Blood Levels Of Radioactivity Research Articles

STUDIES ON METABOLISM OF TRIPAMIDE III. METABOLIC FATE OF 14C-TRIPAMIDE IN RATS AND RABBITS

The metabolic fate of a new antihypertensive agent, tripamide (N-(4-aza-endo-tricyclo[5.2.1.02,6]-decan-4-yl)-4-chloro-3-sulfamoyl-benzamide), in rats and rabbits was studied using its 14C-labeled compound. The blood level of radioactivity in both species reached the maximum at 1 hr after oral administration, indicating the rapid absorption of the drug from the gastrointestinal tract. Following either oral or intravenous administration, a high concentration was observed in the liver of rats, but it was found in the kidney of rabbits. The major metabolite was 4-chloro-3-sulfamoylbenzoic acid in tissues, urine and feces; and in both species, the unchanged drug was only detected in the kidney. The pathway of excretion of radioactivity was via urine and feces in case of rats; but in rabbits, it was predominantly excreted via urine, although significant quantities of radioactivity were excreted with feces. The radioactivity excreted in feces was attributable to that which was excreted in bile, indicating the absorption of almost all the tripamide administered in both species. During the period of repeated dosing, though blood levels increased gradually and became about 1.5 times as high as that in the single dosing, radioactivity did not accumulate in most tissues and organs.

Studies on absorption, distribution and excretion of 14C labelled sodium 7 beta-[(2R, 3S)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-3-hydroxybutanamido]-7-methoxy-3-[(1-methyl-1H-tetrazol-5-YL)thiomethyl]-3-cephem-4-carboxylate (14C-T-1982) in mice and rats

Absorption, distribution and excretion of sodium 7 beta-[(2R,3S)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-3-hydroxybutanamido ]-7 alpha-methoxy-3-[(1-methyl-1 H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylate (T-1982) were studied in rats and mice using of 14C-T-1982. 1. The binding rate of 14C-T-1982 to serum protein was about 16% in mouse, 27% in rat and 50% in human. 2. After intravenous administration to mice and rats, blood levels of radioactivity diminished rapidly. While, after subcutaneous administration to mice and intramuscular administration to rats, blood levels reached rapidly to high concentration and, declined gradually in comparison with intravenous studies. 3. Radioactivity after parenteral administration to rats and mice was distributed high into kidney, following by liver, stomach, heart, lung and ovarium, but low into brain. In new born rats, tissue levels diminished slower than that of adult rats. 4. With regard to oral administration to mice, almost all radioactivity was found in feces. This result suggested that T-1982 was hardly absorbed from gastrointestinal tracts. Urinary excretion rate after intravenous administration was about 60% in mice and 19% in rats, and the other radioactivity was found in feces. 5. In rats, radioactivity was excreted in bile at biliary excretion rate of about 80% after intravenous administration. 6. After intravenous administration to nursed rats, radioactivity was hardly detected in gastrointestinal tracts of sucklings. And from the study on distribution of radioactivity in pregnant mice, it was suggested that T-1982 scarcely passed placenta. 7. Excretion pattern after multiple administration to rats was similar to that of single administration. This result suggested that T-1982 did not produce accumulation of it in body.

Colchicine affects the distribution of isotope-labeled H 2O and extracellular markers in rat liver and hepatomas

Treatment of hepatoma-bearing rats with colchicine (175 or 250 μ g 100 g body wt) greatly diminished the radioactivity in tumors when measured 10 min after subcutaneous injection of 3H 2O. There were relatively small effects of colchicine treatment on the level of radioactivity in blood and little change in the ratio of radioactivity in blood and liver. Inhibitory effects of colchicine were also observed for the distribution in hepatomas of the extracellular markers [ 3H] methoxy-inulin and [ 14C]sucrose. An effect of colchicine on circulation in hepatomas may be a factor in the previously reported inhibitory action on metabolite uptake.

The metabolism of benodanil in the rat

AbstractThe metabolism of benodanil (2‐iodobenzanilide) was studied in rats following an oral dose of 150 mg benodanil kg−1 body weight. The major 24‐h urinary metabolite was found to be the 4′‐hydroxy derivative, both free (≈ 5%) and as the glucuronide (≈ 4%) and sulphate (≈ 4%) conjugates. Over a 6‐day period, about 16% of the administered dose was excreted in the urine and about 80% in the faeces. After dosing with [14C]‐ benodanil, blood radioactivity levels were highest 30 min after dosing, with small broader peaks at 4 and 7 h, while biliary activity levels rose slowly to a maximum about 10–12 h after the dose, some 16% being excreted in 24 h as the glucuronide conjugate of the 4′‐hydroxy derivative.

Protection Against Anthramycin-Induced Toxicity in Mice by Coenzyme Q102

Pretreatment of Swiss Webster mice with coenzyme Q10 (CoQ) markedly reduced the lethality of the antitumor antibiotic anthramycin as well as its ability to decrease ventricular weights. In tumor-bearing mice CoQ pretreatment did not produce any consistent alteration of radioactivity levels in blood, heart, tumor, lungs, kidneys, liver, muscles, brain, or spleen after [15-3H]anthramycin administration. Gross alterations in anthramycin distribution is probably not the mechanism by which CoQ alters the cardiotoxicity and lethality of anthramycin.

The Effect of Sulphur on 75Se Absorption and Retention in Sheep

Four Border-Leicester X Merino wethers were used in a 4 X 4 Latin square experiment to study the effects of dietary sulphur on selenium absorption and retention. The basal diet contained 0.05% S and sodium sulphate was added to give additional treatment levels of 0.11, 0.17 and 0.24% total sulphur. Sodium selenate was added to all diets to bring the dietary selenium level to a constant 0.25 mg/kg. One hundred muCi 75Se as sodium selenate (specific activity 50 muCi/mg Se) was administered to the rumen per fistulam after a 10-day period of adjustment on each diet. Radioactivity in blood, urine, faeces and rumen digesta was measured at intervals over the succeeding 7 days. Twenty percent of the total activity in the rumen fluid was in the TCA supernatant fraction after 3 hours, and this proportion tended to increase slightly as sulphur intake increased. Fecal excretion of selenium accounted for between 44 and 51% of the dose after 7 days, the high levels being associated with increasing sulphur intake. However, these differences were not significant. Urinary excretion of selenium accounted for between 12% (0.05% S) and 22% (0.24% S) of the dose after 7 days, with treatment differences being significant. Levels of radioactivity in blood were significantly higher in sheep fed the 0.05% S diet compared with those fed the higher levels. The results show that sulphur affects apparent selenium excretion and suggest that the metabolism of these two elements is intimately related.

Disposition of ORF 9326, a novel contragestational steroid, in animals

The disposition of ORF 9326 [17β-acetoxy-2α-chloro-3(p-nitrophenoxy) imino-5-androstane], an O-aryl oxime of 2α-chlorodihydrotestosterone acetate, was studied in rats, dogs, monkeys and rabbits. Intravenous administration of 3H-ORF 9326 dissolved in PEG-400 to rats, dogs and monkeys resulted in a rapid decline of radioactivity in blood followed by a terminal slope suggesting long retention of radioactivity. Apparent half lives of radioactivity in blood were calculated to be from 50–95 hours for the three species, with peak levels of radioactivity in whole blood occurring within 4–7 hours after administration of the compound. Tissue distribution studies in the rat and dog indicate that body fat is one of the major depot areas for the drug and/or its metabolites. The major route of excretion for ORF 9326 and/or its metabolites in dog and rat is biliary whereas in monkey and rabbit it appears to be renal. Greater than 90% of the radioactive compounds excreted in the urine of dogs and monkeys following intravenous administration of 3H-ORF 9326 appear to be in the form of conjugates.

Studies on the metabolism and toxicity of dinitrotoluenes--on the absorption and excretion of tritium-labelled 2,4-dinitrotoluene (3H-2, 4-DNT) in the rat.

In order to investigate the detailed absorption and excretion of 2, 4-DNT in the rat, after the single oral administration of 3H2, 4-DNT, the time-course of radioactivity level in blood, liver and digestive organ contents, and of biliary, faecal and urinary excretion were observed. Radioactivity level in blood reaches a peak at 6 hr after the administration and its half-life was about 22 hr. Maximum level of radioactivity in the liver was observed at 6 hr after the administration as well as in the blood. In contrast with the radioactivity levels in blood and liver, amount of radioactivity in small intestine content is markedly decreased for 6 hr after administration. In the biliary excretion, about 10 per cent of the radioactivity administered was excreted in bile within 24 hr. The excretion rate is rising steadily from 6 hr after administration and its peak time was 9-10 hr. In the faecal excretion, the most of the excretion radioactivity was concentrated on 6-9 hr. In the faecal excretion, the most of the excretion radioactivity was concentrated on 6-9 hr faeces as reflected with the biliary excretion pattern. On the other hand, the most of the urinary excretion radioactivity was concentrated on 0-6 hr urine.

鎮痙作用を有する塩基性エーテル化合物R97のラットにおける吸収，分布，排泄，代謝に関する研究

The absorption, distribution, excretion and metabolism of 14C labelled 2-chlorophenyl-1-phenyl-3-(2 methyl-piperidino) propyl ether methyl iodide (14C-R97) were studied by means of direct measurement of radioactivity and autoradiographic technique in rats. 1) With intravenous administration, radioactivity was found in all the tissues and organs immediately after dosing, with particularly high levels in the liver, kidney, heart and lung. Five minutes after administration, the level of radioactivity in blood decreased to about 6% of the initial level, indicating the rapid absorption of radioactive material by other tissues and organs. Radioactivity was not detected in the brain and eye. Thirty minutes after administration, the concentration of radioactivity in the gastrointestinal contents was very high and a certain amount of radioactivity uptake was noted both in gastric and intestinal mucosa. Approximately 12% and 40% of radioactivity administered was excreted in the urine and feces respectively during the first 24 hours, however, the excretion of radioactivity by expiration was not determined. 2) With oral administration, radioactivity was restricted to the gastrointestinal tract. Activities in other tissues and organs were not detectable. Approximately 94% of the radioactivity administered was recovered in feces during the first 24 hours. 3) Radioactivity was not observed in either the foetus or placenta after both intravenous and oral administrations. 4) The results from autoradiographic study were in good accord with those described above.

Localization, distribution, elimination and metabolism of14C-Sulpiride in rats

The localization, distribution, elimination and metabolism of14C-Sulpiride administered in doses of 20 mg/kg by i. p. and oral route in rats is described. Whole-body autoradiography and quantification in organs and tissues as a function of time showed that the distribution of radioactivity throughout the body is general with the highest level in the kidineys, pelvis, liver and hypophysis 1 hour after administration. The blood radioactivity level reaches its maximum 5 minutes after i. p. administration with a value of 11 μg/ml, of which 85 % is due to unchanged Sulpiride. At later determinations, the amount drops to 60–65 % of unchanged Sulpiride. In the bile, the maximum radioactivity is measured between 1 and 1 hour 1/2 in either extra-corporal circuit or choledocal fistula. After i. p. administration, urinary elimination is an average of 64 % of the administered dose in 72 hours, of which 70 % to 55 %, depending on the period, is due to unchanged Sulpiride. Fecal elimination after i. p. administration is an average of 26 % of the administered dose in the 72 hours period. Conversely, after oral administration, urinary elimination represents an average of 18 % of the administered dose in 72 hours and fecal elimination represents an average of 74 % for the same period. Aside from the unchanged product, 7 to 8 metabolites were separated and quantified at the plasmatic, urinary and biliary level. Very low amounts of radioactivity were recovered as14CO2 indicating that the labelled position is very stable.

Transport of thyrotropin-releasing hormone from cerebrospinal fluid to hypophysial portal blood and the release of thyrotropin.

The capacity of the medium eminence to transport thyrotropin-releasing hormone (TRH) from cerebrospinal fluid (CSF) to hypophysial portal blood, and the ability of TRH when introduced into a lateral ventricle to stimulate TSH release from the pituitary gland were investigated. Male rats were injected either intraventricularly or intravenously with 0, 1, 10, or 100 ng of TRH, and plasma TSH concentrations were determined at various times thereafter. TRH administration via both routes resulted in substantial release of TSH. Following intraventricular injection of TRH, there was a delay in reached maximal TSH concentration when compared with the faster elevation and faster decline in TSH concentrations which followed intravenous injection of the same dose of TRH. In a second experiment, 7 muCi of [3H]TRH were introduced intraventricularly or intravenously, and hypophysial portal and arterial blood were simultaneously collected and examined for the presence of radioactivity. The intraventricular injection of [3H]TRH resulted in a peak of radioactivity in portal blood within minutes, which was maintained for 20--30 min and then declined. The concentration of radioactivity in arterial blood from the same animals was considerably lower than that in portal blood. The intravenous administration of [3H]TRH resulted in radioactive peaks in both portal and arterial blood with a higher concentration of radioactive substances in arterial blood. However, the level of radioactivity in portal blood following intravenous injection of [3H]TRH comprised no more than 5--10% of that found following intraventricular administration of the saem dose. The data support the view that TRH is able to cross the medium eminence from CSF into hypophysial portal blood and that it is capable of stimulating the pituitary gland to release TSH.

Metabolism of Triamcinolone Acetonide-21 -phosphate in Dogs, Monkeys, and Rats

The absorption, distribution, and metabolic fate of triamcinolone acetonide-14C-21-phosphate were studied in the dog, monkey, and rat. A comparison of levels of radioactivity in blood or plasma, reached after intramuscular or intravenous administration, indicated that the drug was completely absorbed from the site of intramuscular injection within 10–15min in all three species. Within 1–5min after intramuscular or intravenous administration, the 21-phosphate ester was completely hydrolyzed to triamcinolone acetonide, which was present in the blood. The radioactivity was eliminated rapidly (t1/2 = 1–2 hr) from plasma (dogs, monkeys, and rats) and tissues (rats) after intramuscular or intravenous administration. In the three species, the major route of excretion was via the bile; however, the ratio of biliary to urinary excretion among the species varied considerably (from 1.5 to 15). In rats, excretion of radioactivity as expired carbon dioxide accounted for only 2–3% of the dose. 6β-Hydroxytriamcinolone acetonide was the major metabolite in urine of the three species. Hydrolytic cleavage of the acetonide group did not appear to be significant.

The uptake of 14C-labeled hydroxyanthranilic acid and enantiomers of tryptophan, kynurenine, and hydroxykynurenine in human blood.

Labeled enantiomers of tryptophan, kynurenine, and hydroxykynurenine were given to five patients with scleroderma. Blood samples were drawn periodically over a 24-hr period. When the D-isomers were given, peak blood levels of radioactivity did not appear until 8 hr, whereas with the natural L-isomers peak levels were reached in 2 hr Considerable radioactivity was found firmly bound to the precipitated plasma proteins from both the L- and D-isomers. Incubation studies confirmed the binding of the D-isomers to the serum proteins. These experiments show that the use of pure labeled L-isomers is required, when studying the metabolism of amino acids in man, and that compounds other than L-tryptophan are bound to serum proteins in significant quantities.

The mechanism of carcinogenic action of 1,2-dimethylhydrazine (SDMH) in rats.

The radioactivity level in blood, bile, urine and contents of parts of the gastro-intestinal tract in rats was studied after subcutaneous administration of 3-H-1,2-dimethylhydrazine (3-H-SDMH) which induces colonic tumours. The alkylation of DNA, RNA and protein in the intestinal mucosa, liver and kidneys was estimated 1 h to 28 days after 3-H-SDMH treatment from the 3-H-incorporation into these macromolecules. Administration of 3-H-1,2-diethylhydrazine (3-H-SDEH) which does not induce intestinal tumours was made as a control. Fifteen to 30 min after 3-H-SDMH treatment, marked radioactivity was found in blood, bile, urine and in contents of all regions of gastro-intestinal tract. After 3-H-SDMH administration no label occurred in the contents of localized segments of gastro-intestinal tract although it was present in blood, bile and urine. 3-H-SDMH methylated DNA, RNA and proteins of intestinal mucosa, liver and kidney to a high degree. One hour after 3-H-SDMH treatment the incorporation of label into protein of intestinal mucosa was higher than into liver and kidneys. 3-H-SDEH did not alkylate macromolecules in these organs but did so in thymus, spleen and brain, which are target organs for this carcinogen. After total hepatectomy, 3-H-SDMH did not methylate macromolecules of the intestinal mucosa. The following mechanism for the carcinogenic effect of SDMH is suggested. A carcinogenic metabolite of SDMH forms, in the liver, a conjugate with glucuronic acid. This glucuronide enters the gut both with bile and directly via the circulation. Microbial beta-glucuronidase releases the active metabolite which, in turn, alkylates tissue macromolecules.

Placental transport of creating in the rat.

Pregnant rats near term were injected iv with creatine-1-14C or creatinine-1-14C and the distribution of radioactivity was studied in maternal and fetal blood as well as in the visceralyolk sacs and chorioallantoic placentae. After injection of creatine-1-14C into the dam, the level of radioactivity in fetal blood was somewhat higher than that inmaternal blood at 30 min, reached maximal levels after 30 min, and remained essentially constant for at least 4 hr. The radioactivity in the labyrinth and junctional zone portions of the chorioallantoic placenta and the yolk sac was maximal after 30-6- min and was always considerably higher than that in the fetal and maternal blood. Furthermore, the level of radioactivity in the labyrinth was several times higher than that in the junctional zone portion of the chorioallantoic placenta and the yolk sac in which the radioactivity remained essentially constant after 1 hr. On the other hand, the radioactivity in the labyrinth declined rapidly after the first hour and reached levels which were about one-third of the maximal value after 4 hr. When labeled creatine was injected into the dam, 90% of the radioactivity present in the fetal blood and chorioallantoic placenta was found in free creatine as shown by paper chromatography in three different systems. Ancillary studies showed that the creatine concentration in fetal blood was several times higher than that in the maternal blood on the 21st-22 day of gestation. Creatine concentration in both portions of the chorioallantoic placenta as well as the visceral yolk sac was higher than that in the fetal blood, indicating that a downhill concentration gradient existed between creatine in placental tissues and that in the fetal circulation. When creatinine-1-14C was injected iv into pregnant rats, the level of radioactivity in fetal blood rose to a maximum after 5-15 min, but the radioactivity in the maternal blood was considerably higher than that in either the fetal blood or the chorioallantoic placenta and yolk sac. These studies indicate that creatine is actively accumulated and released by the placental unit to the growing rat fetus, while creatinine is passively transported from mother to conceptus across the placentae, at least during the later stages of rat gestation.

Studies on the metabolic fate of o-hexyloxybenzamide (author's transl)

Absorption, distribution, and excretion of o-hexyloxybenzamide (HBA) were studied in rats by using <14>C-labeled compound, which was prepared from <14>C-salicylic acid. The radioactivity in blood reached maximum level at 2 hr after intraperitoneal administration of the compound dissolved in soybean oil. The level of radioactivity in blood was as low as that in tissues. The rats excreted about 77% of the injected radioactivity in urine, and about 15% in feces within 72 hr. In the case of percutaneous administration of HBA in ointment, about 16% of the administered radioactivity was excreted in urine within 72 hr and about 73% of the administered radioactivity remained at the site of application. In both routes of administration, distribution of radioactivity in rat tissue was more highly located in the kidney and liver than in other tissues. Examination of metabolite in urine showed that no unaltered compound could be detected and main metabolites might be glucuronides of carboxylic acid-type and alcoholic type derivatives derived from the hexyloxy residue of HBA.

Metabolic fate of 2-(7-methoxy-10-methyl-2-phenothiazinyl)-propionic acid (PRT). II (author's transl)

Following oral administration of 3H-2-(7-methoxy-10-methyl-2-phenothiazinyl)-propionic acid (PRT) to rabbits and dogs, radioactivity level in blood increased rapidly to a maximum at 1 hr. In the rabbits, 87% of the administered radioactivity was excreted in the urine, whereas 73% of the administered radioactivity was excreted in the feces in the dogs within 72 hr after dosing. In pregnant rats given 3H-PRT orally, radio-activity in thefetuses did not exceed 1% of the administered radioactivity. When 3H-PRT was given orally to rats having carrageenin-induced edema in one of their hind feet, radioactivity level in the inflamed foot was found to be significantly higher than that in the untreated foot. Aminopyrine demethylase and aniline hydroxylase activities of liver microsome of rats were determined after oral administration of PRT for 4 days and for 30 days, respectively. No significant difference was found in the enzyme activities between the rats given PRT and control animals.

Studies on Caerulein (FI6934). Absorption, Distribution, Metabolism and Excretion of Caerulein

35S-Caerulein (35S-F16934) was administered intramuscularly into rats (280 μg/kg), rabbits (380 μg/kg) and mice (3.3 mg/kg). Blood level of radioactivity in rats and rabbits reached the maximum at 5 and 15 min after administration, respectively, and then decreased rapidly. In both rats and rabbits, the radioactivities were excreted mainly into the urine. The physiological activity of F16934 was detected in the blood of rats and rabbits collected within 15 and 30 min after injection respectively, and in the bile of rats collected within the first 2 hr. In rats, the radioactivities were densely distributed in kidney, liver, pancreas, and intestine. Four metabolites of 35S-FI6934 were isolated by paper chromatography from rat urine (i.m., 500 μg/kg). The main metabolites, F-I and F-II, were negative to nynhydrin and to the Ehrlich reagent and carried no physiological activity. 35S-Chym-I, which was prepared by digesting 35S-F16934 with chymotrypsin, was injected to rats (i.m. 16 or 8 mg/kg). The metabolite, C-I, isolated from the urine was considered to have a very similar structure to F-I from the results of paper chromatography and paper electrophoresis. By amino acid analysis. the structure of C-I was estimated to be as follows:

Studies on Metabolism of Trazodone, II. Metabolic Fate after Intravenous Administration and Effects on Liver Microsomal Drug-Metabolizing Enzymes in Rats

1. The blood level of radioactivity following intravenous injection of [14C]-trazodone hydrochloride (4 mg/kg) decreases with three half-lives of 4.4 min, 49 min and 9.0 h.2. The urinary and faecal excretions of radioactivity and the pattern of urinary and biliary metabolites after injection are approximately similar to those after oral administration.3. A major metabolite of trazodone in rat bile and urine is the glucuronide conjugate of trazodone hydroxylated at C4 of benzene ring.4. The concentration of unchanged trazodone in rat brain is higher than that in plasma.5. Trazodone HCl (80 mg/kg) administered intraperitoneally twice daily for 7 days to rats had no effect on liver weight, microsomal protein content, cyto-chrome P-450 content or on the metabolism of [14C]trazodone HCl and other substrates such as imipramine and aniline.

Metabolism of Chloroform—I. The Metabolism of [14C] Chloroform by Different Species

Abstract1. The metabolism of [14C]chloroform by the mouse, rat and monkey has been investigated. A pronounced species variation was observed.2. In all three strains of mice examined about 80% of a dose of 60 mg/kg 14CHCl3 was converted to 14CO2. In the rat about 60% conversion occurred whilst only 20% conversion occurred in the squirrel monkey.3. [14C]Urea was present in the urine of both rat and mouse, together with at least two other metabolites.4. Whole-body autoradiography was carried out on rat and monkey.5. 14CHCl3 was detected in monkey bile.6. Blood levels of radioactivity were determined after oral dosage of 14CHCl3 to mice and monkeys.