The biodistribution and metabolic fate of inhaled 11C-octanal in the rat after acute exposure

Rats were nose exposed to an atmosphere containing 11.4 ppm of 11C-octanal for 2 min. Inhaled octanal was absorbed from the lungs in a biphasic manner and the greatest concentration of octanal occurred in most tissues at 5 min. Tissue activities calculated on the basis of the administered dose and on the radiolabel retained until the animal was killed indicated a redistribution of the radiolabel as metabolic products after 20 min. The labeled carbon was eliminated in a biphasic manner as 11CO2, which accounted for essentially all of the activity lost by the exposed rats.     

The metabolic fate of [14C] benzoic acid in protein-energy deficient rats

The metabolic fate of [14C] benzoic acid administered i.p. to marasmic-kwashiorkor rats has been investigated. Rats fed a normal diet with benzoic acid administered i.p. at 200 mg/kg, excreted the benzoic acid mainly as hippuric acid (99% of 24 h excretion), while marasmic-kwashiorkor rats excreted 62--85% as hippuric acid and 14--37% as the glucuronide conjugate. 2 weeks after repletion metabolism of benzoic acid by the marasmic-kwashiorkor rats on the stock diet had returned to normal; most of the benzoate was excreted as hippuric acid.     

The fate of [14C]-mesna in the rat

[14C]-Mesna (sodium 2-mercaptoethanesulphonate) has a short serum t1/2 (about 16.5 min) and is excreted in the urine. Within 24 h approx. 77% of the administered dose appeared in the urine. It is bound to serum albumin and immunoglobulins. Total serum protein binding is about 9.7% of the total amount present in serum. [14C]-mesna + [14C]-dimesna (bis[2-mercaptoethane sulphonate]) are present in the blood stream, and so are found in the body organs at low concentration, however, localisation of radioactivity occurs in the kidneys. The binding of [14C]-mesna to proteins and the localisation of [14C]-mesna or [14C]-dimesna in the kidneys are discussed in the context of the cell killing efficacy of the oxazaphosphorines.     

Synthesis and biodistribution of [11C]SN‐38

SN‐38 (7‐ethyl‐10‐hydroxy camptothecin) is a topoisomerase I inhibitor that is the active chemotherapeutic agent of irinotecan, indicated for colon cancer. Because the rate of response to irinotecan treatment is low, it is of interest to have a prognostic indicator to identify and more selectively treat those who are likely to respond to treatment. We have therefore prepared SN‐38 labeled with carbon‐11. SN‐38 was prepared by radical oxidation of 3‐[¹¹C]propionaldehyde and subsequent radical addition of the ethyl fragment to 10‐hydroxycamptothecin. Labeled propionaldehyde was prepared by reaction of methyl iodide with 2‐lithiomethyl‐1,3‐dioxolane. Overall chemical yield was 34% from carbon dioxide. The murine biodistribution and radiation dosimetry of [¹¹C]SN‐38 was measured by PET scanning in preparation for initial human studies. Biodistribution was fairly uniform except for hepatobiliary and urinary excretion. Copyright © 2010 John Wiley & Sons, Ltd.     

Metabolic fate of [1-14C]isobutyric acid in the rat.

Isobutyric acid (IBA) has potential use as a fungistat for the storage of moist grain. Since a complete accounting of the fate of IBA has not been reported, the metabolic fate of [1-¹⁴C]IBA was investigated. [1-¹⁴C]IBA was administered by gavage to male Charles River CD rats at doses of 4, 40, and 400 mg/kg body weight and to female rats at 400 mg/kg. All rats showed a similar excretion pattern. [1-¹⁴C]IBA was eliminated rapidly in the breath as expired ¹⁴CO₂. At 4 hr, 75.4, 83.3, and 66.7% of the dose was eliminated in the breath by male rats dosed with 4, 40, or 400 mg/kg, respectively. At 48 hr, 85–90% of the dose was eliminated in the breath. Urinary radioactivity averaged 3.5% of the dose, with about $\text{2}\text{3}$ of the radioactivity present as urea. Fecal radioactivity was less than 1% of the dose. The excretion of radioactivity by female rats was similar to that of male rats dosed with [1-¹⁴C]IBA. Isobutyric acid disappeared rapidly from the plasma of rats dosed by gavage with 400 mg/kg. These studies show that IBA is rapidly metabolized to CO₂ and its use as a feed fungistat is unlikely to contribute to the endogenous levels of IBA in the flesh, eggs, or milk or grain-consuming animals.     

The metabolic fate of 11-bromo[15-3H]vincamine in man

During 5 days following a single oral dose of 3H-11-bromovincamine (40 mg) to two human subjects, means of 55% and 27% of the 3H dose were excreted in the urine and faeces respectively, mainly within 24 and 48 h. Mean plasma concentrations of 3H reached a peak (1900 ng equiv./ml) at 1 h after dosing and declined biphasically with half-lives of 5 h and 11 h which were similar to half-lives for urinary excretion of 3H. Parent drug and 11-bromovincaminic acid were the major dose-related components in plasma at 1.5 and 3 h. Mean plasma concentrations of 11-bromovincamine reached a peak (620 ng/ml) at 0.75 h and declined biphasically with half-lives of about 1 h and 5 h. The major urinary metabolite was 11-bromovincaminic acid (31% dose). Also present in urine were 11-bromovincamine (3%), 11-bromoapovincamine (1%) and 2 unknown metabolites (9% and 6%). Similar metabolites were detected in faecal extracts. If inadequately stored in biological samples, 11-bromovincamine could be hydrolysed to 11-bromovincaminic acid and be epimerised to 11-bromo-epivincamine.     

The fate of lysergic acid DI[14C]ethylamide ([14C]LSD) in the rat, guinea pig and rhesus monkey and of [14C]iso-LSD in rat.

The qualitative and quantitative aspects of the metabolism and elimination of [¹⁴C]LSD in the rat, guinea pig and rhesus monkey have been investigated. Rats given an i.p. dose (1 mg/kg) excreted 73% of the ¹⁴C in the faeces, 16% in the urine and 3.4% in the expired air as ¹⁴CO₂ in 96 hr. Guinea pigs similarly dosed, excreted 40% in the faeces, 28% (urine) and 18% (expired ¹⁴CO₂) in 96 hr. Rhesus monkeys (0.15 mg/kg i.m.) eliminated 39% of the ¹⁴C in the urine and 23% in the faeces in 96 hr.Extensive biliary excretion of [¹⁴C]LSD occurred in both the rat and guinea pig. Bile duct-cannulated rats excreted 68% of an i.v. dose (1.33 mg/kg) in the bile in 5 hr and the guinea pig 52% in 6 hr.[¹⁴C]LSD is almost completely metabolised by all three species and little unchanged drug is excreted. The metabolites identified were 13- and 14-hydroxy-LSD and their glucuronic acid conjugates. 2-oxo-LSD. de-ethyl LSD and a naphthostyril derivative. There occur, however, important species differences in the nature and amounts of the various metabolites. In the rat and guinea pig the major metabolites were the glucuronic acid conjugates of 13- and 14-hydroxy-LSD which were found in both urine and bile. The guinea pig excreted significant amounts of 2-oxo-LSD in urine and bile. De-ethyl LSD was a minor urinary metabolite in both species.The metabolism of LSD appeared to be more complicated in the rhesus monkey. The urine contained at least nine metabolites of which four were identified as follows: 13- and 14-hydroxy-LSD (as glucuronic acid conjugates) de-ethyl LSD and a naphthostyril derivative. Unlike the rat and guinea pig the glucuronic acid conjugates of 13- and 14-hydroxy-LSD were only present in small amounts. Of the remaining five unidentified metabolites, three were major.The biliary metabolites of [¹⁴C]iso-LSD in the rat have been studied and been shown to be similar to those produced from [¹⁴C]LSD, namely 13- and 14-hydroxy-iso-LSD and their glucuronic acid conjugates and 2-oxo-iso-LSD.     

The pharmacokinetics of [14C]vinylidene chloride in rats following inhalation exposure

Studies on the pharmacokinetics of [¹⁴C]vinylidene chloride (VDC)in rats were undertaken to characterize the disposition of the inhaled chemical and to aid in assessing the hazard associated with VDC exposure. Male rats normally fed or previously fasted for 18 hr were exposed to 10 or 200 ppm of [¹⁴C]VDC vapor for 6 hr, and the elimination of ¹⁴C activity was followed for 72 hr after exposure. Following the exposure to 10 ppm of [¹⁴C]VDC, approximately 98% of the acquired body burden of [¹⁴C]VDC was metabolized to nonvolatile metabolites of VDC. Fasting had no effect on the metabolism of [¹⁴C]VDC at this exposure concentration. However, after exposure to 200 ppm of VDC only 92 to 96% of the body burden was metabolized with fasted rats showing a reduced capacity to metabolize VDC at this exposure concentration. Fasted rats exposed to 200 ppm of [¹⁴C]VDC sustained liver and kidney damage, which was not observed in fed rats at this exposure level or in any rats at 10 ppm. Centrilobular hepatic necrosis in fasted rats exposed to 200 ppm of [¹⁴C]VDC was associated with an increase in covalently bound ¹⁴C activity in the liver over that of fed rats. Two major urinary metabolites of VDC were identified as N-acetyl-S-(2-hydroxyethyl)cysteine and thiodiglycolic acid, indicating that a major pathway for detoxification of VDC is via conjugation with liver glutathione (GSH).     

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 metabolic fate of [3H]econazole in man

1. Following single oral doses of [³H]econazole base (500?mg) to two human subjects, excretion of radioactivity was prolonged, and incomplete after five days (means of 40% and 27% dose in urine and faeces respectively).

2. Plasma concn. of unchanged econazole and total radioactivity attained peak values at approx. the same time for each subject (1±5-3?h), but the former declined much faster than the latter. Most of the ³H in early plasma samples was present as unchanged drug and extractable metabolites, but after 24h concn. of econazole were close to the limit of detection (0±4μg/ml) and very little plasma ³H was extractable, whereas total³H concn. were still measurable after five days (mean 1±54μg/ml). Thus, plasma contained metabolites with much longer half-lives than econazole.

3. The main route of biotransformation of econazole in man involved multiple oxidation of the imidazole ring carbons followed by O-dealkylation and conjugation of the resulting alcohols, probably with glucuronic acid.     

Disposition of [14C]methyl bromide in rats after inhalation

Methyl bromide is used as a disinfectant to fumigate soil and a wide range of stored food commodities in warehouses and mills. Human exposure occurs during the manufacture and use of the chemical. The purpose of this investigation was to determine the disposition and metabolism of [14C]methyl bromide in rats after inhalation. Male Fischer-344 rats were exposed nose only to a vapor concentration of 337 nmol [14C]methyl bromide/liter air (9.0 ppm, 25 degrees C, 620 torr) for 6 hr. Urine, feces, expired air, and tissues were collected for up to 65 hr after exposure. Elimination of 14C as 14CO2 was the major route of excretion with about 47% (3900 nmol/rat) of the total [14C]methyl bromide absorbed excreted by this route. CO2 excretion exhibited a biphasic elimination pattern with 85% of the 14CO2 being excreted with a half-time of 3.9 +/- 0.1 hr (means +/- SE) and 15% excreted with a half-time of 11.4 +/- 0.2 hr. Half-times for elimination of 14C in urine and feces were 9.6 +/- 0.1 and 16.1 +/- 0.1 hr, respectively. By 65 hr after exposure, about 75% of the initial radioactivity had been excreted with 25% remaining in the body. Radioactivity was widely distributed in tissues immediately following exposure with lung (250 nmol equivalents/g), adrenal (240 nmol equivalents/g), kidney (180 nmol equivalents/g), liver (130 nmol equivalents/g), and nasal turbinates (110 nmol equivalents/g) containing the highest concentrations of 14C. Radioactivity in livers immediately after exposure accounted for about 17% of the absorbed methyl bromide. Radioactivity in all other tissues examined accounted for about 10% of the absorbed methyl bromide. Elimination half-times of 14C from tissues were on the order of 1.5 to 8 hr. In all tissues examined, over 90% of the 14C in the tissues was methyl bromide metabolites. The data from this study indicate that after inhalation methyl bromide is rapidly metabolized in tissues and readily excreted.     

14C]normacromerine fate in the rat

The biological fate of [14C] normacromerine , a dimethoxylated phenethylamine derivative with putative hallucinogenic properties, was evaluated in male Sprague-Dawley rats at 100 mg/kg po. Urine was the primary elimination route accounting for 50% of administered carbon-14 after 24 h. Of this urine radioactivity, normacromerine comprised 30% at 8 h decreasing to nondetectable levels at 24h. Carbon-14 in feces represented less than 10% of the administered dose at 24 h, and 14CO2 expiration was not detected. Studies of normacromerine fate in comparison with previously studied phenethylamines may enhance evaluation of hallucinogenic potential of normacromerine .     

Exploration of the labeling of [11C]tubastatin A at the hydroxamic acid site with [11C]carbon monoxide

We aimed to label tubastatin A (1) with carbon‐11 (t_1/2 = 20.4 min) in the hydroxamic acid site to provide a potential radiotracer for imaging histone deacetylase 6 in vivo with positron emission tomography. Initial attempts at a one‐pot Pd‐mediated insertion of [¹¹C]carbon monoxide between the aryl iodide (2) and hydroxylamine gave low radiochemical yields (<5%) of [¹¹C]1. Labeling was achieved in useful radiochemical yields (16.1 ± 5.6%, n = 4) through a two‐step process based on Pd‐mediated insertion of [¹¹C]carbon monoxide between the aryl iodide (2) and p‐nitrophenol to give the [¹¹C]p‐nitrophenyl ester ([¹¹C]5), followed by ultrasound‐assisted hydroxyaminolysis of the activated ester with excess hydroxylamine in a DMSO/THF mixture in the presence of a strong phosphazene base P₁‐t‐Bu. However, success in labeling the hydroxamic acid group of [¹¹C]tubastatin A was not transferable to the labeling of three other model hydroxamic acids.     

The fate of [14C] thalidomide in the pregnant hamster

The embryotoxicity and fate of [¹⁴C]thalidomide in the pregnant European golden hamster have been investigated. Daily administration of thalidomide (1 or 2 g/kg orally) to pregnant hamsters on days 4–12 inclusive of pregnancy was not embryotoxic. [¹⁴C]Thalidomide (150 mg/kg) administered on the 204th hr of pregnancy is well absorbed and about 84% of the ¹⁴C is excreted in the urine and 9% in the faeces in the 3 days after dosing. The urinary ¹⁴C consists of thalidomide (3% of dose), α-(o-carboxybenzamido)glutarimide (26%), 2- and 4-phthalimidoglutaramic acids (8%), 2-phthalimidoglutaric acid (0.2%) and 2- and 4-(o-carboxybenzamido)-glutaramic acids plus 2-(o-carboxybenzamido)glutaric acid (27%). ¹⁴C is present in the embryo and the relative concentrations of radioactivity in the embryo and plasma are about the same at 4, 12 and 24 hr after dosing. At 4 hr after dosing the embryo contains mainly thalidomide, but at 12 hr this has largely disappeared and the ¹⁴C consists of seven hydrolysis products. The lack of embryotoxicity of thalidomide in the hamster is thus not due to an inability of the teratogen to penetrate to the conceptus.     

UPLC-MS,HPLC-radiometric,and NMR-spectroscopic studies on the metabolic fate of 3-fluoro-[U-14C]-aniline in the bile-cannulated rat

1. A study of the rates and routes of excretion of 3-fluoro-[U-¹⁴C]aniline following intraperitoneal administration to male bile-cannulated rats by liquid scintillation counting (LSC) gave a total recovery of ～ 90% in the 48?h following dosing, with the majority of the dose being excreted in the urine during the first 24?h (～ 49%).

2. The total recovery as determined by ¹⁹F-nuclear magnetic resonance (¹⁹F-NMR) was ～ 49%, with the majority of the dose excreted in the first 24?h (～ 41%). The comparatively low recovery in comparison to that obtained from LSC was due to matrix effects in bile and a contribution from metabolic defluorination.

3. High-performance liquid chromatography with radiometric profiling of urine and bile revealed a complex pattern of metabolites with the bulk of the dose excreted as a single peak.

4. Ultra-performance liquid chromatography-orthogonal acceleration time of flight mass spectrometry profiling also showed a complex pattern of metabolites, detecting ～ 21 metabolites of 3-fluoroaniline (3-FA) with six of these detected only in urine and four solely in bile.

5. ¹⁹F-NMR revealed the presence of the parent compound and 15 metabolites in urine collected during the first 24?h after -dosing. The matrix effects of bile on ¹⁹F-NMR spectroscopy made metabolite profiling impractical for this biofluid.

6. The major metabolite of 3-FA was identified as 2-fluoro-4-acetamidophenol-sulfate.