The distribution of 14C-ethoxyquin in rat.

Adult male rats were given the antioxidant 14C-ethoxyquin by oral intubation and were sacrificed at various time intervals from 0.5 hr to 6 days following administration of the drug. The distribution pattern was studied by whole-body autoradiography and liquid scintillation counting. The isotopelabelled antioxidant was distributed throoughout most tissues and the blood at 0.5 hr after administration. The highest radioactivity throughout the experimental period was observed in the liver, the kidney, the gastrointestinal tract and the adipose tissue. No activity was observed in the brain and the central nervous system. Of the dose ingested 2.2 and 0.2% were found in the liver at 0.5 hr and 6 days respectively following dosing. The hepatic peak in radioactivity was measured at 8 hrs and after 6 days 7.5% of this level was still present in the liver. Six days after administration residues of ethoxyquin and metabolites were also present in the kidney cortex, the intestines, the lung, various adipose tissue and blood.     

2,3,7,8-Tetrachlorodibenzofuran tissue distribution and excretion in guinea pigs

The tissue distribution and excretion of [¹⁴C]2,3,7,8-tetrachlorodibenzofuran (TCDF) in adult male guinea pigs was studied up to 9 days following an iv or po administration (6.0 μg/kg, 0.02 μmol/kg). Greater than 90% of the dose was absorbed after po administration. Tissue concentrations and excreta were examined for [¹⁴C]TCDF-derived material for periods ranging from 1 hr to 9 days after administration. Liver, muscle, skin, and adipose tissue were found to be the most important tissues for the distribution of this compound. The highest levels of radioactivity were initially located in the liver and muscle, and then redistributed to the skin and adipose tissue. At 1 day the radioactivity began to be redistributed back to the liver; this second redistribution appeared to be due to the mobilization of fat stores associated with the overt toxicity of TCDF. At all time points, the specific activity of TCDF-derived radioactivity (percentage dose/g tissue) was highest in liver, fat, and adrenals, respectively. The initial phase for the elimination of radioactivity from the liver and muscle had a half-life of 3.9 and 15.7 hr, respectively. Excretion in the urine and feces each accounted for only 6.6 and 6.5% of the dose, respectively, during the 9 days following administration. Greater than 90% of the extracted radioactivity in feces and tissues examined cochromatographed with parent TCDF. However, the radioactivity in the urine did not chromatograph with TCDF and appeared to be a metabolite(s) more polar than TCDF. Studies of the accumulation and distribution of TCDF-derived material after six or more weekly doses of 1 μg/kg TCDF each demonstrated that TCDF is accumulated in liver, adipose tissue, and skin, and that when a body burden of approximately 5.6 to 6.6 μg/kg was attained, the toxicity of this compound was irreversible and resulted in progressive weight loss and death.     

Tissue distribution, disposition, and metabolism of cyclosporine in rats

Tissue distribution, disposition, and metabolism of 3H-cyclosporine were studied in rats after single and repeated oral doses of 10 and 30 mg/kg and after an iv dose of 3 mg/kg. The oral doses of 10 and 30 mg/kg were dissolved in polyethylene glycol 200/ethanol or in olive oil/Labrafil/ethanol. Absorption from both formulations was slow and incomplete, with peak 3H blood levels at 3-4 hr. Approximately 30% of the radioactive dose was absorbed, which is consistent with oral bioavailability data for cyclosporine. More than 70% of the radioactivity was excreted in feces and up to 15% in urine. Elimination via the bile accounted for 10 and 60% of the oral and iv doses, respectively. Since unchanged cyclosporine predominated in both blood and tissues at early time points, the half-lives of the distribution phases (t 1/2 alpha) of parent drug and of total radioactivity were similar. In blood, kidney, liver, and lymph nodes, t 1/2 alpha of cyclosporine ranged from 6-10 hr. Elimination of radioactivity from the systemic circulation was multiphasic, with a terminal half-life of 20-30 hr. 3H-Cyclosporine was extensively distributed throughout the body, with highest concentrations in liver, kidney, endocrine glands, and adipose tissue. The concentrations of both total radioactivity and parent drug were greater in tissues than in blood, which is consistent with the high lipid solubility of cyclosporine and some of its metabolites. Skin and adipose tissue were the main storage sites for unchanged cyclosporine. Elimination half-lives were slower for most tissues than for blood and increased with multiple dosing. The amount of unchanged drug was negligible in urine and bile.(ABSTRACT TRUNCATED AT 250 WORDS)     

Toxicological evaluation in rats and mice of the ingestion of a cheese made from milk with added formaldehyde

Male Swiss albino mice (CD-1) and male Sprague-Dawley rats were given single oral doses of 0.5 g (4.0 microCi) and 2.2 g (18 microCi) 14C-labelled grana cheese, respectively. The cheese was made by the normal process but using milk with added [14C]formaldehyde. The plasma and tissue kinetics of the radiolabelled cheese were studied by monitoring the decay of radioactivity in the plasma, gastrointestinal tract, liver, kidney, lung, testes, spleen, brain, muscle and adipose tissue. The faeces and urine of animals placed in individual metabolism cages were collected between 4 and 64 hr after dosing for rats and between 2 hr and 12 days for mice. Within 32 hr of administration 63-67% of the radioactivity had been excreted in the faeces and urine and 24-28% of the radioactivity had been exhaled as 14CO2, in both species. Maximum concentrations, corresponding to 0.07% and 0.3% of the dose per ml of blood were reached respectively within 8 hr for rats and 2 hr for mice. The toxicokinetic profile appears to be similar in mice and rats because of the similarity of the half-lives of the elimination phase, 27.8 and 26.4 hr respectively, and suggests that accumulation of the 14C-activity does not occur in any of the tissues of either species. The low levels of radioactivity still present 32 hr after the administration of 14C-grana cheese are probably due to the residues of labelled fractions of milk protein not completely metabolized.     

Distribution of 2-ethylhexanoic acid in mice and rats after an intraperitoneal injection

The distribution of 2-ethylhexanoic acid (2-EHA), a new wood preservative agent was studied in mice and rats. 2-14C-EHA in rat blood, brain, liver and kidney was quantitated by liquid scintillation analysis and by wholebody autoradiography in mice. A single intraperitoneal dose of 2-14C-EHA was injected in both species. Animals were sacrificed 30 min., 2 and 6 hr after the administration of 2-14C-EHA in autoradiography experiments. The highest uptake of 2-14C-EHA was observed in the liver, kidney and blood of mice. In contrast, low uptake of 2-14C-EHA was seen in the brain. 2-14C-EHA was well detectable in the olfactory bulb and in the salivary gland. In rats, at 2 hr after administration the highest concentration of 2-14C-EHA occurred in blood (0.3% of the total dose/g tissue). The radioactivity in the liver (0.2%) and kidney (0.1%) was also relatively high. The concentration of 2-14C-EHA was low in the brain (0.02%). By 6 hr. the radioactivity had decreased rapidly and was hardly measurable at 24 hr after the administration. The results suggest that 2-EHA is rapidly cleared from the tissues.     

Cyclic AMP-linked mechanisms in ethanol-induced derangements of metabolism in rat liver and adipose tissue.

An acute ethanol load was achieved by gastric administration of 5 g ethanol per kg body wt to fasted rats. The concentrations of cyclic AMP during the following 24 hr were measured in the liver and adipose tissue and correlated with simultaneously measured concentrations of blood glucose, plasma free fatty acids (FFA), hepatic triglycerides (TG), hepatic glycogen and blood ethanol. Ethanol induced a significant increase in hepatic cAMP reaching a maximum at 16 hr after administration. Hepatic glycogen decreased considerably after 6 hr and blood glucose decreased slightly. Plasma FFA levels decreased, with a minimum at 4 hr. Hepatic TG levels increased steadily from 6 to 24 hr after the ethanol administration. An unexpected small decrease was observed in adipose tissue cAMP. In neither hepatic nor adipose tissue did the cAMP concentration correlate with the blood ethanol concentration. It was concluded that the changes in cAMP were more likely to be due to the regulation of blood glucose than to an unspecific stress response. Experiments with isolated perfused rat livers demonstrated that ethanol has no direct effect on the metabolism of hepatic cAMP.     

Distribution and elimination of 14C-hexachlorobenzene after single oral exposure in the male rat

The distribution and excretion of 14C-hexachlorobenzene (14C-HCB) after administration to rats of a single oral dose of 50 microCi 14C-HCB per kg body weight was studied by whole-body autoradiography and liquid scintillation counting. Radiolabelled HCB was distributed throughout the body in 2 hours. Peak levels were found at 4 hours in the liver and the brown fat and at 24 hours in the abdominal and subcutaneous fat. The highest concentrations were found in the adipose tissues, the bone marrow, the skin, the Harderian gland, the nasal mucosa, the praeputial gland, and the intestinal tract. After 90 days, substantial amounts were present only in the adipose tissue, the skin, the nasal mucosa, and the praeputial gland. Part of the radioactivity in the brown fat, the bone marrow, the praeputial gland, the adrenal gland, the liver, the blood, the kidney, the spleen, the lungs, the heart and the gastrointestinal contents was found not to be evaporable on sections heated to 50 degrees for 24 hrs and was considered to represent metabolites of HCB. Some radioactivity remained in the liver, the kidney, the heart and the intestinal contents after evaporation and extraction of the sections with polar and nonpolar solvents and was supposed to reflect metabolites of HCB associated to tissue macromolecules. Besides urine and faeces, the results indicated the following excretory pathways: Intestinal mucosa, sebacous glands, nasal mucosa and the praeputial and Harderian gland.     

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.     

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.     

Tissue distribution and plasma protein binding of [14C]phenol in rats

The tissue distribution of [¹⁴C]phenol was examined in the rat after oral administration. High concentration ratios between tissues and plasma were found in liver, spleen, kidneys, adrenal gland, thyroid gland, and lungs. Brain, testes, and skeletal muscle had the least concentrations of radioactivity. The total amount of [¹⁴C]phenol in the body reached a peak 0.5 hr after dosing, with only a trace left at 16 hr. Liver was the tissue that accumulated phenol most significantly; 42% of the body phenol was in liver. In blood, 67 to 85% of the ¹⁴C was in the plasma, with 41 to 50% of the radioactivity in plasma bound to plasma protein and/or other macromolecules.     

Distribution of 14C-labelled ochratoxin a in pregnant mice

Autoradiography was used to study the distribution of ¹⁴C-labelled ochratoxin A for up to 4 hr after its iv administration to mice at various stages of pregnancy. The highest ¹⁴C concentration was consistently found in the bile throughout the experimental period. The concentration of radioactivity in the tissues was found, in decreasing order, in the liver, kidney, blood, salivary glands, large vessels, brown fat, myocardium, uterus and lymphatic tissues. The toxin was shown to cross the placental barrier on day 9 of pregnancy, at which time it is most effective in producing foetal malformations.     

Fate of 109Cd-labeled metallothionein in rats.

In order to study the behavior of the cadmium-binding protein, metaliothionein, partially purified ¹⁰⁹Cd-labeled metallothionein was prepared from the livers of rats given ¹⁰⁹CdCl₂. Except for the moiety excreted in urine, the distribution of intravenously injected ¹⁰⁹Cd-labeled metallothionein in rat revealed an overwhelming concentration in the kidney 1 hr following administration. The distribution of radioactivity in the kidney remained essentially constant for up to 7 days after administration. Most of the radioactivity was found as metallothionein in the supernatant fraction. Radioactivity in each of the other organs amounted to less than 1% of that in the kidney. In most of the organs radioactivity decreased with time in proportion to the decrease of the radioactivity in blood. The distribution of cadmium in the living organisms varies according to its existing form. Free cadmium is mainly accumulated in the liver while the bound cadmium is mainly accumulated in the kidney. Metallothioneins from liver and kidney showed the same elution pattern on ion exchange chromatography.     

Disposition of rubratoxin B in the rat

Excretion, tissue concentrations in the kidney and liver, and pharmacokinetic parameters estimated from plasma blood concentrations were determined for rats given a single ip dose of [¹⁴C]rubratoxin B (0.05 mg dissolved in propylene glycol). By 7 days, 80% of the administered radioactivity had been excreted into the urine (41.7%) and feces (38.7%). Urinary excretion was primarily as the parent compound, accounting for 75% of the radioactivity excreted by 7 days. Elimination of radio-activity from the kidneys was monophasic with a half-life of 97.35 hr. Elimination of radioactivity from the liver was biphasic, with a half-life of 13.66 hr for the slow phase. Elimination of rubratoxin B and [¹⁴C]rubratoxin B-derived radioactivity (radioactivity derived from both the parent compound and metabolites) from the plasma was biphasic. The rapid phases of elimination had half-lives of 2.57 and 1.08 hr, and the slow phases had half-lives of 60.80 and 100.46 hr for rubratoxin B and [¹⁴C]rubratoxin B-derived radio-activity respectively. The long plasma half-life of rubratoxin B is suggestive of enterohepatic circulation. The concentration of radioactivity was greatest at 1 hr in the liver and 2 hr in the plasma. Except for the first few hours following injection, the concentration of radioactivity in the liver never exceeded significantly that in the plasma, suggesting a passive absorption process. No glucuronide or sulfate conjugates were detected in the plasma or urine.     

Metabolism and pharmacokinetics of a single oral dose of O-4-bromo-2,5-dichlorophenyl O-methyl phenylphosphonothioate (Leptophos) in hens

The metabolism and pharmacokinetics of a subneurotoxic dose of leptophos were determined in laying hens following a single oral dose of 50 mg/kg (0.9 μCi/hen) of [phenyl¹⁴C]leptophos (O-4-bromo-2,5-dichlorophenyl O-methyl [¹⁴C]phenylphosphonothioate). This study adds confirmatory evidence to the hypothesis that species selectivity for delayed neurotoxicity is related to interspecies differences in pharmacokinetics and metabolism. Oral leptophos was metabolized and excreted slowly in hens. The major portion of the radioactivity (86.5%) was excreted during the 20-day experiment. Significant amounts of the dose were deposited in egg albumen and yolk—3.4 and 2.5%, respectively. Only 1.3% was excreted in expired CO₂. Radioactivity in tissues reached a peak of 14.6% of the dose 12 hr after administration; radioactivity decreased to 6.2% after 20 days (42.6% of peak value). The highest ¹⁴C concentration was present in the bile, followed by the gall bladder, kidney, adipose tissue, and liver. Brain, spinal cord, and sciatic nerve, which are affected by the neurotoxicity of leptophos, had smaller but constant concentrations throughout the experiment. Following the oral administration of [¹⁴C]leptophos the change in the ¹⁴C body burden with time was biexponential. The physiological disposition of leptophos may therefore be defined in terms of a two-compartment open-system model. Radioactivity was excreted at a slow rate, β value of 0.05 day^?1, corresponding to a half-life of 12.0 days. Leptophos was the only compound identified in nerve tissues, muscle, fat, and blood. Most of the radioactive substances in the excreta and liver were identified as unchanged leptophos with minor amounts of polar metabolites. The metabolic fate of leptophos can be explained on the basis of its physical properties of lipid solubility and tissue binding, and the predominant biliary secretion and gastrointestinal excretion of the compound.     

Disposition of 3,3′-dichlorobenzidine in the rat

The disposition of the carcinogen 3,3′-dichlorobenzidine (DCB) was studied in the male rat following oral administration. [¹⁴C]DCB was well absorbed by the rat with the maximum plasma radioactivity levels being found within 8 hr after dosing. The radioactivity was well distributed in the tissues 24 hr after administration with the highest levels found in the liver, followed by kidney, lung, and spleen. Repeated administration (six doses) of [¹⁴C]DCB to animals did not result in a substantial accumulation of ¹⁴C in the tissues. The elimination of radioactivity from the plasma, liver, kidney, and lung was biphasic showing an initial rapid decline (half-lives 1.68, 5.78, 7.14, and 3.85 hr, respectively) followed by a slower disappearance phase (half-lives 33.0, 77.0, 138.6, and 43.3 hr, respectively). Approximately half of the total ¹⁴C in the liver and kidney was covalently bound to cellular macromolecules 72 hr after dosing. [¹⁴C]DCB-derived radioactivity was extensively excreted by rats, mainly via the feces. Approximately 23–33% of the administered dose was recovered in the urine and 58–72% in the feces of rats within 96 hr. More than 65% of the administered ¹⁴C was eliminated in the bile of bile duct-cannulated rats within 24 hr after dosing. The radioactivity excreted in the urine and bile was primarily in the form of free (urine 71.2%, bile 25.5%) and conjugated (urine 19.6%, bile 57.9%) metabolites of DCB. Thus DCB is readily absorbed following oral administration, and then metabolized and excreted mainly via the feces.     

Distribution and residue determination of [3H]zearalenone in broilers

[³H]Zearalenone was intubated into the crops of 7-week-old broiler chickens, and its distribution was monitored at 0, 0.5, 4, 8, 12, 24, and 48 hr. Metabolic products were measured by gas chromatography-mass spectroscopy and radioimmunoassay. The average recovery of administered radioactivity was 83%. Of the edible tissue, the greatest accumulation of radioactivity occurred in the liver 0.5 hr (0.94%) after administration after which it fell off quickly so that by 48 hr only a trace (0.07%) of radioactivity was found. Muscle, abdominal fat, skin, and heart contained only trace quantities of radioactivity. The bile and gall bladder (4.2%) and excreta (87%) contained the major portion of radioactivity. The excreta was the major avenue of elimination. Total zearalenone and α- and β-zearalenols found in the excreta at 0.5 hr after administration were 0.5 to 3.86 ppm, 8.8 to 2.5 ppm at 4 hr, 12.5 to 121 ppm at 8 hr, 10.1 to 82.7 ppm at 12 hr, 1.6 to 122 ppm at 24 hr, and 39 to 43.5 ppm at 48 hr. The concentration in the muscle ranged from 23 to 25 ppb at 0.5 hr to 4 ppb at 48 hr; the maximum residue found was 111 ppb. The muscle contained only zearalenone and no zearalenol. Zearalenone and α- and β-zearalenols were found in the liver with concentrations ranging between 57 and 1103 ppb when measured by RIA and 17.3 and 2543 ppb when measured by GC-MS. The identity of all metabolites was confirmed by mass spectroscopy. The data suggest little danger from residue in the edible portions. Moreover, analysis of the feces can be used as an indicator of intoxication.     

Isolation and identification of metabolites of 2-ethylhexyl diphenyl phosphate in rats

The metabolic fate of 2-ethylhexyl diphenyl phosphate (EHDPP) was studied in male rats. Orally administered ¹⁴C-EHDPP was rapidly absorbed and about 80% of the radioactivity was excreted in the urine and feces in the first 24 h. By 7 days, 48% and 52% of the radioactivity was recovered in urine and feces, respectively. Since biliary excretion was low (6% for 2 days), urine seems to be the major excretion route of EHDPP. Radioactivity was widely distributed in all tissues examined. At 2 h, the concentration was relatively high in blood, liver kidney and adipose tissue. The elimination of radioactivity from adipose tissue and liver was somewhat delayed, but almost all the radioactivity was eliminated by 7 days. The major metabolites in the urine were diphenyl phosphate (DPP) and phenol. p-Hydroxyphenyl phenyl phosphate (OH-DPP) and monophenyl phosphate (MPP) were also identified as minor metabolites.     

Author Index to Volume 22

Abstract

In vivo percutaneous penetration and tissue distribution of radioactivity following a topical application of ¹⁴C-labeled butyl 2-chloroethyl sulfide (BCS) were determined in the laboratory rat. Up to 70% of the topical BCS was lost by evaporation. Only a portion of BCS in the skin was extracted with ethanol. At 1 hr, approximately two-thirds of the applied BCS was ethanol-extractable. This level decreased to about 6% at 24 hr. Radioactivity in blood was detected 5 min after application. Thereafter, a linear increase in blood radioactivity was observed throughout the entire 4 hr experimental period. Topical BCS was absorbed into the circulation and was incorporated into various organs and tissues. The liver, kidneys, heart, lungs, skeletal muscle, brain, eyes, and bone marrow were radioactive. On an equal weight basis, the kidneys and lungs contained the highest level of radioactivity. Following a subcutaneous injection of BCS, over 2% of the dose appeared in expired air. No radioactivity was detected in expired carbon dioxide. In 24 hr, up to 70% of the applied radioactivity was excreted in the urine. Four urinary metabolites of BCS were found. This study demonstrates that skin contact with BCS forms an extensive reservoir of ethanol-extractable labeled BCS and/or its metabolites in the affected skin site.     

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.     

Tissue distribution and pharmacokinetics of 3-t-[methyl-14C] butyl-4-hydroxyanisole in rats

Tissue distribution and pharmacokinetics of 3-t-[methyl-14C]butyl-4-hydroxyanisole was studied in male rats. 3-t-[methyl-14C]butyl-4-hydroxyanisole was administered by gavage at a single dose of 1.5 mmol/kg. Urine, feces, blood, and 20 major tissues were collected at 0.5, 1, 3, 6, 12, 16, 17, 18, 24, 48, 72, 168, and 240 hr after dosing and were analyzed for radioactivity. Almost all radioactivity was eliminated from rats in 48 hrs. Forty one per cent of the administered dose was recovered in urine, while feces accounted for 53%. At early time points radioactivity was mainly found in gastrointestinal tissues with concentrations remaining high up to 16-18 hr after administration indicating a slow absorption and elimination of the compound. The maximum concentration of radiolabel in kidney, liver, bladder, spleen, heart, pancreas, and brain was reached at 6 hr and remained up to 24 hr. The concentration of radioactivity in liver and kidney was approximately 10-fold higher than other tissues at the peak time of 16-18 hrs. Calculated absorption and elimination rate constants demonstrated slow uptake and clearance of label by many tissues. Covalent binding in eight representative tissues at 10 time points was also studied. Results indicate that binding increases slowly and exponentially with time reaching maximum levels at 12-24 hr in most of the tissues followed by a slow decline with time.