Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat

The metabolism and disposition of tri-p-cresyl phosphate (TPCP) were studied in the rat after a single oral administration of [methyl-14C] TPCP. At a dosage of 7.8 mg/kg, most of the administered radioactivity was excreted in the urine (41%) and feces (44%) in 7 days. For 3 days, the expiratory excretion as 14CO2 amounted to 18% of the radioactivity, but was reduced to 3% by treatment of the animal with neomycin. In separate rats, the biliary excretion amounted to 28% of the dose in 24 hr. At a dose of 89.6 mg/kg, the radioactivity was excreted in urine (12%) and feces (77%) in 7 days, and the expired air (6%) in 3 days. At 24, 72, and 168 hr after oral administration, the concentration of radioactivity was relatively high in adipose tissue, liver, and kidney. The major urinary metabolites were p-hydroxybenzoic acid, di-p-cresyl phosphate (DCP), and p-cresyl p-carboxyphenyl phosphate (1coDCP). The biliary metabolites were DCP, 1coDCP, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate (1coTPCP), and p-cresyl di-p-carboxyphenyl phosphate (2coTPCP). The main fecal metabolite was TPCP, and the others were similar to those of bile. Following oral administration, TPCP was absorbed from the intestine, distributed to the fatty tissues, and moderately metabolized to a variety of products of oxidation and dearylation of TPCP, which were then excreted in the urine, feces, bile, and expired air. The intestinal microflora appeared to play an important role in degrading biliary metabolites to 14CO2 through the enterohepatic circulation in rats.     

Absorption, distribution, metabolism, and excretion of 1,2-dihydro-2,2,4-trimethylquinoline in the male F344 rat

1,2-Dihydro-2,2,4-trimethylquinoline (TMQ), an antioxidant used in the rubber industry, was readily absorbed from the gastrointestinal tract of the male Fischer 344/N rat and rapidly distributed throughout the body tissues. Absorption, distribution, metabolism, and excretion were not significantly affected by dose in the range 11.5-1150 mumol/kg. Following iv administration, the greatest amounts of TMQ-derived radioactivity were present in the high volume tissues including muscle, adipose, skin, liver, and blood. TMQ had no particular affinity for any tissue. TMQ-derived radioactivity was excreted primarily in urine (60-70%) and feces (20-30%) within 3 days after administration. Greater than 99% of the TMQ dose excreted in urine and feces was in the form of metabolites. Urine contained two major and ten minor metabolites while feces contained two major and four minor metabolites. The two major TMQ metabolites in urine were identified by NMR and mass spectroscopy as the O-sulfate conjugate of 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline and the monosulfate conjugate of 1,2-dihydro-1,6-dihydroxy-2,2,4-trimethylquinoline. In vitro studies with liver subcellular fractions suggest that most of the metabolites present in urine, feces, and bile are the products of mixed function oxidase activity and conjugates of these metabolites. Multiple exposure of rats to high TMQ doses (1150 mumol/kg) resulted in some bioaccumulation of TMQ-derived radioactivity in all tissues examined, but these residues did not persist when dosing was discontinued.     

Metabolism and disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin in guinea pigs

Marked interspecies variability exists in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with the guinea pig being the mammalian species most sensitive to the acute toxicity of TCDD. The metabolism and disposition of TCDD was investigated in guinea pigs for 45 days following a single exposure to purified [3H]TCDD (0.56 microgram/kg, ip). Guinea pigs included in the toxicokinetic study gained body weight, maintained a normal relative body composition, and exhibited no gross signs of toxicity during the 45-day study. Approximately 36% of the dose of TCDD-derived 3H remained in the adipose tissue at 45 days following exposure to [3H]TCDD, while the liver, pelt, and skeletal muscle and carcass each contained about 7% of the administered dose. Although most of the TCDD-derived radioactivity in liver, kidney, perirenal adipose tissue, and skeletal muscle represented unchanged TCDD, from 4 to 28% of the 3H was associated with metabolites of TCDD. This unexpected finding suggests that TCDD metabolites are not efficiently excreted from guinea pigs. The urinary and fecal excretion of TCDD-derived radioactivity followed apparent first-order kinetics, with an elimination half-life of 93.7 +/- 15.5 days (mean +/- SD). HPLC analysis of urine and bile from [3H]TCDD-treated guinea pigs showed that all of the radioactivity represented metabolites of TCDD, indicating that these routes of elimination are dependent on prior metabolism of TCDD. However, 70 to 90% of the radioactivity in fecal samples was found to represent unmetabolized TCDD throughout the 45-day excretion study. The presence of TCDD in feces and its absence in bile suggest that the fecal excretion of unchanged TCDD resulted from the direct intestinal elimination of the lipophilic toxin. Furthermore, the cumulative excretion of TCDD-derived radioactivity over 45 days indicated that 74.3% of the 3H was excreted in feces as unchanged TCDD, while 25.7% of the 3H was excreted in urine and feces as TCDD metabolites. Thus, TCDD is primarily eliminated unchanged in the feces of guinea pigs, indicating that the metabolism of TCDD does not play a major role in the ultimate elimination of the toxin from the guinea pig. This may in part explain the relatively long excretion half-life for TCDD in the guinea pig and may contribute to the remarkable sensitivity of the guinea pig to the acute toxicity of TCDD.     

Absorption,distribution, metabolism and excretion of gemigliptin,a novel dipeptidyl peptidase IV inhibitor,in rats

Abstract

1.?The absorption, distribution, metabolism and excretion of a novel dipeptidyl peptidase IV inhibitor, gemigliptin, were examined following single oral administration of ¹⁴C-labeled gemigliptin to rats.

2.?The ¹⁴C-labeled gemigliptin was rapidly absorbed after oral administration, and its bioavailability was 95.2% (by total radioactivity). Distribution to specific tissues other than the digestive organs was not observed. Within 7 days after oral administration, 43.6% of the administered dose was excreted via urine and 41.2% was excreted via feces. Biliary excretion of the radioactivity was about 17.7% for the first 24?h. After oral administration of gemigliptin to rats, the in vivo metabolism of gemigliptin was investigated with bile, urine, feces, plasma and liver samples.

3.?The major metabolic pathway was hydroxylation, and the major circulating metabolites were a dehydrated metabolite (LC15-0516) and hydroxylated metabolites (LC15-0635 and LC15-0636).     

Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans.

The metabolism and excretion of [(14)C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 muCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.     

Disposition and excretion of 2,3,7,8-tetrachlorodibenzofuran in the rat

The absorption, distribution, and excretion of the highly toxic halogenated aromatic hydrocarbon, 2,3,7,8-tetrachlorodibenzofuran (TCDF) was studied in the male Fischer rat. [¹⁴C]TCDF was completely absorbed after oral doses of 0.1 and 1.0 μmol/kg body wt. The distribution pattern was the same whether treatment was by oral or intravenous administration. The liver was the major depot of TCDF, with small amounts being redistributed to the skin and adipose tissue. TCDF was primarily excreted via the bile into the feces. Less than 6% was ever removed in the urine. More than half was excreted in the feces within 2 days. [¹⁴C]TCDF-derived radioactivity in the tissues cochromatographed with the parent compound, while in the excreta, only metabolites were detected. Thus, TCDF is readily absorbed, metabolized, and excreted in the feces. This rapid detoxification may account for the relative resistance of the rat to the acute toxicity of TCDF.     

Chlophentermine-induced abnormalcytoplasmic inclusions in peripheral blood cells of rats and guinea pigs.

The metabolic fate of [¹⁴C]gossypol was studied in the pig following a single oral dose of 6.7 mg/kg (3.7 μCi). Radioactivity was rapidly excreted from the animal body via feces. After 20 days, the total radioactivity recovered in the feces was 94.6% of the administered dose. A total of 2.1% of the radioactivity of administered dose was recovered in the expired CO₂ collected continually for 20 days. This indicates that decarbonilation of gossypol is not a major route of gossypol metabolism in the pig. Radioactivity was least excreted via urine; only 0.7% of the administered dose was recovered in the urine. One day after the administration, the tissues had 32.9% of the administered dose, which was decreased to 1.2% at 20 days. The conceptration of gossypol and its metabolites in the tissues (as indicated by radioactivity) was highest in the muscle, followed by liver, adipose tissues, and the blood. The half-life for the disappearance of radioactivity from the animal body following the administration of [¹⁴C]gossypol was 78 hr. Identification of metabolites was carried out by ultraviolet, infrared, and mass spectrometry in connection with thin-layer autoradiography. Compounds isolated from pig liver were characterized as gossypol, gossypolone, gossypolonic acid, demethylated gossic acid, and presumably apogossypol. Gossypol and metabolites may be conjugated to form glucuronides, sulfates, or hybrids.     

Distribution,metabolism, and excretion of musk xylene in rats

Distribution, metabolism and excretion of musk xylene (MX) were investigated in male Wistar rats. Urinary and fecal excretion accounted for 10 and 75% of the dose (70 mg/kg), respectively, on day 7 after orally administration of³H-MX to rats. Total residue of radioactivity in tissues on day 7 was less than 2.0% of the administered dose. The highest concentration was found in adipose tissue and the second was in liver. Some metabolites of MX were identified using GC-MS and NMR after purification by column or thin layer chromatography of feces, bile and urine extracts. MX, 2-NH₂-MX, 2-Ac-MX, 2-NH₂-3-CH₂OH-MX, and 2-NH₂-5-tert-BuOH-MX were found in feces, bile and urine. 4-NH₂-MX and metabolite X were found in feces and urine. 4-NH₂-3-CH₂OH-MX was found in urine. HO-MX was found in bile. The major route of excretion for MX was the feces via bile. The reduction of the 2-nitro group of MX to the amino group was a key step in metabolism. Further metabolism of 2-NH₂-MX may proceed by decreased steric hindrance of functional group.     

Disposition and excretion of intravenous 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) in rats

Polybrominated dibenzodioxins and dibenzofurans are of toxicologic interest due to potential occupational and environmental exposure and because of their structural similarity to the highly toxic chlorinated analogues. The excretion and terminal tissue distribution of [3H]TBDD was studied in male F344 rats for 56 days following single iv doses of .001 or 0.1 mumol/kg. The major tissue depots of radioactivity were liver, adipose tissue, and skin, and tissue distribution was dose-dependent. At 56 days, liver concentrations in the high dose group were disproportionately increased compared to those of the low dose group. Liver:adipose tissue concentration ratios were 0.2 and 2.6 at the low and high doses, respectively. Elimination of radioactivity in the feces, the major route of excretion, and urine was also nonlinear with respect to dose. By Day 56, feces accounted for approximately 50% of the administered dose at the low dose versus 70% at the high dose. Based on fecal excretion, the apparent terminal whole body half-life was estimated to be 18 days for both dose groups. The time-dependent pattern of tissue disposition was characterized at the low dose over a 56-day period. Blood levels of radioactivity declined rapidly with 2% remaining in the blood by 24 hr. Radioactivity levels in the liver peaked by 7 hr and then gradually declined concomitant with a slow accumulation in adipose tissue. The terminal excretion half-life of radioactivity in adipose tissue was estimated to be 60 days. Liver:adipose tissue concentration ratios declined with time. Thus, the overall disposition of TBDD appears similar to that observed for the chlorinated analogue, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The results of these studies are consistent with the hypothesis that TBDD, like TCDD, induces a binding species in the liver which accounts for higher liver:adipose tissue concentration ratios at the high dose. The dose-dependent tissue disposition and excretion kinetics of these compounds suggest important considerations for extrapolations from high to low doses.     

Absorption, distribution, excretion and metabolism of a single oral dose of [14C]tri-o-cresyl phosphate (TOCP) in the male rat

A single oral dose of 50 mg/kg of [14C]TOCP was administered in corn oil to male rats. Three animals were sacrificed at each of 2, 6 and 12 h and 1, 2 and 5 days following dosing, and tissues and excreta were analyzed for 14C. Within 5 days, 63 and 36% of the dose were recovered in the urine and feces, respectively. Initially, the highest concentrations of radioactivity were observed in the gastrointestinal tract, its contents, the urinary bladder, liver and kidneys. Appreciable concentrations of 14C were detected in plasma, red blood cells, lungs and adipose tissues, while neural tissues, muscle, spleen and testes contained lower concentrations of radioactivity. Among neural tissues, the sciatic nerve contained the highest concentrations of 14C at all time points studied. The concentration of TOCP in plasma was at maximum by 6 h then declined biexponentially with terminal half-life of 46 h. The predominant metabolites in plasma were o-cresyl dihydrogen phosphate, di-o-cresyl hydrogen phosphate and o-hydroxybenzoic acid (salicylic acid). Small concentrations of the neurotoxic metabolite of saligenin cyclic-o-tolyl phosphate, were detected in plasma at all but the last time point analyzed. Most of the radioactivity extracted from the livers of rats sacrificed at 2 and 4 h were metabolites. No TOCP was detected in the urine or feces collected within 3 days after dosing. The major metabolite in the urine and feces was o-cresyl dihydrogen phosphate followed by di-o-cresyl hydrogen phosphate, salicylic acid, o-hydroxybenzyl alcohol and o-cresol. This study supports the hypothesis that the insensitivity of the rat to TOCP-induced delayed neurotoxicity may be attributed, in part, to the disposition and metabolism of this chemical.     

Studies on the metabolism of the neurotoxic tri-o-cresyl phosphate. Distribution, excretion, and metabolism in male cats after a single, dermal application

The metabolism of a single, dermal dose of 50 mg/kg of [14C]tri-o-cresyl phosphate (TOCP) was studied in male cats. TOCP was applied to an unprotected, preclipped area on the back of the neck. Three animals were sacrificed on each of 0.5, 1, 2, 5, and 10 days following application. Radioactivity disappeared biexponentially from the dosing site with a faster initial rate; 73% of the dose disappeared in the first 12 h followed by a slower phase with a half-life of 2.03 days. No radioactivity was detected in the expired air. TOCP was absorbed from the skin and subsequently distributed throughout the body. Generally, the highest concentrations of radioactivity were associated with bile, gall bladder, urinary bladder, kidneys, and liver; the lowest were found in the neural tissues, muscle, and spleen. Within the 10-day experimental period, approximately 28% and 20% of the applied dose were recovered in the urine and feces, respectively. TOCP and its metabolites in the urine, feces, bile, and plasma were analyzed by high performance liquid chromatography and liquid scintillation counting. TOCP was the predominant compound in the feces (26.3% of total fecal radioactivity); it was detected in a smaller percentage in the urine (2.3% of total urinary radioactivity). The major metabolite in the urine was o-cresol followed by di-o-cresyl hydrogen phosphate and o-cresyl dihydrogen phosphate; in the feces di-o-cresyl hydrogen phosphate was the predominant metabolite followed by o-cresyl dihydrogen phosphate. Trace amounts of saligenin cyclic-o-tolyl phosphate, hydroxymethyl, and di(hydroxymethyl) TOCP were also detected in the urine and feces. Other metabolites identified in the urine and feces were the stepwise oxidation products of the methyl group of o-cresol. Unlike the feces, the bile contained mostly metabolites with only trace amounts of TOCP detected at 12 h and 24 h following application. o-Cresyl dihydrogen phosphate and di-o-cresyl hydrogen phosphate were the prevalent metabolites in the bile and plasma. While di(hydroxymethyl) TOCP was present in trace amounts in plasma, an appreciable amount of saligenin cyclic-o-tolyl phosphate, believed to be the active neurotoxic metabolite, was detected. This study shows that skin is an important port of entry for TOCP. Since TOCP represents organophosphorous chemicals capable of producing delayed neurotoxicity in test animals and in humans, it is essential that industrial hygiene control prevents skin contamination of workers handling these chemicals.     

Metabolism and disposition of the flame retardant tris(2,3-dibromopropyl)phosphate in the rat

The metabolism and disposition of the flame retardant, tris(2,3-dibromopropyl)phosphate (Tris-BP), were studied after po and iv administration of the 14C-labeled compound to the male rat. Tris-BP was readily absorbed from the gastrointestinal tract and rapidly distributed throughout the body. The distribution and excretion of Tris-BP derived radioactivity were similar after either po or iv administration. The only effects of route of administration on tissue distribution were slightly higher concentrations in liver after po administration and in lung after iv administration. The initial elimination of Tris-BP derived radioactivity in urine, feces, and as CO2 accounted for approximately 50% of the dose in 24 hr. An analysis of Tris-BP derived radioactivity remaining in the tissues one day after administration indicated that most of the radioactivity in all tissues was in the form of various metabolites rather than the parent compound. The terminal clearance of Tris-BP derived radioactivity from most of the tissues studied was best described by a single component exponential decay with a half-life of approximately 2.5 days. Clearance from liver and kidney was somewhat slower having a half-life of approximately 3.8 days. Approximately 33% of the radioactivity excreted in urine and approximately 50% of the radioactivity excreted in bile were identified by cochromatography with synthesized standards on high performance liquid chromatography (HPLC). Six metabolites and a trace of the parent compound were identified in urine and bile by this method. The six metabolites products of dealkylation and dehydrobromination of the parent compound. The metabolites of Tris-BP isolated from urine and bile were also formed in vitro by NADPH-dependent microsomal enzymes from rat liver. The soluble enzymes from liver metabolized Tris-BP to at least three unidentified polar metabolites.     

Distribution, excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J, DBA/2J, and B6D2F1/J mice

The strains of mice, C57BL/6J, DBA/2J, and B6D2F1/J, have been used as models to study the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The distribution, excretion, and metabolism of this compound was studied in male C57BL/6J, DBA/2J, and B6D2F1/J mice following the intraperitoneal administration of radiolabeled TCDD at a dose of 10 micrograms/kg. In all strains, the liver and adipose tissue were the major sites for the accumulation of 3H-TCDD, with more 3H-TCDD being distributed to the livers of the C57BL/6J and B6D2F1/J strains as compared to the DBA/2J strain. While in all strains the feces were the major route of elimination, the total amount of 3H-TCDD-derived radioactivity excreted in the feces amounted to approximately 72% of the original dose in the C57BL/6J and B6D2F1/J strains whereas this was only 54% in the DBA/2J strain. The half-lives for the cumulative excretion of radioactivity in the feces were similar in all strains. The half-life for the excretion of radioactivity in the urine was considerably greater in the DBA/2J strain as compared to the C57BL/6J and B6D2F1/J strains. The estimated half-lives for the total cumulative excretion of 3H-TCDD-derived radioactivity by all routes was 11.0, 24.4, and 12.6 days for the C57BL/6J, DBA/2J, and B6D2F1/J strains, respectively. Greater than 85% of the total radioactivity excreted in urine, bile, and feces from all three mouse strains was present as metabolites of TCDD.     

Excretion of [3H]triptolide and its metabolites in rats after oral administration

Aim： To investigate the routes of elimination and excretion for triptolide recovered in rats.
Methods： After a single oral administration of [3H]triptolide （0.8 mg/kg, 100 μCi/kg） in Sprague Dawley rats, urine and fecal samples were collected for 168 h. To study biliary excretion, bile samples were collected for 24 h through bile duct cannulation. Radioactivity was measured using a liquid scintillation analyzer, and excretion pathway analysis was performed using an HPLC/on-line radioactivity detector.

Results： The total radioactivity recovered from the urine and feces of rats without bile duct ligation ranged from 86.6%–89.1%. Most of the radioactivity （68.6%–72.0%） was recovered in the feces within 72 h after oral administration, while the radioactivity recovered in the urine and bile was 17.1%–18.0% and 39.0%–39.4%, respectively. The HPLC/on-line radiochromatographic analysis revealed that most of the drug-related radioactivity was in the form of metabolites. In addition, significant gender differences in the quantity of these metabolites were found： monohydroxytriptolide sulfates were the major metabolites detected in the urine, feces, and bile of female rats, while only traces of these metabolites were found in male rats.

Conclusion： Radiolabeled triptolide is mainly secreted in bile and eliminated in feces. The absorbed radioactivity is primarily eliminated in the form of metabolites, and significant gender differences are observed in the quantity of recovered metabolites, which are likely caused by the gender-specific expression of sulfotransferases.     

Absorption, metabolism, and excretion of [14C]MK-0767 (2-methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) in humans.

MK-0767 (KRP-297; 2-methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) is a thiazolidinedione (TZD)-containing dual agonist of the peroxisome proliferator-activated receptors alpha and gamma that has been studied as a potential treatment for patients with type 2 diabetes. The metabolism and excretion of [14C]MK-0767 were evaluated in six human volunteers after a 5-mg (200 microCi) oral dose. Excretion of 14C radioactivity was found to be nearly equal into the urine (approximately 50%) and feces (approximately 40%). Elimination of [14C]MK-0767 was primarily by metabolism, with minimal excretion of parent compound into the urine (<0.5% of dose) and feces (approximately 14% of the dose). [14C]MK-0767 was the major circulating compound-related entity (>96% of radioactivity) through 48 h postdose. It was also found that approximately 91% of the total radioactivity area under the curve was due to intact MK-0767. Several minor metabolites were detected in plasma (<1% of radioactivity, each), formed by cleavage of the TZD ring and subsequent S-methylation and oxidation. All the metabolites excreted into urine were formed by TZD cleavage, whereas the major metabolite in feces was the O-demethylated derivative of MK-0767.     

2,3,7,8-Tetrachlorodibenzo-p-dioxin tissue distribution, excretion, and effects on clinical chemical parameters in guinea pigs

The tissue distribution of ¹⁴C-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in adult male guines pigs was studied up to 15 days following its ip injection (2.0 μg/kg). On Day 1, the highest levels of radioactivity (% of original dose/g tissue) were located in the adipose tissue, adrenals, liver, spleen, intestine, and skin. All other tissues examined contained less than 0.3%/g tissue. By Day 15, the level of radioactivity in the liver increased to nearly three times its initial value. An increase in radioactivity was also noted in the adrenals, kidneys, and lungs. These increases appeared to be due to the mobilization of fat stores and the subsequent redistribution of radioactivity contained in these stores to other organs. Following a single intraperitoneal dose of 0.5 μg [³H]TCDD/kg the excretion of ³H in the urine and feces appeared to be linear up to 23 days. Assuming the excretion of radioactivity would continue in a linear manner, the time for excretion of half the administered dose by way of the urine and feces was calculated to be 30.2 ± 5.8 days. The effect of TCDD (1.0 μg/kg) upon various clinical chemical parameters was determined periodically up to 14 days and compared to pairfed controls. Statistically significant increases in plasma albumin, total protein, iron, urea nitrogen, cholesterol, and triglycerides were observed in TCDD-treated pigs.     

Absorption,Distribution, Metabolism,and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Orally to Rats

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [hexyl-1-¹⁴C] N-octylbicycloheptene dicarboximide (MGK 264).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered fhexyl-1-¹⁴C] MGK 264 at a single oral dose of 100 mg/kg, at a single oral dose of 1000 mg/kg, and at a daily oral dose of 100 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 100 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 100 mg/kg. Each animal was administered 18-30 μCi radioactivity.

Urine and feces were collected for all groups at predetermined time intervals. Seven days after dose administration, the rats were euthanized and selected tissues and organs were harvested. Samples of urine, feces, and tissues were subsequently analyzed for ¹⁴C content.

In the blood kinetics study, radioactivity peaked at approximately 4 h for the males and 6 h for the females. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity was approximately 8 h for males and 6 h for females.

Female rats excreted 71.45-73.05% of the radioactivity in urine and 20.87-25.28% in feces, whereas male rats excreted 49.49-63.49% of the administered radioactivity in urine and 31.76-46.67% in feces. Total tissue residues of radioactivity at 7 days ranged from 0.13 to 0.43% of the administered dose for all dosage regimens. The only tissues with ¹⁴C residues consistently higher than that of plasma were the liver, stomach, intestines, and carcass. The total mean recovered radioactivity of the administered dose in the studies ranged between 93.1 and 97.4%. No parent compound was detected in the urine.

Four major metabolites and one minor metabolite were isolated from the urine by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS). The four major metabolites were shown to be carboxylic acids produced by either ω-1 oxidation or β-oxidation of the side chain and oxidation of the norbornene ring double bond. The minor metabolite was the carboxylic acid of the intact norbornene ring.

The gender of the animals affected the rate, route of excretion, and metabolic profile. The urinary excretion rate was faster in females than in males and the amount excreted was also greater in female rats.     

Metabolism,distribution, and excretion of the flame retardant,Tris(2,3-dibromopropyl) phosphate (Tris-BP) in the rat: Identification of mutagenic and nephrotoxic metabolites

The mutagenic, nephrotoxic, and carcinogenic flame retardant Tris-BP underwent rapid and extensive metabolism in the rat. Five days after administration of [¹⁴C]Tris-BP, 86% of the radiolabel had been excreted in the form of metabolites in the urine (58%), feces (9%) and expired air (19% as ¹⁴CO₂); 9% was recovered in the body. [¹⁴C]Tris-BP and its metabolites were analyzed by high-pressure liquid chormatography and liquid scintillation counting. Tris-BP was not detected in the excreta. A metabolite present in urine, feces, bile, and tissues was identified by mass spectrometry as bis(2,3-dibromopropyl) phosphate (Bis-BP). 2,3-Dibromopropanol (DBP) was also identified in tissues and in urine. Biliary excretion and enterohepatic recirculation were major routes in the disposition of Tris-BP. All tissues contained Tris-BP-derived radioactivity; however, the concentration of radiolabel in kidney was 11 times the average body concentration 5 days after dosing. Bis-BP was mutagenic to Salmonella typhimurium (TA100) in the presence of Aroclor-induced liver homogenates. The mutagenic potency was greater than that of DBP but less than that of Tris-BP. Also, Bis-BP was an acute nephrotoxin and was more potent than Tris-BP itself. Results from these studies demonstrated that the tissues toward which Tris-BP was selectively toxic, kidney and colon, were also the tissues which were exposed to selectively high concentrations of Tris-BP-derived radioactivity. Tris-BP, which has a short in vivo half-life, was metabolized to a long-acting mutagenic and nephrotoxic metabolite, Bis-BP.     

Fate and distribution of H-labeled T-2 mycotoxin in guinea pigs

T-2 toxin is a potent cytotoxic metabolite produced by the Fusarium species. The fate and distribution of ³H-labeled T-2 toxin were examined in male guinea pigs. Radioactivity was detected in all body tissues within 30 min after an im injection of an LD50 dose (1.04 mg/kg) of T-2 toxin. The plasma concentration of trichothecene molar equivalents versus time was multiphasic, with an initial absorption half-life equal to or less than 30 min. Bile contained a large amount of radioacivity which was identified as HT-2, 4-deacetylneosolaniol, 3′-hydroxy HT-2, 3′-hydroxy T-2 triol, and several more-polar unknowns. These T-2 metabolites are excreted from liver via bile into the intestine. Within 5 days, 75% of the total radioactivity was excreted in urine and feces at a ratio of 4 to 1. The appearance of radioactivity in the excreta was biphasic. Metabolic derivatives of T-2 excreted in urine were T-2 tetraol, 4-deacetylneosolaniol, 3′-hydroxy HT-2, and several unknowns. These studies showed a rapid appearance in and subsequent loss of radioactivity from tissues and body fluids. Only 0.01% of the total administered radioactivity was still detectable in tissues at 28 days. The distribution patterns and excretion rates suggest that liver and kidney are the principal organs of detoxication and excretion of T-2 toxin and its metabolites.     

Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects.

The absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan was investigated in healthy male subjects by administration of 14C-labeled compound. Four subjects received a single oral dose of 500 mg of bosentan (3.7 MBq), and four other subjects received a single i.v. dose of 250 mg of bosentan (3.7 MBq). Radioactivity and concentrations of bosentan and its metabolites were measured in plasma, urine, and feces samples. More than 97% of drug-related material was recovered on average within 3.5 days after oral dosing and within 5 days after i.v. dosing. More than 90% of radioactivity was found in feces after both oral and i.v. dosing. Most of the radioactivity in urine and feces represented bosentan and three metabolites. Ro 48-5033, the major metabolite in plasma, urine, and feces, is the result of hydroxylation at the t-butyl group of bosentan. The two other metabolites Ro 47-8634 and Ro 64-1056 represent minor metabolite species. Ro 47-8634 is the product of O-demethylation of the phenolic methyl ester, and Ro 64-1056 is generated by both demethylation and hydroxylation. The radioactivity in plasma could almost entirely be attributed to bosentan and the two metabolites Ro 48-5033 and Ro 47-8634, whereby both metabolites exhibited much lower plasma levels than bosentan. Hepatic metabolism followed by biliary excretion of the metabolites apparently represents the major pathway of elimination for bosentan in humans.