The Distribution of 14C-Ethoxyquin in Rat

Abstract 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 throughout 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.     

Irreversible in vivo binding of thiabendazole to macromolecules in pregnant mice and its relation to teratogenicity

The binding of [14C]thiabendazole ([14C]TBZ) to macromolecules in the liver, foetus and other tissues was investigated in Jcl:ICR mice on day 13 of gestation. TBZ suspended in olive oil was given orally in a dose of 1 g/kg body weight (5 microCi/mouse) and the mice (in groups of three) were killed 0.5, 1, 3, 6, 24 and 96 hr later. The bound radioactivity in the liver and foetus was at a maximum between 3 and 24 hr after treatment. The rate of decrease of the bound radioactivity was slower than that of total radioactivity. Bound radioactivity was also present in other tissues (including kidney, lung, heart, placenta and spleen). The level of bound radioactivity was measured in the liver and foetuses after oral administration of teratogenic doses of 200-1600 mg/kg. Disproportionate increases in bound radioactivity were observed in both tissues after administration of the highest dose.     

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.     

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.     

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.     

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.     

Studies on the distribution and covalent binding of 1,1-dichloroethylene in the mouse. Effect of various pretreatments on covalent binding in vivo

The distribution and covalent binding of a single dose of [1,2-14C] 1,1-dichloroethylene (DCE; 125 mg/kg, i.p.) was studied in male C57Bl/6N mice. Total radioactivity was distributed in whole homogenates of all tissues studied, with peak levels occurring within 6 hr. Covalent binding of radioactive material peaked at 6-12 hr in all tissues, and highest levels were found in kidney, liver, and lung with smaller amounts in skeletal muscle, heart, spleen, and gut. Covalent binding in kidney, liver, and lung fell to 50% of peak levels in about 4 days. Between 12 hr and 4 days after DCE administration, 70-100% of total radioactivity present in homogenates of kidney, liver, and lung was covalently bound. The three tissues showed a similar spread in total radioactivity in subcellular fractions 24 hr after exposure to DCE; most of the radioactivity was covalently bound (60-100%) and distributed fairly uniformly with a slight tendency to concentrate in the mitochondrial fraction. Phenobarbital (PB) and 3-methylcholanthrene (3-MC) pretreatments increased the covalent binding in the liver and lung but had no effect in the kidney. Piperonyl butoxide and SKF-525A decreased the covalent binding in liver and lung, but the latter increased binding in the kidney while the former decreased it. Diethylmaleate administration increased the covalent binding (2- to 3-fold) in all three tissues as well as increasing lethal toxicity. These results are consistent with the view that DCE is metabolized to some reactive intermediate(s) which may be detoxified by conjugation with glutathione.     

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.     

Tissue distribution and excretion of octachlorodibenzo-rho-dioxin in the rat.

The contamination of several commercial compounds by chlorinated dibenzo-?-dioxins and the health hazards presented by certain dioxins have been well documented. In this study the relative absence of toxicity following high dosages of octachlorodibenzo-?-dioxin (OCDD) in rats was confirmed. A moderate proliferation of the hepatic endoplasmic reticulum (ER) and hepatomegaly occurred. Daily administration of a radioactive analog of OCDD to rats by gastric intubation for 21 days resulted in the recovery of over 90% of the total dose in the feces as unabsorbed material. A small lipid-soluble fraction was excreted in the urine. After 21 days of administration, less than 1% of the total dose was present in the rat tissues. The liver contained the highest concentration with approximately 50% of the body load found within this organ. The radioactivity in the adipose tissue was approximately 25% that in the liver. Significant levels of radioactivity were found in the kidneys, heart, testes, skeletal muscle, skin, and serum. The greatest reservoirs of the material were liver, skin, and adipose tissue. Over 95% of the radioactivity within the liver was associated with the microsomes and was equally distributed within the rough and smooth fractions. Distribution of the detectable radioactivity within rats that subsequently received a control diet for 6 wk was confined to the liver, adipose tissue, and skin at levels approximately 20–25% that found immediately after the 21-day period of administration. The route of excretion was through the urinary system and the rate corresponded to a biological half-life of approximately 3 wk. Toxicity, hepatic alterations, percentage of absorption, body distribution, and biological half-life of OCDD are compared to those parameters of the extremely toxic tetrachlorodibenzo-?-dioxin (TCDD). Microsomal localization of the compounds is postulated to result in sequestration of the material.     

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 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 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.     

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)     

Absorption, distribution and excretion of a new thienodiazepine derivative (Y-7131) in rats and mice.

The synthesis of radioactive 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepine (Y-7131), a new psychotropic agent, is descirbed. The labelled compound was rapidly and completely absorbed following oral administration to rats and mice. The blood levels of radioactivity reached maximum at 0.5 h in rats, and 1 h in mice, respectively, and then declined rapidly with biological half-lives of about 1.5 h in both animals, although the level was higher in mice than in rats. Approximately 45% of the radioactivity in the serum was bound to the serum protein at 1 h after oral administration. The dosed radioactivity was almost completely excreted within 3 days. In rats, more radioactivity was excreted in feces than in urine, while the reverse was noted in mice. An extensive biliary excretion of radioactivity was evidenced in rats after oral dosing. The highest concentrations of radioactivity were found in the liver, kidney, and adrenals, while relatively low levels in the brain of rats. The distribution patterns of radioactivity in mice were similar to those in rats except for the serum and liver. No remarkable accumulation of radioactivity in rat tissues was observed by repeated oral doses of the labelled compound for periods up to 21 days. The metabolic pathways of Y-7131 were qualitatively similar in rats and mice, and one of them was demonstrated to be the hydroxylation at alpha-position in the ethyl side chain.     

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.     

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.     

Ocular Toxicity of Systemic and Topical Exposure to Butyl 2-Chloroethyl Sulfide

Abstract

Systemic exposure to the vesicant butyl 2-chloroethyl sulfide (BCS) produces significant metabolic and morphologic aberrations in the eyes of rats. Four hours after injection of [¹⁴C]BCS (10 μCi, subcutaneously [sc]), with the exception of the pooled aqueous and vitreous humors, the highest level of radioactivity was found in the retina, followed by choroid/sclera, lens, and cornea. At 24 hr after injection of BCS (10 μl, sc) the retinas showed an edematous swelling of the inner layers. At 48 hr, the outer segments of photoreceptors from untreated control rats were normal while those from rats exposed to BCS were disrupted. Some of the vessels of the choroid contained large clusters of activated platelets. These effects were preceded by a significant increase in thiobarbituric acid-reactive products observed in the eyes after a 30, 60, and 240 min exposure to BCS. In another series of experiments, tissue and ocular distribution of radioactivity in guinea pigs following topical corneal administration of [¹⁴C]BCS was determined. At 0.5, 2, and 5 hr the highest level of total tissue radioactivity was found in the choroid/sclera, cornea, retina, and the lens. The vitreous and aqueous humors were also radioactive. In addition, high levels of radioactivity were found in the liver, followed by kidneys and the lungs. A lower amount of radioactivity was detected in the muscle, adipose tissue, and adrenal glands. These results suggest that systemic exposure to BCS produces metabolic and histologic aberrations consistent with oxidative stress and lipid peroxidation.     

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

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

The effect of S-warfarin administration on vitamin K 2,3-epoxide reductase activity in liver, kidney and testis of the rat

The dithiothreitol-dependent vitamin K 2,3-epoxide (vitamin KO) reductase activity was assayed in rat liver, kidney and testis microsomes. Rat kidney and testis showed vitamin KO reductase activity. The activity was about one tenth of the activity present in liver microsomes. The effect of in vivo S-warfarin was investigated after single doses, i.e. 0.2, 0.4 and 1 mg/kg, and after its chronic administration, i.e. 4.8 micrograms/kg/hr for 3 days. At 20 hr following the acute warfarin administration vitamin KO reductase in liver microsomes was depressed in a dose-dependent way, 50, 30 and 20% of control activity. Vitamin KO reductase in testis was not affected, and in kidney reductase activity was only reduced after the highest warfarin dose, 40% of control activity. Following chronic administration of warfarin, vitamin KO reductase activity was reduced in liver as well as in kidney and testis microsomes, 15-20, 40 and 60% of control activity in liver, kidney and testis, respectively. Blood clotting activity was about 14% of normal (thrombotest). Vitamin KO reductase activity in tissue microsomes was inhibited by warfarin added in vitro. Tissue and microsomal warfarin concentration were assayed. Following the acute administration, warfarin was poorly distributed into kidney and testis. Following the chronic administration, warfarin tissue to plasma ratio was about 3 for liver, but 0.5 for kidney and testis. The results indicate that during chronic therapy with oral anticoagulants vitamin K-dependent systems in non-hepatic tissues are reduced. However, this reduction is less than the reduction of the hepatic system. This is determined mainly by the pharmacokinetic behaviour of the 4-hydroxycoumarins.     

The absorption, distribution, excretion, and metabolism of a single oral dose of O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens

The disposition and metabolism of a single oral 10 mg/kg (LD50) of uniformly phenyl-labeled [14C]EPN (O-ethyl O-4-nitrophenyl [14C]phenylphosphonothioate) were studied in adult hens. The birds were protected from acute toxicity with atropine sulfate. Three treated hens were killed at each time interval (days): 0.5, 2, 4, 8, 12. Radioactivity was adsorbed from the gastrointestinal tract and distributed in all tissues. Most of the dose was excreted in the combined urinary-fecal excreta (74%). Only traces of the radioactivity (0.2%) were detected in expired CO2. Most of the excreted radioactive materials were identified as phenylphosphonic acid (PPA), O-ethyl phenylphosphonic acid (EPPA), and O-ethyl phenylphosphonothioc acid (EPPTA). Radioactivity in tissues reached a peak of 11.8% in 12 days. The highest concentration of radioactivity was present in the liver followed by bile, kidney, adipose tissue, and muscle. EPN was the major compound identified in brain, spinal cord, sciatic nerve, kidney, and plasma. Most of the radioactivity in the liver was identified as EPPA followed by EPPTA and PPA. Kinetic studies showed that EPN disappeared exponentially from tissues. The half-life of the elimination of EPN from plasma was 16.5 days corresponding to a constant rate value of 0.04 day-1. Relative residence (RR) of EPN relative to plasma was shortest in liver and longest in adipose tissue followed by sciatic nerve and spinal cord.