizer have been investigated.In humans, absorption of Triclocarban through skin after bathing daily for 28 days has been investigated by chemical analysis of blood and urine.The data show that elimination by the rat is rapid and complete principally via the faeces. Blood levels after parenteral injection are low and comparison of the radioactivity and chemical determinations suggest rapid metabolism of the Triclocarban. After application to the skin, blood levels based on ¹⁴C are very low.Absorption of [^14C] Triclocarban through occluded rat skin was greater from DMF than from soaps. With non-occluded rat skin, absorption from soaps was less and was dependent on concentration but independent of duration of contract. The use of a solubilizer did not increase absorption through skin.No measurable Triclocarban (< 25 ppb) was present in blood and urine samples of volunteers during or shortly after a 28-day intensive bathing regimen.     

Elimination pattern and biodistribution of pcichlorferron in rats

Administration of [¹⁴C]chlorferron in a single oral dose of 0.5 and 20 mg/kg body weight to female rats resulted in a urinary excretion of > 74% of the given dose during the first 24 h. Approx. 8% of the dose was eliminated in faeces within 7 days. 7 days after dosing, very low levels of [¹⁴C]chlorferron-derived residues were detected in all analyzed organs. These findings indicated that chlorferron was absorbed from the gastro-intestinal tract in appreciable quantities, but was rapidly excreted mainly via the urine with small amounts only in the faeces.     

Disposition of timiperone, 4-fluoro-4-[4-(2-thioxo-1-benzimidazolinyl)piperidino]butyrophenone,a neuroleptic,in the rat on repeated oral dosage

1. The metabolic disposition of [¹⁴C]timiperone was studied in male Wistar strain rats receiving an oral dose of 0.5?mg kg consecutively daily for 21 days.

2. Blood concentrations of ¹⁴C indicate that absorption of [¹⁴C]timiperone on repeated dosage may be similar to that after a single dose.

3. Tissue levels of ¹⁴C after repeated doses were increased to up to double those after a single dose, but the decline of tissue concentrations after the 21st dose was similar to that after a single dose. Thus, no rat tissues show accumulation.

4. Repeated administration did not affect the metabolism of timiperone.

5. Excretion of ¹⁴C on the third day of repeated medication was urine, 44.7% and faeces 52.4% of the cumulative dose, and total daily excretions were more than approx. 97% of the cumulative dose in days 3.21 of the repeat dosage schedule.     

Synthesis of 13C and 15N labeled 2,4‐dinitroanisole

Syntheses of [¹³C₆]‐2,4‐dinitroanisole (ring‐¹³C₆) from [¹³C₆]‐anisole (ring‐¹³C₆) and [¹⁵N₂]‐2,4‐dinitroanisole from anisole using in situ generated acetyl nitrate and [¹⁵N]‐acetyl nitrate, respectively, are described. Treatment of [¹³C₆]‐anisole (ring‐¹³C₆) with acetyl nitrate generated in 100% HNO₃ gave [¹³C₆]‐2,4‐dinitroanisole (ring‐¹³C₆) in 83% yield. Treatment of anisole with [¹⁵N]‐acetyl nitrate generated in 10 N [¹⁵N]‐HNO₃ gave [¹⁵N₂]‐2,4‐dinitroanisole in 44% yield after two cycles of nitration. Byproducts in the latter reaction included [¹⁵N]‐2‐nitroanisole and [¹⁵N]‐4‐nitroanisole.     

Absorption,metabolism and excretion of darexaban (YM150), a new direct factor Xa inhibitor in humans

1.?The absorption, metabolism and excretion of darexaban (YM150), a novel oral direct factor Xa inhibitor, were investigated after a single oral administration of [¹⁴C]darexaban maleate at a dose of 60?mg in healthy male human subjects.

2.?[¹⁴C]Darexaban was rapidly absorbed, with both blood and plasma concentrations peaking at approximately 0.75?h post-dose. Plasma concentrations of darexaban glucuronide (M1), the pharmacological activity of which is equipotent to darexaban in vitro, also peaked at approximately 0.75?h.

3.?Similar amounts of dosed radioactivity were excreted via faeces (51.9%) and urine (46.4%) by 168?h post-dose, suggesting that at least approximately half of the administered dose is absorbed from the gastrointestinal tract.

4.?M1 was the major drug-related component in plasma and urine, accounting for up to 95.8% of radioactivity in plasma. The N-oxides of M1, a mixture of two diastereomers designated as M2 and M3, were also present in plasma and urine, accounting for up to 13.2% of radioactivity in plasma. In faeces, darexaban was the major drug-related component, and N-demethyl darexaban (M5) was detected as a minor metabolite.

5.?These findings suggested that, following oral administration of darexaban in humans, M1 is quickly formed during first-pass metabolism via UDP-glucuronosyltransferases, exerting its pharmacological activity in blood before being excreted into urine and faeces.     

Disposition of fragrance ingredient [14C]1-(1,2,3,4,5,6,7,8-octahydro-2,3,8,8-tetramethyl-2-naphthalenyl)ethanone in male Fisher rats following oral administration and dermal application

Abstract

1. Disposition of 1-(1,2,3,4,5,6,7,8-octahydro-2,3,8,8-tetramethyl-2-naphthalenyl)ethanone (β-OTNE), a fragrance ingredient in variety of consumer products, was investigated following a single oral (20?mg/kg) or a dermal (55 or 550?mg/kg) dose of [¹⁴C]β-OTNE to male Fisher rats.

2. Following oral administration, 28% and 39% of the dose was recovered in urine and feces, respectively, 48?h following administration. About 73% of a 20?mg/kg dose was excreted in bile within 48?h post-administration supporting significant oral absorption of [¹⁴C]β-OTNE.

3. Following dermal application to a covered site, absorption of [¹⁴C]β-OTNE 96?h following application was low (ca. 14%) and dose-independent. When the dose site was uncovered, the absorption increased to ca. 33% (55?mg/kg) and ca. 72% (550?mg/kg).

4. [¹⁴C]β-OTNE was distributed to tissues following both routes of exposure with the highest radioactive equivalents found in bladder, liver, kidney, adipose and pancreas.

5. Elimination of [¹⁴C]β-OTNE equivalents in blood and tissues was slow following both oral and dermal application suggesting potential for accumulation following multiple exposure.     

The metabolic disposition of C-labelled carmoisine in the rat after oral and intravenous administration

The absorption, distribution and excretion of the red azo dye carmoisine (Ext. D & C No. 10) was studied in male rats. [14C]Carmoisine was administered in a dose of 200 mg/kg (25 microCi) by gavage or in the same dose (200 mg/kg; 3 microCi) by intravenous injection, and radioactivity was measured in blood, tissue, faeces and urine at different times after dosing. After oral administration of the dye, no radioactivity was detected in the brain, adipose tissue, muscle, testes, spleen or lung, and recovery of the administered activity in faeces and urine was almost complete by 32 hr. The radioactivity profile of the blood indicated rapid but poor absorption of [14C]carmoisine, a maximum radioactivity content corresponding to 0.01% of the dose per ml of blood being reached within 10 min. The decay curve for 14C radioactivity in the blood after iv injection of [14C]carmoisine indicated rapid distribution to the tissues and could be described in terms of a two-compartment mathematical model. The highest levels of radioactivity occurred in the gastro-intestinal tract and liver after the injection but after 24 hr no radioactivity was detectable in these or other tissues. All the radioactivity was recovered in the faeces and urine in the 24 hr following iv injection, the 79% of the dose present in faeces indicating active excretion of the dye and its metabolites in the bile and poor reabsorption from the intestine. The bioavailability of [14C]carmoisine, calculated from the blood-radioactivity curves after oral and iv administration, was less than 10%.     

Metabolism of tetramethrin isomers in rat: II. Identification and quantitation of metabolites

To examine the metabolic fate of (1RS, trans)- or (1RS, cis)-tetramethrin [3, 4, 5, 6-tetrahydrophthalimidomethyl (1RS, trans)- or (1RS, cis)-chrysanthemate], rat was administered a single oral dose of trans- or cis-[alcohol-¹⁴C]tetramethrin at dose levels of 2 or 250 mg/kg.

2. The radiocarbon was almost completely eliminated from rat within 7 days after administration in all groups. ¹⁴C-recoveries (expressed as percentages relative to the dosed ¹⁴C) in faeces and urine were 38–58 and 42–58% respectively in rat administrated trans-[alcohol-¹⁴C]tetramethrin, and in faeces and urine were 66–91 and 9–31% respectively in rat administered cis-[alcohol-¹⁴C]tetramethrin.

3. Fourteen metabolites found in excreta were purified by using several chromato-graphic techniques and identified by spectroanalyses (nmr and MS). Five sulphonate derivatives and three dicarboxylic acid derivatives were found.

4. The main metabolites were sulphonate derivatives in the faeces, and in the urine, alcohols, dicarboxylic acid and reduced metabolites derived from the 3,4,5,6-tetrahydroph-thalimide moiety.     

Metabolism of ethynodiol diacetate in the rhesus monkey before and after administration of rifampicin

1. On administration of a single oral dose of [4- ¹⁴C]ethynodiol diacetate (0·15 mg/kg) to rhesus monkey, plasma concn. of total ¹⁴C peaked after about 4 h. About 60% of the plasma radioactivity was present as glucuronide conjugates and no unchanged drug was detected.

2. Some 67 ±6% (mean ± S. D.) of the dose of ¹⁴C was excreted in 4 days, 50 ± 6% in urine and 18 ± 2% in faeces. Most of the urinary excretion occurred within 24 h of dosage.

3. Glucuronide conjugates accounted for 60% of the urinary ¹⁴C, and 46% of the faecal ¹⁴C was free steroids.

4. Norethisterone and its tetrahydro metabolites were identified in the free, glucuronide and sulphate fractions of plasma and urine. Keto-4,5-dihydronorethisterones and trihydroxy metabolites were identified in the conjugated fractions of urine, and a complex mixture of polar metabolites was detected in faeces.

5. Rifampicin treatment (7·5 mg/kg/day, orally) for 8 days decreased the half-life of total ¹⁴C in plasma following a single oral dose of 4-[¹⁴C]ethynodiol diacetate (0·15 mg/kg) from 44±4 to 24±2h.

6. Faecal elimination of total ¹⁴C was significantly increased to 29±5% of the dose following rifampicin treatment, but urinary excretion was unchanged.

7. Rifampicin treatment increased the amount of polar metabolites and decreased the amount of norethisterone in the free and conjugated fractions of plasma and urine. The amounts of sulphate and non-hydrolysed conjugates in faeces were increased after rifampicin treatment.     

The fate of saccharin impurities. The excretion and metabolism of [14C]toluene-4-sulphonamide and 4-sulphamoyl[14C]benzoic acid in the rat

1. 4-Sulphamoyl[carboxy-14C]benzoic acid was rapidly eliminateda after oral administration to rats (94% dose in 24 h). After 6 days most of the 14C (73-83% dose) was recovered in the urine with significant amounts (18-32% dose) in the faeces due to incomplete absorption. 2. The 14C in the urine and faeces was unchanged 4-sulphamoylbenzoic acid. No 14CO2 was detected in the expired air. 3. After oral administration of [methyl-14C]toluene-4-sulphonamide to rats the label was rapidly eliminated largely in the urine (66-89% dose) with little in the faeces (2-8% dose). The 14C in the faeces was 4-sulphamoylbenzoic acid, which probably originated in the tissues since the gut flora was unable to effect this biotransformation. 4. The urine of rats given [14C]toluene-4-sulphonamide contained 4-sulphamoylbenzoic acid as the major metabolite (93% of the urinary 14C) together with small amounts of unchanged compound (1.5-2.3% of urinary 14C), 4-sulphamoylbenzyl alcohol (2.0-3.9%), 4-sulphamoylbenzaldehyde (0-1.5%) and at higher doses N-acetyltoluene-4-sulphonamide (2.1-2.3%).     

The absorption, metabolism and tissue distribution of di(2-ethylhexyl)phthalate in rats

Rats given a single oral dose of [¹⁴C] di(2-ethylhexyl) phthalate [¹⁴C] (DEHP) excreted 42% and 57% of the dose in the urine and faeces respectively in 7 days. A significant proportion (14%) of the dose is excreted in bile. Rats fed 1000 ppm DEHP in the diet for 7 days prior to dosing with [¹⁴C] DEHP excreted 57% and 38% in the urine and faeces respectively in 4 days.When fed continuously to rats at dietary concentrations of 1000 and 5000 ppm, the amount of the ester in liver and abdominal fat rapidly attains a steady-state concentration and there is no evidence of accumulation. When returned to a normal diet, the radioactivity in the liver declined with a half life of 1–2 days while that in fat declined rather more slowly to give a half life of 3–5 days. The relative liver weight increased to a level 50% above normal in rats receiving 5000 ppm DEHP and returned to normal within 1 week after being returned to normal diet.When administered intravenously DEHP is preferentially localised in lung, liver and spleen from where it is eliminated with a half-life of 1–2 days.The hexobarbital sleeping time was reduced by 30–40% in rats following repeated oral administration of DEHP; when the ester was administered intravenously sleeping time was increased by approx. 40%.DEHP is extensively metabolised after oral administration, the principal metabolites being identified as the acid, alcohol and ketone resulting from ω- and (ω-1)-oxidation of mono(2-ethylhexyl) phthalate (MEHP). DEHP is rapidly hydrolysed to the half-ester by pancreatic lipase.     

Comparative metabolism of 3,5-di-tert-butyl-4-hydroxytoluene (BHT) in mice and rats

In male and female DDY/Slc mice given single oral doses (20 or 500 mg/kg body weight) of 3,5-di-tert-butyl-4-hydroxytoluene (BHT) labelled with ¹⁴C at the p-ethyl group, ¹⁴C was distributed mainly in the stomach, intestines, liver and kidney, and then excreted in the urine, faeces and expired air. During the 7 days after treatment, 41–65, 26–50 and 6–9% of the ¹⁴C dose was excreted in faeces, urine and expired air, respectively, and the total recovery was 96–98%. Levels of ¹⁴C in 21 male and 22 female tissues 7 days after treatment were less than 1 μg BHT equivalents/g tissue (ppm) in mice given 20 mg/kg and less than 11 ppm in mice given 500 mg/kg. When [¹⁴C]BHT was given orally to male mice at 20 mg/kg/day for 10 days, ¹⁴C was rapidly excreted and did not exhibit any tendency to accumulate in any tissues.Thin-layer chromatography and high-performance liquid chromatography analyses showed that more than 43 metabolites were present in the urine and faeces of both species, and all of these were identified to determine metabolic pathways for BHT in mice and rats. Major metabolic reactions of [¹⁴C]BHT in mice were the oxidation of the p-methyl group attached to the benzene ring and of the tert-butyl groups. The products from the latter reaction were cyclized to some extent by reacting with the adjacent phenolic OH group to give hemiacetals or lactones. The carboxyl derivatives from the p-methyl oxidation were conjugated with glucuronic acid.When single oral doses of 20 or 500 mg [¹⁴C]BHT/kg were given to male Sprague-Dawley rats, metabolites similar to those in mice were found. However, the major biotransformation was oxidation of the p-methyl group, and oxidation of the tert-butyl groups was a minor reaction in rats.     

The fate of ( 14 C)disodium cromoglycate in man

The fate of [¹⁴C]disodium cromoglycate (DSCG) has been examined in 12 asthmatic patients. Maximum plasma concentrations (mean 9.2 ng/ml) were obtained within 15 min of inhaling DSCG (20 mg) and the average plasma half-life was 81 min. Although absorption from the lung is rapid, most of the inhaled dose is swallowed. Only 2.0% of the dose was excreted in the urine, and 84% was recovered from the faeces. DSCG is poorly absorbed from the gastrointestinal tract, only 0.4 % of an oral dose (20 mg) appeared in the 24 h urine and 83 % was recovered from the faeces. Intravenous administration of DSCG resulted in approximately equal amounts (30–50% of dose) being excreted via the urine and faeces. No metabolites of DSCG were detected chromatographically.     

Metabolism of the dyestuff intermediate 2,4-diaminoanisole in the rat.

1. 2,4-Diamino[ring-U-14C]anisole.2HCl administered intraperitoneally to rats is excreted chiefly via the urine (79 and 85% of the dose in 24 and 48 h, respectively). The isotope in the faeces was 2.1 and 8.9% of the dose at 24 and 48 h. 2. The major metabolic pathway was acetylation of the amine groups(s), resulting in 4-acetylamino-2-aminoanisole and 2,4-diacetylaminoanisole. 3. Oxidate pathways yielded 2,4-diacetylaminophenol (O-demethylation), 5-hydroxy-2,4-diacetylaminoanisole (ring hydroxylation), and 2-methoxy-5-(glycol-amido)acetanilide or its isomer (omega-oxidation). 4. These major metabolites were excreted in the urine both as free and glucuronic acid conjugates.     

Mass balance and metabolism of Z-215, a novel proton pump inhibitor,in healthy volunteers

The human mass balance of [^14?C]Z-215, a novel proton pump inhibitor, was characterised in six healthy male volunteers following single oral administration of [^14?C]Z-215 (20?mg, 3.7 MBq) to determine the elimination pathway of Z-215 and the distribution of its metabolites in plasma, urine, and faeces (NCT02618629). [^14?C]Z-215 was rapidly absorbed, with a C_max of 434?ng/mL at 0.38?h for Z-215 and 732?ng eq./mL at 0.5?h for total radioactivity. Means of 59.61% and 31.36% of the administered radioactive dose were excreted in urine and faeces, respectively, within 168?h post-dose. The majority of the dose was recovered within 24?h in urine and 96?h in faeces. Unchanged Z-215 was excreted in urine at trace levels but was not detected in faeces. The main components in plasma were Z-215 and Z-215 sulphone, accounting for 29.8% and 13.3% of the total circulating radioactivity, respectively. Additionally, Z-215 was metabolised through oxidation, reduction and conjugation. Our in vitro Z-215 metabolism study showed that the major isozyme contributing to the oxidation of Z-215, including the formation of Z-215 sulphone, was CYP3A4. In conclusion, Z-215 is well absorbed in humans and primarily eliminated via metabolism, where CYP3A4 plays an important role.     

The Fate of [14C]Saccharin in Man,Rat and Rabbit and of 2-Sulphamoyl[14C]benzoic Acid in the Rat

1. [¹⁴C]Saccharin administered orally was excreted entirely unchanged by rats on a normal diet and by rats on a 1% and 5% saccharin diet for up to 12 months. Some 90% dose was excreted in 24?h, about 70–80% in urine and 10–20% in faeces. No metabolite was detected in the excreta by chromatography or reverse isotope dilution. No ¹⁴CO₂ was found in the expired air and no ¹⁴CO₃^2- or 2-sulphamoylbenzoic acid in the urine.

2. When [¹⁴C]saccharin was injected into bile-duct cannulated rats kept on a normal diet or on a 1% saccharin diet for 19 and 23 months, 0.1–0.3% dose appeared in the bile in 3?h and no more at 24?h after dosing. Most of the saccharin was excreted in the urine, 0.6% appearing in the faeces.

3. [¹⁴C]Saccharin given orally to rabbits kept on untreated water and on water containing 1% saccharin for 6 months was excreted unchanged, 60–80% in 24?h, with 70% in urine and 3–11% in faeces.

4. [3-¹⁴C]Saccharin taken orally was excreted unchanged mainly in urine (85–92% in 24?h) by 3 adult humans both before and after taking 1 g of saccharin daily for 21 days. No metabolite of saccharin was found.

5. When [¹⁴C]saccharin was administered orally to pregnant rats on the 21st day of gestation only at most 0.6% of dose entered the foetuses. The ¹⁴C cleared more slowly from the urinary bladder than from other maternal or foetal tissues.

6. Saccharin was not metabolized in vitro by liver microsomal preparations or faecal homogenates from rats kept on a normal diet or on a 1% saccharin diet for two years.

7. 2-Sulphamoyl[¹⁴C]benzoic acid given orally to rats was excreted unchanged more slowly than saccharin. It was not cyclized to saccharin in vivo.     

Intestinal absorption, intestinal distribution, and excretion of (14C) labelled hyoscine N-butylbromide (butylscopolamine) in the rat

Butylscopolamine was labelled with ¹⁴C and its gastrointestinal absorption, biliary and urinary excretion, enterohepatic circulation and gastrointestinal distribution were examined in anaesthetized rats. Biliary excretion was the main elimination route of intra-portally administered [¹⁴C]butylscopolamine, with 42% of the dose recovered in the bile during 12 h. About 6% of the radioactivity administered orally as [¹⁴C]butylscopolamine was excreted in the bile and 1.2 % in the urine during 24 h, which indicates poor gastrointestinal absorption of butylscopolamine in the rat. When collected radioactive bile was readministered intrajejunally, only about 7% of the radioactivity was recovered in bile and urine during 12 h, which suggests that only a small fraction of butylscopolamine and its metabolites engage in an enterohepatic circulation. After oral administration of [¹⁴C]butylscopolamine, radioactivity was found to accumulate in the wall of the distal small intestine, and about 20% of the dose was found in this tissue 24 h after drug administration. As a result, local anti-acetylcholine effects of butylscopolamine might be expected.     

N-[C14]甲酰溶肉瘤素在肿瘤病人的吸收和排泄

精原细胞瘤病人口服N[C¹⁴]-甲酰溶肉瘤素15毫克(约30微居里)后72小时内,C¹⁴自尿及大便的总排出量为剂量的68.0-77.4%;其中由尿及大便所排出的放射性各约半量.尿中的放射性绝大部分为给药后前5小时内排出的,大便中的放射性则主要在给药后48小时(两次大便,便秘患者除外)内排出.在服药后24小时内,血液(全血、血浆及血球)、唾液及呼出的二氧化碳仅有痕迹量放射性存在.口服N-甲C¹⁴的同时,口服大量非标记的N-甲,并未显著地影响C¹⁴的排泄.     

Percutaneous absorption of 2-amino-4-nitrophenol in the rat

The absorption of ¹⁴C-labelled 2-amino-4-nitrophenol (ANP) in two hair dyeing formulations was investigated after application to the skin of rats. After 1 and 5 days, 0.21 and 0.36%, respectively, of the administered radioactivity was absorbed from formulation 1 which contained carboxymethylcellulose as a thickening agent. Absorption was greater (1.12% after 1 day, 1.67% after 5 days) from formulation 2 which contained oleic acid and isopropanol. Complementary studies of absorption after administration of [¹⁴C]ANP by sc injection or oral gavage were also carried out. The radioactivity was rapidly excreted, predominantly in the urine, in both cases. Biliary excretion was also detected in an oral study.     

Comparison of celecoxib metabolism and excretion in mouse,rabbit, dog,cynomolgus monkey and rhesus monkey

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit,the EM(extensive) and PM(poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [¹⁴C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [¹⁴C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.