Tissue Distribution and Toxicokinetics of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Rats after Intravenous Injection

Tissue Distribution and Toxicokinetics of 2,3,7,8-Tetrachlorodibenzo-p-dioxinin Rats after Intravenous Injection. WEBER, L. W. D., ERNST,S. W., STAHL, B. U., AND ROZMAN, K. (1993). Fundam. Appl. Toxicol.21, 523–534. Male Sprague-Dawley rats (240–290 g) received intravenouslya nonlethal (9.25 µg/kg) or a lethal (72.7 µg/kg)dose of ¹⁴C-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)administered as an emulsion. Animals were euthanized between5 min and 16 days (lethal dose) or 32 days (nonlethal dose)after treatment. Tissue distribution was considered completeafter 24 hr, as by this time radioactivity levels in white adiposetissue had reached a maximum. The highest levels of radioactivitywere found in liver (5% of dose/g tissue), followed by whitefat (1% of dose/g tissue); serum was lowest at 0.01% of dose/mlserum. Relatively high levels of radioactivity were also detectedin most known target organs of TCDD toxicity, e.g., brown fat,adrenals, and thyroid. The pattern of organ distribution ofTCDD was essentially the same after the lethal and the nonlethaldose, but did not follow a simple lipophilicity relationship,as levels in liver were higher than those in white fat, andthose in brain were extremely low. A pool of TCDD in liposomesinitially trapped in lung and spleen was redistributed within24 hr mainly to liver and adipose tissue. Affinity of TCDD tostorage fat seemed to play a more important role as a drivingforce for redistribution than did induction of cytochrome P4501A2. The terminal slope of elimination of TCDD from tissuesindicated a half-life of 16 days after the nonlethal dose. Afterthe lethal dose radioactivity declined in all tissues for 2to 8 days and then increased again, reflecting shrinking tissuevolumes as well as remobilization of TCDD caused by the processof body mass wasting. Distribution data for 17 tissues and serumwere subjected to regression analysis and resulted in up totwo uptake phases and up to three elimination phases for a giventissue. After the nonlethal dose TCDD was mainly excreted viafeces; combined urinary and fecal excretions occurred with abiological half-life of 16.3 ± 3.0 days. Much longerhalf-lives were detected in white fat and skin. After the lethaldose, the fecal excretion of TCDD-derived radioactivity decreasedafter 8 days, and urinary excretion increased starting 12 daysafter dosing. Radioactivity in liver and white fat and the extractableportion in feces was mainly unchanged TCDD, as determined bythin-layer chromatography. Radioactivity in urine indicatedthe presence of a metabolite(s) of TCDD only.     

Absorption, metabolism and excretion of 14C-sultopride in the rat

Rats received (14C)-Sultopride (St) in doses of 20 mg/kg by ip. and oral route. After ip.-administration, urinary elimination was 62% of administered dose in 72 hours, fecal excretion, 25% in 96 hours. Conversely, at 120 hours after oral administration, renal elimination was 46% and fecal elimination 34%. From these data 75% absorption of St in rat intestine may be deduced. From total excreted radioactivity (feces plus urine; ip. route) 35% is due to unchanged St. Seven metabolites were isolated from the urine. By comparison of isolated compounds with chemically synthesized putative metabolites using spectrophotometric and radiometric TLC scanning procedures 5 metabolites were identified: O-desmethylated St (DMSt; 20% of total radioactivity excreted), sulfon-desethylated St (SDESt; 13%), 5-pyrrolidine-oxo St (OSt; 3%), the product of hydrolysis of the central amide bond (MESS; 4%) and the secondary metabolite O-desmethyl-oxo St (ODMST; less than 1%). Two metabolites both minor (1% or less), remained unidentified. In guinea-pigs, metabolism of St leads almost exclusively to OSt while in mice, to DMSt.     

Mass balance study of [1?C]eribulin in patients with advanced solid tumors

This mass balance study investigated the metabolism and excretion of eribulin, a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, in patients with advanced solid tumors. A single approximately 2 mg (approximately 80 μCi) dose of [1?C]eribulin acetate was administered as a 2 to 5 min bolus injection to six patients on day 1. Blood, urine, and fecal samples were collected at specified time points on days 1 to 8 or until sample radioactivity was ≤1% of the administered dose. Mean plasma eribulin exposure (627 ng · h/ml) was comparable with that of total radioactivity (568 ng Eq · h/ml). Time-matched concentration ratios of eribulin to total radioactivity approached unity in blood and plasma, indicating that unchanged parent compound constituted almost all of the eribulin-derived radioactivity. Only minor metabolites were detected in plasma samples up to 60 min postdose, pooled across patients, each metabolite representing ≤0.6% of eribulin. Elimination half-lives for eribulin (45.6 h) and total radioactivity (42.3 h) were comparable. Eribulin-derived radioactivity excreted in feces was 81.5%, and that of unchanged eribulin was 61.9%. Renal clearance (0.301 l/h) was a minor component of total eribulin clearance (3.93 l/h). Eribulin-derived radioactivity excreted in urine (8.9%) was comparable with that of unchanged eribulin (8.1%), indicating minimal excretion of metabolite(s) in urine. Total recovery of the radioactive dose was 90.4% in urine and feces. Overall, no major metabolites of eribulin were detected in plasma. Eribulin is eliminated primarily unchanged in feces, whereas urine constitutes a minor route of elimination.     

Metabolism and excretion of 3H-digitoxin in the rat

After oral administration of 25 μg/kg ³H-labelled digitoxin (sp. act. 26.2 mCi/mg) to female rats, the total radioactivity in blood and in urine was eliminated with a half-life time of 2 and 1.7 days, respectively. The fecal elimination half-life time had a. biphasic course. The chloroform-soluble and chloroform-insoluble metabolites excreted in urine and feces were determined in order to explain the much shorter half-life time of 0.4 days in feces during the early phase of elimination. In the feces, 45 per cent of the dose excreted within 5 days consisted of chloroform-soluble substances. In this fraction, the main excretion product was digoxigenin-bis-digitoxoside (20 per cent), whereas the percentages of the other glycosides, after the last collection period, amounted to significantly less: 9% digitoxin, 9% digoxin. 5% digitoxigenin-bis-digitoxoside, and 2% digitoxigenin-mono-digitoxoside. The Chromatographic analysis of the chloroform-insoluble fraction, which accounted for 15 per cent of the dose. revealed a conjugation of glucuronic and sulfuric acid with digoxin, and digoxin, 5% digitoxigenin-bis-digitoxosidc. and 2% digitoxigenin-mono-digitoxoside. The contrast, sulfuric acid alone was the main conjugation partner of 3-epi-digitoxigenin. In urine, 4.6 per cent of the administered radioactivity was represented by digoxin, 2 per cent by digitoxin, 1 per cent by digoxigenin-bis-digitoxoside, and 1.4 per cent by polar metabolites. Only traces of digitoxigenin-bis-digitoxoside cind digoxigenin-mono-digitoxoside were detected. The much shorter half-life time of the eliminated radioactivity in feces seems to be due to the higher portion of poorly reabsorbed conjugation products and digoxigeninbis-digitoxoside.     

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.     

In vivo and in vitro metabolism of 2-methylnaphthalene in the guinea pig

The metabolism of 2-methylnaphthalene (2-MN) in guinea pigs (in vivo and in vitro) was investigated. Excretion of 2-MN from guinea pigs took place rapidly. In the first 24 hr, nearly 80% of the orally administered 2-[3H]-MN was excreted in the urine in the form of several metabolites, and about 10% of it was recovered in the feces. The major metabolites in the urine were oxidative products of the methyl group of 2-MN (naphthoic acid and its glycine and glucuronic acid conjugates) and accounted for 76% of the total urinary radioactivity in the first 24 hr. S-(7-Methyl-1-naphthyl)cysteine and glucuronic acid and sulfate conjugates of 7-methyl-1-naphthol were also identified as minor metabolites (18% of the total urinary radioactivity). As an in vitro metabolite, the formation of S-(7-methyl-1-naphthyl)glutathione was indicated using the 9,000g supernatant of the homogenate of guinea pig liver. The oral administration of 2-MN (500 mg/kg) to guinea pigs significantly lowered the trichloroacetic acid-soluble sulfhydryl content in the liver.     

Metabolism, plasma or serum levels, and elimination of phenformin in guinea pigs, rats, and dogs.

14C-Phenformin hydrochloride was used for investigating the metabolism, plasma or serum levels, and elimination of the drug following 1.5-mg/kg po or iv doses to guinea pigs, rats, and dogs. The amounts of individual metabolites and unchanged drug were assessed in urine as well as in plasma or serum. The glucuronide of 1-(p-hydroxyphenethyl)biguanide was a major metabolite in the blood and urine of all three species. Guinea pig serum and urine contained a sizable quantity of unchanged drug. Dog plasma and urine had significant amounts of nonconjugated 1-(p-hydroxyphenethyl)biguanide and of an unidentified major metabolite. In all three species following intravenous drug administration, unchanged drug contributed significantly to the radioactivity found in blood and urine. The apparent half-lives of phenformin eliminateion were 0.3-0.8 day for guinea pigs and rats and 1-1.5 days for dogs. Urinary excretion data indicate apparent half-lives of approximately 1.3-1.5 days for the elimination of each of the three major metabolites in dogs.     

Elimination pathways of [14C]losoxantrone in four cancer patients.

Losoxantrone is an anthrapyrazole derivative in Phase III development in the U.S. for solid tumors, notably breast cancer. To obtain information on the routes of elimination of the drug, a study was conducted in four patients with advanced solid tumors, which involved intravenous administration of 100 microCi of [14C]losoxantrone for a total dose of 50 mg/m(2) during the first course of losoxantrone therapy. Blood, urine, and feces were collected for up to 2 weeks and were analyzed for total radioactivity and parent drug. In addition, feces were profiled for the presence of metabolites. Plasma concentrations of total radioactivity exhibited a temporal pattern similar to the parent drug. Combined recovery of administered total radioactivity from urine and feces was 70% with the majority (87%) of this radioactivity excreted in the feces, presumably via biliary excretion. Feces extracts were profiled for metabolites using a high-performance liquid chromatography method developed to separate synthetic standards of previously identified human urinary metabolites. Only intact losoxantrone was found in the feces. About 9% of the dose was excreted in the urine, primarily during the first 24 h and mostly in the form of parent compound. Collectively, these data indicate that fecal excretion of unmetabolized drug via biliary and/or intestinal excretion is the primary pathway of intravenously administered losoxantrone elimination in cancer patients with refractory solid tumors.     

Tissue distribution,excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Golden Syrian hamster

The hamster has been reported to be the least sensitive mammalian species to the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The fate of a single dose of [³H]- or [¹⁴C]TCDD (650 μg/kg, ip or po) was assessed in male hamsters for up to 35 days following treatment. The greatest content (percentage dose/g tissue) of radioactivity was found in the liver, adipose tissue, and adrenals. The radioactivity in liver and adipose tissue was identified as unmetabolized TCDD. The rate of ³H or ¹⁴C elimination in urine and feces suggested a first-order process. Similar half-life of elimination ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$) values of 12.0 ± 2.0 and 10.8 ± 2.4 days (mean ± SD) were obtianed with ip administered [³H]- and [¹⁴C]TCDD, respectively. With both [³H]- and [¹⁴C]TCDD, approximately 35 and 50% of the radioactivity was eliminated in urine and feces, respectively. The $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ for po administered [³H]TCDD was 15.0 ± 2.5 days. High-pressure liquid chromatography of the urine and bile of animals receiving [¹⁴C]TCDD revealed one major and several minor radioactive peaks, none of which corresponded to [¹⁴C]TCDD. The apparent absence of TCDD metabolites in extracts of liver or adipose tissue indicates that the biotransformed products of TCDD are readily excreted in urine and bile. The enhanced rate of metabolism and excretion of TCDD in hamsters relative to other species may in part contribute to, but not totally explain its unusual resistance to TCDD toxicity.     

Fate and distribution of 3H-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 radioactivity 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.     

Species differences in the metabolism of a tricyclic psychotropic agent,SQ 11,290-C

The metabolism of SQ 11,290-¹⁴C (4-[3-(7-chloro-5,11-dihydrodibenz[b,e]-[1,4]-oxazepin-5-yl)propyl]-α,β-¹⁴C₂-1-piperazineethanol, dihydrochloride) was studied in mice, rats, guinea pigs, hamsters, New Zealand White or Dutch rabbits, monkeys and man after po administration. The excretion of SQ 11,290-¹⁴C, its metabolites, or both, was chiefly in the feces (with the exception of hamsters and man). Rats and rabbits of either strain excreted 2–5% of the dose—mice and hamsters excreted 20–42%—as ¹⁴CO₂. Hamsters appeared to excrete radioactivity in a quantitative manner most similar to that observed in man, but the metabolites found in the urine and feces of these 2 species were not similar. The disposition of SQ 11,290-¹⁴C in albino and pigmented rabbits cannot be distinguished on the basis of the excretion of radioactivity, but different metabolites appear to be excreted in the urine. No unchanged SQ 11,290-¹⁴C was detected in the excreta of humans. One percent of the dose or less was present as unchanged SQ 11,290-¹⁴C in the urine of any animal species. In the feces, an average of 2–6% of the dose was excreted by animal species as unchanged SQ 11,290-¹⁴C. Whereas albino rabbits excreted in the feces only 3.6% of the dose as unchanged drug, Dutch rabbits excreted about 16.7% of the dose as unchanged drug. In those human subjects excreting large amounts of radioactivity as ¹⁴CO₂, cleavage or degradation of the side chain, or both, rather than hydroxylation of the ring system as had been found previously in dogs, appeared to be a major metabolic pathway.     

Metabolism and disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin in ring-necked pheasant hens, chicks, and eggs.

The T 1/2 for whole-body elimination of [3H]-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) derived radioactivity in ring-necked pheasant hatchlings was 13 d, whereas in adult hen pheasants that were not producing eggs it was 378 d. All TCDD-derived radioactivity in hen tissues was from the parent compound. The oral bioavailability of TCDD in the adult hen pheasant varied with the environmental matrix, with 30% of the dose absorbed from a suspension of earthworms, 33% absorbed from a soil suspension, 41% absorbed from a suspension of paper mill sludge, and 58% absorbed from a suspension of crickets. A cumulative dose of 1.0 micrograms TCDD/kg body weight, administered as weekly doses of 0.1 micrograms/kg for 10 wk, did not adversely affect hen condition or egg production. Under these exposure conditions, hens translocated about 1% of their cumulative TCDD dose to each of the first 15 eggs laid. All of the TCDD-derived radioactivity in the eggs was the parent compound and was confined entirely to the yolk; no TCDD was detected in egg albumin. We conclude that TCDD was more persistent in pheasant hens than in chicks and that egg laying was an important route of elimination in the hen.     

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.     

Disposition of 1,2,3,7,8-pentachlorodibenzofuran in the rat

1,2,3,7,8-Pentachlorodibenzofuran (1PeCDF) is one of several toxic polychlorinated dibenzofurans (PCDFs) which are ubiquitous environmental contaminants. Related in structure and toxicity to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), PCDFs have been detected in municipal and industrial effluents, PCB mixtures, and in a variety of antiseptics and preservative solutions. The objective of this study was to evaluate the distribution and elimination of 1PeCDF in the rat and to compare these parameters with that of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF) and 2,3,7,8-tetrachlorodibenzofuran (TCDF). After iv administration of 0.1 mumol [3H]1PeCDF/kg, 1PeCDF was rapidly cleared from the blood and distributed to the liver, muscle, skin, and adipose tissue in a manner similar to that for other dibenzofurans. The initial pool sizes of 1PeCDF-derived radioactivity in the liver, muscle, skin, and adipose tissue were 43,35,10, and 7% of the administered dose, respectively. In all cases, loss of radioactivity from these tissues could be described by exponential decay and the initial half-lives for these tissues were 1.36, 0.03, 13, and 1 day, respectively. After redistribution from the muscle, skin, and adipose tissues to the liver, 1PeCDF was metabolized to a polar metabolite(s) and excreted from the body via the bile into the feces. No parent compound was detected in the bile and fecal excretion was the major route of elimination. Most of the radioactivity in the urine was excreted within the first day, after which less than 0.5% of the dose/day was detected. More than half of the administered dose was excreted in the urine and feces within 2 days. The whole-body half-life of related compounds is 4PeCDF much greater than 1PeCDF greater than or equal to TCDF. Therefore, persistence appears to be inversely related to the metabolism of these compounds and metabolism is inhibited by chlorine-substituted carbon atoms adjacent to the oxygen atom in the dibenzofuran ring.     

Metabolism of 1,2,3,4-, 1,2,3,5-, and 1,2,4,5-tetrachlorobenzene in the squirrel monkey

The metabolism of three tetrachlorobenzene isomers (TeCB) was investigated in the squirrel monkey. The animals were administered orally 6 single doses of 14C-labeled 1,2,3,4-, 1,2,4,5-, or 1,2,3,5-tetrachlorobenzene over a 3-wk period at levels ranging from 50 to 100 mg/kg body weight (b.w.) and kept in individual metabolism cages to collect urine and feces for radioassay. Approximately 38% (1,2,3,4-TeCB), 36% (1,2,3,5-TeCB), and 18% (1,2,4,5-TeCB) of the doses were excreted respectively in the feces 48 h postadministration. In monkeys dosed with 1,2,3,4-TeCB, unchanged compound accounted for 50% of the fecal radioactivity; its fecal metabolites were identified as 1,2,4,5-tetrachlorophenol (TeCP, 22%), N-acetyl-S-(2,3,4,5-tetrachlorophenyl) cysteine (18%), 2,3,4,5-tetrachlorophenyl sulfinic acid (3%), 2,3,4-trichlorophenyl methyl sulfide (0.6%), and 2,3,4,5-tetrachlorophenyl methyl sulfide (0.2%). As was the case with 1,2,3,4-TeCB, unchanged compound accounted for more than 50% of the fecal radioactivity found in the monkeys dosed with 1,2,3,5-TeCB. The fecal metabolites of 1,2,3,5-TeCB consisted of 2,3,4,5-TeCP (2%), 2,3,4,6-TeCP (14%), 2,3,5,6-TeCP (9%), and 2,3,5,6-tetrachlorophenyl sulfinic acid (15%). No metabolites were detected in the feces of monkeys dosed with 1,2,4,5-TeCB. While the fecal route represented the major route of excretion for 1,2,3,4-TeCB, the other two isomers were eliminated exclusively in the feces. The above data in the squirrel monkey are different from those obtained with the rat and the rabbit, and demonstrate the different metabolic pathways for the isomers.     

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.     

Metabolism of mephentermine in male guinea pigs and male mice.

1. Urinary metabolites of mephentermine (MP), after i.p. administration of MP to male Hartley guinea pigs and mice, were identified by g.l.c.-electron impact (EI) mass spectrometry. Excretion of urinary radioactivity, and metabolites of 3H-MP, after i.p. administration, were determined by preparative t.l.c.-liquid scintillation counting. 2. About 27% of the radioactivity administered was excreted in the 24 h urine of guinea pigs, and 36% dose was excreted in 5 days. In mice, about 47% of the radioactivity was excreted in the 24 h urine, and 52% in 5 days. 3. Excretion rates of metabolites detected in the 24 h urine of guinea pigs were phentermine (Ph, 7.8%), a conjugate of N-hydroxyphentermine (N-hydroxy-Ph, 3.6%), p-hydroxyphentermine (p-hydroxy-Ph, 1.0%) and its conjugate (2.9%), and other metabolites (conjugates of MP and Ph, N-hydroxymephentermine (N-hydroxy-MP) and its conjugate, p-hydroxymephentermine (p-hydroxy-MP) and its conjugate, and N-hydroxy-Ph; less than 1.0%). The rates of excretion for mice were Ph (11.7%), conjugates of p-hydroxy-MP (3.1%), Ph (2.7%) and p-hydroxy-Ph (1.6%), and N-hydroxy-Ph (1.2%) and other metabolites (conjugates of MP and N-hydroxy-Ph, N-hydroxy-MP and its conjugate, p-hydroxy-Ph, and p-hydroxy-MP; less than 1.0%). 4. These results indicate that MP administered to mice is metabolized mainly to Ph and p-hydroxy-MP by N-demethylation and p-hydroxylation of the parent compound, and in guinea pigs the primary metabolic reaction of MP is N-demethylation producing Ph.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Disposition of 10–10′ Oxybisphenoxarsine (OBPA) in Rats,Rabbits and Guinea Pigs

ABSTRACT

The disposition of 10–10’ oxybisphenoxarsine (OBPA), a potent, wide spectrum anti-microbial agent widely used in plastics, was investigated in rats, guinea pigs and rabbits. All animals were given a single dose of [U- ¹⁴C]OBPA by gavage. Urine and feces were collected daily for 7 days, at which time the animals were sacrificed and tissue samples removed for analysis. In all three species, approximately 90% of the administered dose was excreted within 7 days. The rabbits and guinea pigs excreted about 58% via the feces and 32% via the urine. The rats, however, excreted 82% via the feces and 10% via the urine. There were significant differences in the tissue distribution of radioactivity between the three species. The most prominent difference was that the erythrocytes of the rat retained 3.2% of the administered radiolabel while only 0.08% and 0.03% of the dose remained in the erythrocytes of the guinea pig and rabbit, respectively.     

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.     

Metabolism and disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rainbow trout

Accumulation, tissue distribution, and depuration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-derived 3H were studied in fingerling rainbow trout fed a diet containing 494 ppt [3H]TCDD for 13 weeks followed by the same diet without TCDD for 13 weeks. This exposure did not cause fin rot, cutaneous hemorrhage, reduced growth rate, or an increase in relative lethality in TCDD-exposed fish. Visceral fat, carcass, skin, and pyloric caeca and all fatty tissues, accounted for greater than 90% of the TCDD-derived 3H in the fish after the 13-week exposure period. The remaining TCDD-derived radioactivity was distributed to skeletal muscle, gill, gastrointestinal tract, liver, kidney, heart, and spleen. High-pressure liquid chromatographic analysis of 3H in skeletal muscle, liver, kidney, carcass, and visceral fat showed that it was primarily due to TCDD (greater than or equal to 98%) and not metabolites (less than or equal to 2%). The t1/2 for whole-body depuration of TCDD-derived 3H was 15 weeks, and individual organ t1/2 values ranged from 8 to 19 weeks. To determine if rainbow trout metabolize TCDD, adult fish were injected with [14C]TCDD (60 micrograms/kg, ip), and gallbladder bile, liver, skeletal muscle, and kidney were analyzed 1 week later. While only the parent compound was found in the tissues, bile contained at least three TCDD metabolites and the parent compound. beta-Glucuronidase treatment of the bile suggested that at least one TCDD metabolite was a glucuronide conjugate.