Maximum Concentration Of Radioactivity Research Articles

A practical study to determine the percentage of radiation in medicinal herbs used in the Iraqi market

Some commonly used medicinal plants have been chosen to find out the radioactivity concentration and their annual effective dose for 10 samples, Because of that naturally arising radionuclides of 238U, 232Th and 40K., Have used Gamma ray spectroscopy was used to find activity concentrations and the results of the analysis indicated that the average activity concentration of 238U, 232Th and 40K in the medicinal plants, where the results was 38.12 ± 1.619 Bq kg-1, 12.95 ± 0.896 Bq kg-1 and 570.70 ± 31.453 Bq kg−1 correspondingly. Chamomile noted ha the greatest concentration of activity to the 238U and 40K Whereas the maximum concentrations of radioactivity for 232Th in Officinalis Borago were noted. The values of the radium corresponding mean (62.715) Bq.kg−1. (Outdoor and indoor absorbed dose, Outdoor annual effective dose equivalent, Indoor annual effective dose equivalent and Total annual effective dose equivalent). Where the effective committed annual dose value was less than the world average (0.3 for ingestion of probable radionuclides contained in the UNSCEAR 2000 report. Also Well we found a risk factor was (1.4325*10−5) significantly less than the ICRP cancer risk, all values were below the internationally allowed limits, the results provide baseline values that may be useful in developing radiation protection rules and regulations in addition to setting ideals and rules for the usage of therapeutic plants or herbal to the competent establishments.

Abstract P2-08-35: A significance of SUVmax levels on FDG-PET as a prognostic factor may be mediated by local immune environment of breast cancer

Abstract (Background) SUVmax levels (maximum radioactivity concentration per a pixel) on FDG-PET reflect glucose uptake and it is clinically useful as a prognostic factor. It is reported that breast cancer with high levels of SUVmax causes insufficient glucose concentration in stromal tissue, which results in suppressed cytotoxic T-lymphocytes function. These data may indicate that the prognostic significance of SUVmax levels is influenced by local immune environment of breast cancer. The aim of this study is to investigate whether local immune responses of breast cancer affect correlation of SUVmax levels and prognosis. (Method) The 278 invasive breast cancer patients were recruited who underwent surgery at Hyogo College of Medicine Hospital and whose SUVmax levels in the breast were examined before surgery or neo-adjuvant therapy. The cutoff value of SUVmax levels was set at 3.585. Tumor infiltrate lymphocytes (TILs) were evaluated as a local immune response and the distributions of TILs were divided into three groups, inflamed (intra-tumoral lymphocytes, Inf), immune excluded (peri-tumoral lymphocytes, IE) and immune desert (very few lymphocytes, ID). During follow-up period (median 39 months), 21 patients relapsed. (Results) Relapse free survival (RFS) in the SUVmax-high group was significantly worse than in the SUVmax–low group (p=0.0026). There was no correlation between TILs distribution patterns and RFS. In the IE+ID group (175 patients) SUVmax levels were not correlated with prognosis, but in the Inf group (103 patients) RFS of SUVmax-high was significantly worse than of SUVmax-low (p=0.0051). In the multivariate analysis including nodal status and nuclear grade, SUVmax levels of the Inf group was an independent prognostic factor. (Discussion and conclusion) SUVmax levels in primary lesions were correlated with prognosis only in the Inf group and were not in the IE+ID group. A significance of SUVmax levels as a prognostic factor may be diverse depending on the local immune environment of breast cancer. A novel therapeutic strategy such as inducing suppression of glucose uptake in cancer cells is suggested for breast cancer with immune inflamed. Citation Format: Fujimoto Y, Higuchi T, Watanabe T, Hida AI, Imamura M, Kitajima K, Miyoshi Y. A significance of SUVmax levels on FDG-PET as a prognostic factor may be mediated by local immune environment of breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-35.

Radiological safety assessment for incident-free transportation of radioactive decontamination waste after the Fukushima nuclear power plant accident

Radioactive decontamination waste generated by remediation following the Fukushima nuclear power plant accident was recently transported from its temporary storage sites to interim storage facilities as a pilot test. A transportation plan for the radioactive decontamination waste will be developed based on this pilot transportation experience and radiological safety assessment of pilot transportation. The objective of this study was to assess radiation doses to the public and crew workers released during incident-free pilot transportation. External dose rates around a transportation vehicle were calculated by using the Monte Carlo N-Particle code. Collective doses and maximally exposed individual doses to the public and effective doses to crew workers were calculated by using INTERTRAN. Two transportation routes, Asakawa-machi to Okuma-machi and Iwaki-shi to Okuma-machi, were considered. The maximum radioactivity concentration in the decontamination waste was calculated to be 660 kBqkg?1 which meets the value laid down by the guidelines of Japan's Ministry of the Environment. The collective doses to the public per shipment were 1.9 10?3 person-mSv for the Asakawa route and 2.2 10?4 person-mSv for the Iwaki route. Maximally exposed individual doses to the public were 9.6 10?7 mSv for the Asakawa route and 2.7 10?5 mSv for the Iwaki route. The total effective doses to crew workers were 0.27 mSv for the Asakawa route assuming five shipments per worker and 1.07 mSv for the Iwaki route assuming 45 shipments per worker. The radiation dose levels to the public and workers evaluated in this study were much lower than the annual dose limits for the general public and radiation workers. These study results can be used to develop transportation plans and guidelines for decontamination waste transportation.

Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates.

Background:Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug.Methods:The drugs were radiolabeled with 11C (t 1/2 = 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (K P) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (V T). Unbound K P (K P u,u) was obtained by correction for the free fraction in brain and plasma.Results:After intravenous injection, the maximum radioactivity concentration (C max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C max, %ID was >2%, indicating a preferential distribution to brain. A lower C max, %ID was observed for morphine, sulpiride, and verapamil. K P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had K P u,u close to unity. For morphine, sulpiride, and verapamil, K P u,u was <0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs.Conclusions:This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates.

Absorption, Metabolism, Distribution, and Excretion of Longer Acting rFVIII (BAX 855) Following Intravenous Administration to Rats

Abstract 4358Baxter and Nektar have developed BAX 855, a PEGylated variant of Baxter's rFVIII product based on the ADVATE™ manufacturing process using Nektar's polymer technology. The absorption, metabolism, distribution and excretion (ADME) of radiolabeled PEG-rFVIII was investigated after single dose i.v. injection to male and female rats. Radiolabeled BAX 855 was synthesized by conjugation of rFVIII with tritiated [3H] PEG polymer, where several hydrogens [1H] were replaced by tritium atoms [3H] on the PEG backbone.The animals designated for the collection of excreta and animals designated for the collection of blood received a single intravenous 1 mg/kg dose of [3H] PEG-rFVIII at a dose volume of 0.68 mL/kg. The animals designated for whole body autoradiography (WBA) were administered a single intravenous 2 mg/kg dose at 1.36 mL/kg. The radioactivity dose for 1 mg/kg was 122 μ Ci/kg and 2 mg/kg for 251 μ Ci/kg. With a specific activity of 2088 IU/mg, these single doses correspond to an FVIII activity dose of 2088 and 4176 IU/kg, respectively. Urine and feces were collected for 1008 hours post-dose and selected tissues were collected for metabolite profiling. Blood was collected at specified times during 1008 hours post-dose. Blood, plasma, urine, and feces were analyzed for total radioactivity. Rats designated for WBA were killed at specified times during 168 hours post-dose and rats designated for tissue excision were killed at specified times during 1008 hours post-dose. In addition, selected plasma, urine, feces, kidney, liver and lung samples were profiled for the parent compound and its metabolites.Radioactivity was eliminated from blood and plasma with half-lives (t1/2) of 827 and 655 hours, respectively, in males, and 306 and 276 hours, respectively, in females. The distribution of drug-derived radioactivity was extensive in both males and females, with radioactivity quantifiable in blood and plasma and all matrices analyzed. The maximum concentrations (Cmax) of radioactivity for tissues were observed at the 1-, 8-, 24-, and 168-hour collections. The highest maximum concentrations of radioactivity were observed in the plasma, blood, mesenteric lymph nodes, spleen, liver, adrenal glands, and kidneys in both males and females. Radioactivity in the spleen analyzed by WBA presented a mottled appearance with most of the radioactivity in the red pulp. Elimination of radioactivity occurred primarily via urine. At 1008 hours post-dose, urine, feces, and daily cage rinse corresponded to 51.9, 38.4 and 4.01% of the dose administered to males, and 55.7, 45.0 and 3.53% of the dose administered to females. The mean overall recoveries in males and females were 97.4 and 107%, respectively.In conclusion, the results of this study show that radio-labeled PEG-rFVIII was distributed to tissues analyzed without binding to the cellular blood components and radioactivity was excreted quantitatively within 6 weeks via urine and feces. Disclosures:Stidl:Baxter Innovations GmbH: Employment. Siekmann:Baxter Innovations GmbH: Employment. Culbertson:Nektar Therapeutics: Employment. Vinson:Nektar Therapeutics: Employment. Kozlowski:Nektar Therapeutics: Employment. Shen:Nektar Therapeutics: Employment. Bossard:Nektar Therapeutics: Employment. Rottensteiner:Baxter Innovations GmbH: Employment. Dietrich:Baxter Innovations GmbH: Employment. Cook:Baxter Technology Resources, Roun Lake, IL: Employment. Turecek:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment.

Ocular Distribution of Difluprednate Ophthalmic Emulsion 0.05% in Rabbits

To evaluate ocular distribution and excretion of tritium-labeled difluprednate ((3)H-DFBA) ophthalmic emulsion 0.05% after a single or repeated instillation to pigmented rabbit eyes. (3)H-DFBA ophthalmic emulsion 0.05% was instilled in the right eyes of pigmented rabbits, in either a single or repeated quater in die (QID) for 3 days or 7 days) dose of 25 μg/50 μL. The radioactivity in right and left ocular tissues, urine, blood, plasma, and feces were measured with a liquid scintillation counter. Additionally, the distribution of radioactivity around ocular tissues was investigated with autoradiography. After a single instillation, the highest maximum radioactive concentrations were found in the cornea (2,081 ng eq./g), followed by the iris/ciliary body (926 ng eq./g), conjunctiva (330 ng eq./g), anterior retina/choroid (273 ng eq./g), sclera (222 ng eq./g), and aqueous humor (144 ng eq./mL) of treated eyes. The maximum radioactivity concentration of the posterior retina/choroid was 59 ng eq./g, and difluprednate delivered as a topical ophthalmic emulsion reached the back of the eye. However, radioactivity in untreated eyes was very low. Total radioactivity excreted in urine and feces 168 h after a single instillation was 99.5% of the total dose. Radioactivity concentration levels measured 24 h after 28 instillations were no more than twice those measured 24 h after 12 instillations. Radioactive concentrations in ocular and periocular tissues were highest at 0.5 or 1 h after a single instillation, and were mostly eliminated from these tissues by the end of the study. Radioactivity was barely detectable in the blood, with very little accumulation even after multiple doses. After instillation of (3)H-DFBA ophthalmic emulsion 0.05% in rabbit eyes, radioactivity was distributed at the anterior segment and cleared rapidly. Some radioactivity was detected in the posterior retina/choroid, suggesting that difluprednate and its metabolites reach these tissues. These results suggest that difluprednate delivered as a topical ophthalmic emulsion reached the anterior and posterior segments of the eye quickly and may be a potential treatment for ocular inflammation in these areas.

Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects

Two studies were conducted to: (i) quantify the amount of drug-related radioactivity in blood, plasma, urine and faeces following a (14)C-labelled dose of maraviroc; and (ii) investigate the pharmacokinetics, safety and tolerability of intravenous (i.v.) maraviroc and determine the absolute bioavailability of oral maraviroc. Metabolite profiling was also conducted. Data from both of these studies were used to construct a mass-balance model for maraviroc. Study 1 was an open-label study in three healthy male subjects. All subjects received a single 300-mg oral solution dose of (14)C-labelled maraviroc. Study 2 included two cohorts of subjects. Cohort 1 involved a double-blind (third party open), four-way crossover study where eight subjects received escalating i.v. doses of maraviroc (3, 10 and 30 mg) with placebo insertion. Cohort 2 involved an open, two-way crossover study where 12 subjects received 30 mg maraviroc by i.v. infusion and 100 mg maraviroc orally in random order. In study 1, blood samples and all urine and faeces were collected up to at least 120 h postdose. In study 2, blood samples were taken at intervals up to 48 h postdose. Urine was also collected up to 24 h postdose in cohort 1 only. After oral administration in study 1, maraviroc was rapidly absorbed with a plasma T(max) reached by 2 h postdose for all three subjects. The maximum concentrations of radioactivity also occurred within 2 h for all subjects. There was a higher amount of radioactivity in plasma than in blood (blood/plasma ratio approximately 0.6 for AUC(t) and C(max)). Unchanged maraviroc was the major circulating component in plasma, accounting for approximately 42% of the circulating radioactivity. Following a 300-mg (14)C-labelled maraviroc dose, means of 76.4% and 19.6% of radioactivity were recovered in the faeces and urine, respectively. The mean total recovery of dosed radioactivity was 96%, with the majority of radioactivity being recovered within 96 h postdose. Profiling of the urine and faeces showed similar and extensive metabolism in all subjects. Unchanged maraviroc was the major excreted component (33%). The major metabolic pathways were determined and involved oxidation and N-dealkylation. Intravenous doses of maraviroc (3-30 mg) were well tolerated in study 2, and drug exposure was approximately proportional to dose within the studied range. Approximately 23% of total clearance (44 l h(-1)) was accounted for by renal clearance (10.2 l h(-1)). Mean volume of distribution at steady state was 194 l. Absolute bioavailability of a 100-mg oral tablet dose, by comparison with a 30-mg i.v. dose, was calculated to be 23.1%. Maraviroc is rapidly absorbed and extensively metabolized, although unchanged maraviroc is the major circulating component in plasma and is the major excreted component after oral dosing. The pharmacokinetics of maraviroc after i.v. administration is approximately proportional over the dose range studied. Renal clearance contributes 23% of total clearance. The absolute bioavailability of 100 mg oral maraviroc is 23%.

Rapid Uptake, Metabolism, and Elimination of Inhaled Sulfuryl Fluoride Fumigant by Rats

Sulfuryl fluoride (SO(2)F(2)) is a structural fumigant gas used to control drywood termites and wood-boring beetles. The pharmacokinetics and metabolism of inhaled SO(2)F(2) were evaluated in male Fischer-344 rats exposed to 30 or 300 ppm (35)S-labeled SO(2)F(2) for 4 h. Blood, urine and feces were collected during and after the exposures and analyzed for radioactivity, (35)S-labeled fluorosulfate and sulfate, and fluoride (urine and feces only). Selected tissues were collected 7 days post-exposure and analyzed for radioactivity. During and after unlabeled SO(2)F(2) exposures, blood, brain, and kidney were collected and analyzed for fluoride ion. SO(2)F(2) was rapidly absorbed, achieving maximum concentrations of radioactivity in both plasma and red blood cells (RBC) near the end of the 4-h exposure period. Radioactivity was rapidly excreted, mostly via the urine. Seven days post-exposure, small amounts of radioactivity were distributed among several tissues, with the highest concentration detected in respiratory tissues. Radioactivity associated with the RBC remained elevated 7 days post-exposure, and highly perfused tissues had higher levels of radioactivity than other non-respiratory tissues. Radioactivity cleared from plasma and RBC with initial half-lives of 2.5 h after 30 ppm and 1-2.5 h after 300 ppm exposures. The terminal half-life of radioactivity was 2.5-fold longer in RBC than plasma. Based on the radiochemical profiles, there was no evidence of parent (35)SO(2)F(2) in blood. Identification of fluorosulfate and sulfate in blood and urine suggests that SO(2)F(2) is hydrolyzed to fluorosulfate, with release of fluoride, followed by further hydrolysis to sulfate and release of the remaining fluoride.

Pharmacokinetic profile and placental transfer of a single intravenous injection of [(14)C]chlorpyrifos in pregnant rats.

The pharmacokinetics and placental transfer of a single intravenous dose of 5.0 mg/kg (10 micro Ci/kg) ring-labeled [(14)C]chlorpyrifos were investigated in pregnant Sprague-Dawley rats at 11-13 days of gestation. Three rats were killed at 5, 15 or 30 min, or 1, 2, 4, 8, 12, 18, 24, 36, 48, 72 or 96 h after dosing. Radioactivity and 3,5,6-trichloropyridinol (TCP) were detected in all tissues 5 min after dosing. Chlorpyrifos was only found in maternal plasma and liver. Peak maternal plasma concentration of radioactivity ( micro g chlorpyrifos equivalents/ml) was 157 at 5 min, compared with 1.9 for fetal plasma at 15 min. The maximum concentrations of radioactivity ( micro g chlorpyrifos equivalents/g), detected in most tissues within 12 h of dosing, were, in descending order: liver (30), brain (29), placenta (21), and fetus (2). All peaks occurred at 5 min except for fetus and fetal plasma, which were at 15 min. TCP was detected by HPLC as the major compound identified in plasma and tissues. The maximum concentration detected was in plasma, at 12.4 micro g/ml, and for the following tissues was: liver 4.3 ng/g fresh tissue, fetus 4 ng/g, placenta 2.97 ng/g, brain 1.68 ng/g, and fetal plasma 0.52 ng/g. All TCP peaks occurred at 5 min except for fetus at 30 min and fetal plasma at 15 min. Parent chlorpyrifos was detected in maternal plasma and liver at maximum concentrations of 5.1 micro g/ml and 0.40 micro g/g, respectively, at 5 min. Chlorpyrifos was detectable in maternal plasma up to 36 h after dosing, and in liver up to 24 h after dosing. Pharmacokinetic analysis best described radioactivity, chlorpyrifos, and TCP as disappearing biexponentially from plasma and tissues. The terminal elimination half-lives of radioactivity, chlorpyrifos and TCP from maternal plasma were 16, 18, and 16 h, respectively. The results indicate that (1). chlorpyrifos undergoes a rapid metabolism to its major metabolites (TCP); (2). chlorpyrifos and its metabolites are distributed to all maternal and fetal tissues and plasma; and (3). the elimination of chlorpyrifos and TCP is slow, with redistribution from lipid stores a likely determinant of elimination rates.

Placental transfer and pharmacokinetics of a single oral dose of [14C]p-nitrophenol in rats.

The pharmacokinetics and placental transfer of a single oral dose of 100 mg/kg (10 microCi/kg, 16% of acute oral LD50) of uniformly phenyl-labeled [14C]p-nitrophenol were investigated in pregnant Sprague-Dawley rats at 14-18 days of gestation. Three animals were killed on gestation day 18, at 0.5, 1, 2, 4, 12, 24, and 48 h after dosing. Radioactivity was rapidly absorbed and distributed throughout the maternal and fetal tissues. The gastrointestinal tract contents retained 20% and 2% of the dose at 0.5 h and 4 h after dosing. The peak maternal plasma concentration of radioactivity (microg p-nitrophenol equivalent/ml) was 7.17 compared with 0.37 for fetal plasma at 0.5 h. Maximum concentration of radioactivity (microg p-nitrophenol equivalent/g fresh tissue) was detected in most tissues 0.5 h after dosing and was in descending order: kidney 23.27, liver 12.37, placenta 3.56, fetus 2.17, and brain 1.99. Radioactivity was eliminated from plasma and all tissues beiexponentially. The half-lives of elimination of 14C were 34.65 h and 69.30 h for maternal and fetal plasma, respectively. p-Nitrophenol, detected by HPLC, was the major compound identified in plasma and tissues. While p-nitrophenol disappeared biphasically from maternal plasma and kidney, it was eliminated monophasically from brain, placenta, and liver. p-Nitrocatechol and p-aminophenol were detected in the liver with peak concentrations at 0.5 h of 1.13 and 1.00 microg/g fresh tissue, respectively. While the change in the concentration of p-nitrocatechol with time was monophasic, that of p-aminophenol showed a biphasic pattern with elimination half-lives of 1.93 h and 4.95 h, respectively. Radioactivity was rapidly excreted in the urine mostly as polar metabolites, while only 3% of the dose was recovered in the feces. Radioactive materials excreted in the urine comprised: glucuronides 4%, sulfates 8%, hot-acid hydrolysates 11%, nonconjugated compounds 16%, and water-soluble metabolites 61%. This study demonstrated that although orally administered p-nitrophenol is a rapidly absorbed and excreted compound, it is transported to the maternal brain and the fetus and may pose a health risk following exposure to toxic doses during pregnancy.

Placental transfer and pharmacokinetics of a single dermal dose of [14C]methyl parathion in rats.

The pharmacokinetics and placental transfer of a single dermal 10.0 mg (10microCi)/kg dose of uniformly phenyl-labeled [14C] methyl parathion (0,0-dimethyl 0-4-nitrophenyl phosphorothioate) were investigated in pregnant Sprague-Dawley rats at 14-18 days of gestation. Three rats were killed at each time interval: 1, 2, 4, 12, 24, 48, 72, and 96 h after dosing. Radioactivity disappeared biexponentially from the administration sites, which retained 50% and 3% of the dose after 1 h and 96 h, respectively. Most of the absorbed radioactivity was excreted in the urine (91%). Only 3% of the 14C was recovered in the feces. One h after the administration, radioactivity was detected in all tissues, including fetal tissue. The peak maternal plasma concentration of radioactivity (ng methyl parathion equivalent/ml) was 1005 at 2 h, compared to 318 ng for fetal plasma at 12 h. The maximum concentrations of radioactivity (ng methyl parathion equivalent/g), detected in most tissues within 12 h of dosing, were, in descending order: adipose tissue (67,532), kidney (1,571), spleen (1,256), spinal cord (1,004), heart (729), liver (706), brain (546), placenta (389), and fetus (256). The metabolism studies showed that methyl parathion, detected by HPLC, was the major compound identified in plasma and tissues. The maximum concentration detected was in plasma, at 513 ng/ml, and in the following tissues (ng/g fresh tissue): kidney (819), fetus (668), placenta (394), liver (375), and brain (282). The metabolite methyl paraoxon was detected in maternal brain and liver at maximum concentrations (ng/g fresh tissue) of 135 and 64 after 12 h and 4 h respectively, while p-nitrophenol was only detected in liver at a maximum concentration of 21 ng/g 72 h after dosing. Pharmacokinetic studies showed that methyl parathion disappeared monoexponentially from plasma and tissues. The half-life of elimination of methyl parathion from plasma was 11 h corresponding to a constant rate value of 0.06 h(-1). The results indicate that skin and placenta are poor barriers against methyl parathion permeability, resulting in a rapid and extensive dermal absorption of this insecticide and extensive placental transfer. This is indicated by the relative residence (R(R)) of methyl parathion in the plasma, which was largest in the placenta followed by the fetus. This study suggests that pregnant women and fetuses may be at risk of cholinergic toxicity following dermal exposure to methyl parathion.

Dose-dependent kinetics and metabolism of 1,2-dichlorobenzene in rat: effect of pretreatment with phenobarbital.

1. Toxicity of halobenzenes has been ascribed mainly to their epoxides, but recent studies with bromobenzene have shown that secondary quinone metabolites are also involved in the alkylation of hepatic proteins. However, the relative contribution of the quinones and the epoxides to the toxicity of halobenzenes is still unclear. In order to investigate the relation between metabolism and toxicity of 1,2-dichlorobenzene (1,2-DCB), the biotransformation, tissue distribution, blood kinetics, and excretion at three different oral dose levels (5, 50 and 250 mg/kg) of the radiolabelled compound were investigated in the male Wistar rat. A toxic dose level (250 mg/kg, as demonstrated by Allis et al. 1992) was included. 2. The major route of elimination (75-85%) was renal excretion. Excretion via the faeces ranged from 19% for the low dose to 7% for the high-dose level. Excretion was nearly complete within 24 h for the low and mid-dose level, and within 48 h for the high-dose level. Pretreatment with phenobarbital resulted in a more rapid excretion for the high-dose level and an overall higher urinary excretion. Biliary excretion was 50-60%, indicating a considerable enterohepatic circulation. 3. Highest concentrations of radioactivity after a low dose were found in fat, liver and kidney at 6 h after administration, and then declined rapidly. 4. The maximum concentration of radioactivity in blood was reached at 6-8 h for the low and mid-dose level, and at 24 h for the high-dose level. The concentration of parent chemical was essentially constant during 3 and 6 h for the mid- and high-dose level respectively, and then declined. 1,2-DCB could only be detected in blood in the first 2 h after administration of the 5-mg/kg dose. 5. The major route of biotransformation was via the glutathione pathway and 60% of the urinary metabolites were mercapturic acids. In addition, the major metabolites in bile were conjugates of glutathione. Other major metabolites in urine were the sulphate conjugates of 2,3- and 3,4-dichlorophenol (DCP). No significant differences in metabolic profiles were observed between the different doses. Induction with phenobarbital resulted in the increased excretion of sulphate conjugates (30% in the induced rat, 20% in the control rat), mainly the conjugate of 3,4-DCP. 6. The mercapturic acids in urine and glutathione conjugates in bile were epoxide-derived, whereas no quinone- or hydroquinone-derived metabolites were observed. Therefore the hepatotoxicity of 1,2-dichlorobenzene is assumed to be related, at least partly, to the presence of the intermediate arene oxide. A high dose of 1,2-DCB will result in depletion of GSH, followed by oxidative stress and possible binding to macromolecules.

Studies on Metabolic Fate of 14C-RU44570: Placental Transfer, Transfer into Milk, Absorption Site and Repeated Dosing in Rats, and Metabolism in Rats and Dogs.

The placental transfer, excretion into milk and site of absorption of 14C RU44570 were investigated in normal rats and male rats with ligated loops of gas trointestinal tract. The absorption, distribution, metabolism and excretion of 14C-RU44570 were examined during and after repeated oral administration to male rats at a daily dose of 1 mg/kg for 21 days. In addition, the metabolism of 14C-RU44570 in male dogs was studied after a single oral administration at a dose of 1 mg/kg. 1. In pregnant rats, receiving orally 1 mg/kg of 14C-RU44570 on the 18th days gestation, the level of radioactivity in fetus was lower than that in maternal plasma, and then ratio of the radioactivity was only 0.01% of the dose. In most of fetal tissues, the radioactivity levels decreased rapidly, however, relatively higher level was observed in the lung at 24 hr after the dosing. 2. The maximum concentration of radioactivity in the milk was found at 8 hr following oral administration of 14C-RU44570 at 1 mg/kg to lactating rats. The radioactivity concentration decreased with a half-life of 43 hr. 3. In a study of gastrointestinal absorption in situ, the most of 14C-RU44570 was found to be absorbed from duodenum and jejunum. 4. During repeated daily oral administration, plasma concentration of radioactivity at 24 hr did not increase significantly after the 7th dose. The elimination half-life of plasma radioactivity after the final dosing was comparable to that after the 1st dose. The radioactivity in most of tissues reached a steady state after the 7th or 14th dose during repeated administration. At 672 hr after the final dose, higher level of radioactivity was observed in the lung, while the concentration in other tissues decreased to lower level or even below the detection limit. 5. In plasma, urine, feces, bile or tissues, RU44403, which is a pharmacologically active form, was mainly found after both of single and repeated oral administration to male rats. Unchanged compound, RU44570, was not observed in plas ma and tissues. In addition, any conjugates of the metabolites were not found. 6. In plasma, urine or feces of male dogs, RU44403 was found as a major metabolite, however, RU44570 was also observed in dog plasma.

Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers.

FCE 22891 is a prodrug of the penem antibiotic FCE 22101 and is suitable for oral administration. The pharmacokinetics of FCE 22891 were investigated in four healthy male volunteers following the oral administration of 500 mg of [14C]FCE 22891. Levels of radioactivity in plasma were always higher and persisted for longer than those of FCE 22101. The time to the maximum concentration of radioactivity in plasma generally coincided with that of FCE 22101. The respective values for the maximum concentrations of radioactivity in plasma were, on average, 8.57 +/- 2.95 micrograms equivalent/ml and 2.97 +/- 2.05 micrograms/ml. Over a 5-day period, mean urinary and fecal recovery of radioactivity accounted for 53.2 and 41.0% of the dose, respectively. The average amount of FCE 22101 excreted in urine and feces corresponded to 9.0 and 1.6% of the dose, respectively. The urinary recovery of the open-ring metabolite P1 and of its 5-S epimer P2 accounted for about 6.5 and 1.2% of the dose, respectively. Other chromatographic peaks corresponding to nonidentified compounds accounted for about 14.0% (polar metabolite fraction; peak P), 3.7% (less polar fraction; peak X), and 15.4% (least polar fraction) of the dose. Elimination of radioactivity and FCE 22101 in urine was rapid. Intersubject variability in the kinetics of total radioactivity in plasma was far less than that observed for FCE 22101. The results of the present study support suggestions that presystemic metabolism of FCE 22101 and/or transformation of the prodrug to compounds other than FCE 22101 are the main cause of intersubject variability in the kinetics of FCE 22101 produced in plasma following oral administration of its prodrug.

Metabolic Fate of Nifedipine Suppository in Rats.

14C-Nifedipine suppository was administered intrarectally (i.r.) in rat, in order to investigate its absorption, distribution, metabolism and excretion, comparing with the data after intravenous (i.v.) or oral (p.o.) administration of 14C nifedipine solution. Also the metabolic fate was investigated after daily dosing of 14C-nifedipine suppository. 1. After i.v. administration, the level of radioactivity in the blood decreased biphasically, with the corresponding half-lives of 1. Ohr and 38.5hr, respectively. The maximum concentration of radioactivity in the blood at 45min after i.r. administration was higher than that observed after p.o. application. 2. The excretion ratio of radioactivity in the urine and feces was similar among those 96hr after i.r., i.v. and p. o. administration ; 51 ?? 53 and 46 ?? 41% of dose in the urine and feces, respectively. 3. The distrubution of radioactivity in tissues after i.r. administration was similar to that of p.o. administration except that in gastro-intestinal tract. At 45min after i.r. administration, the tissue levels of radioactivity were higher in the liver, kidney and plasma than blood, and very low in brain. 4. Metabolites in the plasma and urine after 3 different administration routes were simil ar. Unchanged 14C-Nifedipine was found in plasma at the early period after administration, but not in urine. 5. During the repeated intrarectal administration, the level of radioactivity in the blood at 24hr after daily dosing continued to increase till the 7th day, then reached to the plateau. The excretion rates of radioactivity in the urine and feces were nearly constant during the period of repeats, and were similar to those after a single administration. The tissue levels of radioactivity appeared not to be accumulated in the tissues.

Studies on the Metabolic Fate of Betamethasone Butyrate Propionate. (IV). Absorption, distribution and excretion in rats and rabbits.

3H-BBPをラットおよびウサギに0.25mg/kgで経皮(非密封法)，あるいは1mg/kgで皮下投与し，その吸収，分布，排泄について検討し，以下の結果を得た．1．軟膏またはクリームを正常皮膚動物に経皮投与した際，全身系への経皮吸収率は雄性ラットでは約3～5%，雌性ラットでは約14%，また雄性ウサギでは約14%であった．損傷皮膚雄性ラットでは約30～50%であった．2．正常皮膚動物における血液または血漿中放射能濃度の最高到達時間および最高値は雄性ラット:24時間，0.6～0.8ng/ml，雌性ラット:8時間，4.7ng/ml雄性ウサギ:13時間，3.0ng/mlであった．また，損傷皮膚雄性ラットでは5時間，8.6～15.7ng/mlであった．3．主排泄経路はラットでは糞であったが，ウサギの尿糞中排泄率の割合はほぼ同じであった．4．正常皮膚雄性ラットにおける組織内放射能濃度は，投与後8時間あるいは24時間に最高濃度を示し，肝臓，腎臓副腎，貯精嚢および膀胱に高い濃度が認められた．各組織からの消失は緩慢であり，特に血液かbの消失が遅延した．塗布部皮膚のミクロオートラジオグラムより，BBPの経皮吸収経路として付属器官を経由するルートと経表皮ルートが確認された．5．正常皮膚雄性ラットに7回反復投与した際，毎回投与後24時間における血液および組織中放射能濃度は，投与回数に伴い上昇する傾向を示した．7回投与後の血液および組織中からの放射能の消失は緩慢であったが，7回投与後の尿および糞中排泄率は単回投与群と相違が認められなかった．6．妊娠ラットに3H-BBPを皮下投与した際の全身オートラジオグラムより，胎盤通過性が確認されたものの，放射能が胎仔組織に残留する傾向は認められなかった．

Studies on the metabolic fate of 15(R)-15-methylprostaglandin E&lt;SUB&gt;2&lt;/SUB&gt; (Arbaprostil) in rats (IV): Blood level and excretion after administration of 15(S)-15-methylprostaglandin E&lt;SUB&gt;2&lt;/SUB&gt;

15(R)-15-Methylprostaglandin E2 (CU-83) is converted to its epimer (CU-83(S)) in gastric acid after oral administration. In this study, the blood level and excretion of radioactivity were investigated in rats after intravenous and oral administration of 3H-CU-83(S) at a dose of 25 μg/kg. After intravenous dosing, the peak blood concentration of radioactivity, of 25.74 ng eq./ml, was observed at 45 min. Thereafter, the concentrations of radioactivity area under the blood concentration-time curve (AUC) during 72 hr period after the dosing was 135.42 ng eq.·hr/ml. After oral dosing, the maximum concentration of radioactivity in blood was 4.10 ng eq./ml at 3 hr and then declined bi-exponentially with the following half-lives of 4.46 and 26.83 hr. AUC was 48.62 ng eq.·hr/ml for 72 hr. After intravenous dosing, excretion of radioactivity was 30.52 % of the dose in urine and 60.42 % in feces during 72 hr. After oral dosing, excretion of radioactivity was 40.34 % in urine and 69.24 % in feces within 72 hr.

Studies on the metabolic disposition of ethyl eicosapentaenoate(EPA-E) in rats and dogs.

Plasma level, tissue distribution and excretion of ethyl eicosapentaenoate(EPA-E) were studied after oral administration of 14C-uniformly labelled EPA-E to rats and dogs and the following results were obtained. 1. The maximum concentration of radioactivity in plasma was obtained at 6-9 hr and at 24hr after dosing in rats and dogs, respectively. The elimination of radioactivity from plasma was biphasic. 2. The radioactivity administered to rats was mainly excreted in expired air. 3. The cumulative biliary excretion of radioactivity was 2.9 % of the dose within 24 hr. 4. The concentration of radioactivity in each tissue reached maximum at 9-24hr after dosing except for brain, fat, skin, muscle and aorta in which the concentration reached maximum at 1 week and subsequently decreased gradually. The elimination rate of radioactivity from each tissue was almost as same as that from plasma or a little slower. 5. Foeto-placental transfer of radioactivity in the pregnant rats at 12 and 19 days of gestation was observed but its extent was low. 6. The milk level of radioactivty in the lactating rats reached maximum at 24 hr and was 6-14 times higher than that in the maternal blood after 24hr. 7. Radioactive substances in plasma were mainly bound to plasma protein in rats and dogs. 8. During daily repeated administration to rats, the concentration of radioactivity in plasma at 24hr after every dosing reached plateau level within the 12 days but that in each tissue increased with increase in the number of doses. No remarkable difference in elimination half-lives of radioactivity in each tissue between the single and repeated dosing was observed.

Influence of nuclear reactor accident at Chernobyl' on the environmental radioactivity in Toyama

The environmental radioactivity caused by the reactor accident at Chernobyl' was investigated from May 7 to May 31 of 1986 in Toyama. Measurement of radioactivities in airborne particles, rain water, drinking water, milk, and mugwort are carried out by gamma-ray spectrometry (pure Ge detector; ORTEC GMX-23195). Ten different nuclides (103Ru, 106Ru, 131I, 132Te-I, 134Cs, 136Cs, 137Cs, 140Ba-La) are identified from samples of airborne particles. In the air samples, a maximum radioactivity concentration of each nuclide is observed on 13th May 1986. The time of the reactor shut-down and the flux of thermal neutron at the reactor were calculated from 131I/132I and 137Cs/134Cs ratio. The exposure dose in Toyama by this accident is given as follows: internal exposure; [thyroid] adult-59 microSv, child-140 microSv, baby-130 microSv, [total body] adult-0.2 microSv, child, baby-0.4 microSv, external exposure; 7 microSv, effective dose equivalent; adult-9 microSv, child-12 Sv, baby-11 microSv.

Prostaglandin F-2 alpha is transferred from the uterus to the ovary in the sheep by lymphatic and blood vascular pathways.

[3H]Prostaglandin F-2 alpha (PGF-2 alpha) was infused into a uterine lymphatic vessel or a uterine vein for up to 1 h, or injected into the uterine lumen of anaesthetized non-pregnant sheep 7-15 days after oestrus. After an intraluminal injection, labelled PGF-2 alpha was recovered in uterine lymph and peak radioactivity was reached 50 min after injection. [3H]PGF-2 alpha infused at a constant rate into a uterine lymphatic vessel resulted in a maximum concentration of radioactivity in plasma which was 5.6- and 1.7-fold higher in the adjacent utero-ovarian and ovarian vein, respectively, than in carotid arterial plasma. Estimation of the amount of infusate transferred from a lymphatic into ovarian venous blood gave a value (0.4%) similar to that for transfer from a uterine vein (0.3%). Evidence for local transfer was substantiated by the presence of significantly higher concentrations of 3H-labelled compounds in the ovary and corpus luteum adjacent to the site of intra-lymphatic infusion compared with those in the opposite organs. The concentrations in the adjacent ovary and corpus luteum were significantly greater when an intra-lymphatic rather than intra-uterine vein infusion was adopted. The results show that [3H]PGF-2 alpha is transferred locally from uterine lymphatic vessels into the adjacent ovary, corpus luteum and ovarian vein.