Differential distribution and placental transport of 2- and 3-t-[methyl-14C]butyl-4-hydroxyanisole(BHA) in pregnant mice

The placental transport and localization in fetal and maternal tissues of ¹⁴C-BHA isomers, 2-t-[methyl-¹⁴C]butyl-4-hydroxyanisole (2-BHA) and 3-t-[methyl-¹⁴C]butyl-4-hydroxyanisole (3-BHA), were studied in pregnant mice by whole-body autoradiography techniques. BHA isomers were given (iv 50 μCi/100 g as a tracer dose) to pregnant mice at Day 11 (organogenesis) and Day 18 (postorganogenesis) of gestation. Peak levels of radioactivity occurred in various tissues 1–4 hr after iv administration of both isomers. 3-BHA and its metabolites have a higher affinity to fatty tissues and livers of pregnant mice. The concentration of radiocarbon in maternal liver and brown fat following treatment with ¹⁴C-3-BHA was much higher than the radioactivity concentration in the corresponding tissues of mothers treated with 2-BHA. On the other hand, the fetal concentration of radioactivity was higher in animals treated with 2-BHA than in those treated with 3-BHA. The radioactivity derived from both isomers accumulated in the fetal gastrointestinal tract. In both groups the radioactivity accumulated in the maternal nasal cavity and mucosa and the gastrointestinal contents. At 24 hr after treatment, retention of radioactivity in maternal lungs, amniotic fluid, and fetal gastrointestinal tissues was observed. Results from this study indicate that there are differences in the magnitude and extent of placental transport of 3-BHA and 2-BHA. Differences also exist in maternal organ uptake and radioactivity distribution of both isomers. Findings from this study are consistent with pharmacological differences existing between the isomers.     

Disposition and metabolism of double-labeled [3H and 14C] N-methyl-2-pyrrolidinone in the rat

The disposition of N-methyl-2-pyrrolidinone (NMP) was studied in the rat using tritium-labeled ([4-3H]NMP) and carbon-14-labeled ([methyl-14C]NMP and [ring-14C]NMP) radioisomers. Male Sprague-Dawley rats were administered a single intravenous dose (45 mg/kg) of 5.0 microCi of 3H or 14C for single-labeled disposition studies or 5.0 microCi of 3H and 2.5 microCi of 14C for double-labeled studies (2:1 ratio, 3H:14C). Plasma levels of intact NMP were analyzed by HPLC through 6 hr after dosing and suggested a rapid distribution phase followed by a slow elimination phase. The half-life for the terminal elimination phase from plasma was about 7 hr for both 14C-isomers and 9.9 hr for the 3H-isomer. The major route of excretion of radioactivity was via the urine and accounted for about 70% of the dose within 12 hr. After 24 hr, cumulative excretion in urine represented about 80% of the dose. The 2:1 ratio of administered 3H:14C was maintained in urine through 6 hr. Measurement of radioactivity in tissues at 6 hr showed the liver and intestines to contain the highest accumulations of radioactivity, representing approximately 2% and 3% of the dose, respectively. Tissue distribution of radioactivity was similar for all three radiolabeled isomers and showed that NMP was extensively distributed to all major organs. Radiomonitored HPLC analyses of urine revealed the presence of one major and two minor metabolites. The major metabolite, representing 70-75% of the administered dose of radioactivity, was found to retain all three radiolabeled positions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential Distribution and Placental Transport of 2- and 3-t-[methy/-14C]Butyl-4-hydroxyanisole(BHA) in Pregnant Mice

The placental transport and localization in fetal and maternaltissues of ¹⁴C-BHA isomers, 2-r-[methy/-¹⁴C]butyl-4-hydroxyanisole(2-BHA) and 3-/-[methy/-¹⁴Clbutyl-4-hydroxyanisole (3-BHA),were studied in pregnant mice by whole-body autoradiographytechniques. BHA isomers were given (iv 50 µCi/100 g asa tracer dose) to pregnant mice at Day 11 (organogenesis) andDay 18 (postorganogenesis) of gestation. Peak levels of radioactivityoccurred in various tissues 1-4 hr after iv administration ofboth isomers. 3-BHA and its metabolites have a higher affinityto fatty tissues and livers of pregnant mice. The concentrationof radiocarbon in maternal liver and brown fat following treatmentwith ¹⁴C-3-BHA was much higher than the radioactivity concentrationin the corresponding tissues of mothers treated with 2-BHA.On the other hand, the fetal concentration of radioactivitywas higher in animals treated with 2-BHA than in those treatedwith 3-BHA. The radioactivity derived from both isomers accumulatedin the fetal gastrointestinal tract. In both groups the radioactivityaccumulated in the maternal nasal cavity and mucosa and thegastrointestinal contents. At 24 hr after treatment, retentionof radioactivity in maternal lungs, amniotic fluid, and fetalgastrointestinal tissues was observed. Results from this studyindicate that there are differences in the magnitude and extentof placental transport of 3-BHA and 2-BHA. Differences alsoexist in maternal organ uptake and radioactivity distributionof both isomers. Findings from this study are consistent withpharmacological differences existing between the isomers.     

The absorption and distribution of 14C-bacitracin in rainbow trout (Salmo gairdneri) after a single oral dose, as observed by whole body autoradiography

This study was performed to investigate the absorption, distribution and elimination of orally given radiolabelled bacitracin methylene disalicylate (BMD) in rainbow trout kept in salt water. The level of radioactivity in skeletal muscle tissue remained low, but stable throughout the experiment, while radioactivity in bile and liver tissue increased for about 48 hr, before decreasing. There was a trapping of BMD and/or its metabolites in excretory kidney tissue, where the amount of radioactivity continued to increase when radioactive material was being removed from other tissues. The maximum concentration found in excretory kidney tissue was about 7 times as high as the maximum concentration found in the liver. Even though there is no appreciable absorption of BMD from the gastrointestinal tract in homoiotherms, we found the absorption in rainbow trout to be significant.     

Tissue distribution and fate of budesonide in the mouse

The tissue distribution and pharmacokinetics of 3H-budesonide were studied in the mouse after intravenous administration. The drug was rapidly (t1/2 alpha = 0.062 hrs) and extensively distributed into tissues and organs (V beta = 20.3 l/kg and Vss = 9.4 l/kg). The short elimination half-life (t1/2 beta = 1.55 hrs) and high blood clearance (Cl = 9.04 l/hr/kg) demonstrated a rapid elimination of budesonide from the body. Whole-body autoradiography showed very high amounts of radioactivity in the excretory organs liver and kidney. Also in the lung and lymphatic tissues high amounts of radioactivity were noted. The adrenal cortex but not the medulla was heavily labelled. Radioactivity passed the blood-placenta barrier and to some extent the blood-brain barrier. The identity of the radioactivity in some organs was analysed by liquid chromatography. At all times after dosing (up to 4 hours), the dominating part of the lung, spleen and brain radioactivity was attributable to unchanged budesonide. After 60 min., the dominating part of the kidney radioactivity was identified as polar metabolites of budesonide. The liver radioactivity was at all observation times found to consist mainly of polar metabolites, reflecting the efficient liver biotransformation of budesonide.     

Toxicokinetics of a Single 50 mg/kg Oral Dose of [2,3-14C]Acrylamide in White Leghorn Hens

A single oral dose of [2,3-¹⁴C]acrylamide (50 mg/kg) was administeredin water to adult white leghorn hens. Seven groups of threehens were euthanized between 2 and 120 hr after administration.Within 12 hr, the hens excreted 70% of the administered dose,and more than 99% within 48 hr. Blood, plasma, liver, and musclecontained the greatest percentage of administered dose at 4hr after dosing. Less than 0.02% of the administered dose appearedin brain at any time. Radiolabel accumulated in the eggs, with0.52% of the administered dose accumulated within 5 days. Bindingof radiolabel to erythrocytes was minimal. Elimination of radiolabel from all tissues were biphasic. Terminal eliminationhalf-lives for 14 were longer than 10 days, at which time lessthan 0.2% of the administered dose remains in the tissues. Distributionhalf-lives for ¹⁴C were longest for whole blood and shortestfor kidney. Radioactivity in the blood and plasma reached apeak at between 4 and 12 hr. Most of this radioactivity wasidentified as acrylamide, which disappeared biexponentiallywith terminal elimination half-lives longer than 10 days. Distributionhalf-lives for acrylamide were longest in brain and shortestin whole blood. These results show that orally administeredacrylamide is poorly absorbed and rapidly eliminated from hensand accumulates in their eggs in a nonextractable form.     

Comparative tissue distribution and excretion of orally administered [3H]diacetoxyscirpenol (anguidine) in rats and mice

A quantitative comparison of tissue distribution and excretion of an orally administered sublethal dose of [3H]diacetoxyscirpenol (anguidine) was made in rats and mice 90 min, 24 hr, and 7 days after treatment. Total recoveries of 95-100% were obtained. Approximately 90% of the dose was excreted in urine and feces during the first 24 hr with a feces:urine ratio of about 1:4.5 in both species. Carcass and tissue radioactivity dropped rapidly during the first 24 hr but remained relatively constant at low, but detectable, levels (1.5-3.5% of dose) over the course of the experiment. Few substantive interspecies differences were noted in tissue distribution. At 90 min the highest percentage of dose was in tissues involved in sequestering diacetoxyscirpenol because of high body water/lipid content (carcass, skin) or the absorption (stomach, small intestine), metabolism (liver), or excretion (kidney) of the toxin. The rank order of these tissues was generally stable over the course of the experiment. When data were expressed as specific radioactivity (dpm/g tissue) instead, the carcass and skin dropped from the top rank tissues at 90 min and were replaced by the spleen and cecum. At 24 hr and 7 days the top-ranked order of tissues shifted to include organs associated with trichothecene-induced toxicity such as the lymphohematopoietic system (spleen, thymus, and femur bone marrow), heart, and testis (in mouse) as well as the cecum and large intestine. In addition, the rate of loss of radioactivity with time generally did not decrease as rapidly in these target organs as observed in liver, kidney, skin, and carcass. Brain radioactivity, though very low, also diminished relatively slowly. Significant differences in specific radioactivity which did occur between the rat and mouse tended to occur in target organs and with the higher levels present in the mouse. These data were discussed in terms of interspecies differences in lethality and target organ toxicity.     

Urinary pharmacokinetics of physostigmine in the rat

Urinary pharmacokinetics of 3H-Physostigmine (Phy) were studied in rat after an intramuscular administration of 650 micrograms/kg. Urine was collected at 0-1, 1-2, 2-4, 4-6, and 6-24 hr and every 24 hr for seven days. The rats were sacrificed by decapitation and the tissues were analyzed for radioactivity. Less than one percent (.87%) of the dose remained in tissues after the seventh day. Liver, followed by kidney, accounted for the highest activity compared to other tissues. The amounts of 3H-Phy and metabolites were determined by HPLC and the rapid decline of Phy in urine was observed. Most of the radioactivity found in the urine was due to metabolites (47% of dose in 24 hr) indicating extensive metabolism. The cumulative percent of radioactivity excreted in the urine was 30.3 +/- 12.6% in 6 hr, 44.4 +/- 13.1% in 24 hr which increased to 52.7 +/- 12.0% after seven days. Urinary elimination rate constant (Ku) of Phy was found to be .051 +/- .009 hr-1 indicating that the urinary elimination of Phy accounted for a minor part (2.5-4.%) of the systemic elimination.     

Disposition of rubratoxin B in the rat

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

Disposition, pharmacokinetics, and metabolism of a dermal dose of [14C]2,5-hexanedione in hens

A dermal dose of 50 mg/kg (7.5 microCi/kg) of [14C]2,5-hexanedione (2,5-HD) was applied on a protected area on the backs of hens. Five groups of three hens were killed after 4, 8, 24, 36, and 48 hr. 2,5-HD disappeared monoexponentially from the application site with a half-life of 6 hr. After 48 hr, 35% of the radioactivity was expired as volatile material, largely as 2,5-HD. The combined urinary fecal excreta accounted for 15% of the eliminated radioactivity, while the 14CO2 accounted for 11.9% of the radioactive dose. The highest concentration of 14C was detected in the bile. Among tissues analyzed, liver and kidney contained the highest concentrations of radioactivity, whereas the brain, spinal cord, and peripheral nerves showed smaller concentrations. The half-lives for the elimination of 14C were longest for muscle (71 hr) and shortest for adipose tissue (12 hr), while the remaining tissues showed half-lives ranging from 20 to 30 hr. Radioactivity in the plasma reached a peak at 4 hr. Most of this radioactivity was identified as 5-hydroxy-2-hexanone followed by 2,5-HD and 2,5-dimethylfuran; these chemicals then disappeared biexponentially with terminal half-lives of 7.6 hr, 12.6 hr, and 28.6 hr, respectively. 2,5-HD was the most accounted chemical found in the liver, lung, and kidney, while 5-hydroxy-2-hexanone was found to be most abundant in the combined urinary-fecal excreta.     

The absorption and excretion of butylated hydroxyanisole in beagle dogs

Recent studies have indicated that administration of [14C]butylated hydroxyanisole (BHA) to rats, either orally or by intraperitoneal (i.p.) injection, resulted in high retention of radioactivity in the forestomach. The present study was undertaken to investigate the fate of [14C]BHA in non-rodents. 2 Groups of 5-mth-old male beagle dogs were fed a diet containing either 3% or 0.03% BHA for 7 days, and were injected i.p. with 3-tert-[methyl-14C]butyl-4-hydroxyanisole (Amersham International) at a dose of 30 muCi/kg. On the 7th day after [14C]BHA injection, all dogs were killed after fasting overnight, and the liver, kidney, heart, fat tissue and stomach were collected for radioanalysis. An additional 3 beagles served as control group. The fate of BHA after the single i.p. injection of [14C]BHA was examined by the determination of 14C-radioactivity in whole body, blood, urine, feces and several tissues. Blood, urine and feces samples were collected daily for 7 days. Blood samples were collected at intervals for 24 h. BHA was rapidly taken up in the bloodstream, and 50-80% of the total radioactivity was recovered in the urine within 2 days. 15-30% Appeared in the feces within 2 days. The tissue distribution of radioactivity 7 days after [14C]BHA injection showed only a small portion remaining in the stomach (0.16-0.19% of dose/g), liver (0.3-1.7%) and other tissues (0.02%). The radio-activity was almost evenly distributed in the three parts of the stomach (cardia, corpus and pylorus). These findings are in contrast with the previous data in rats that BHA can accumulate in high concentrations in the forestomach.     

Evidence for a different metabolic behaviour of cytidine diphosphate choline after oral and intravenous administration to rats

Radioactivity plasma decay was studied in rats after intravenous and oral administration of cytidine diphosphate [methyl-14C]choline at doses of 25 and 300 mg/kg. The kinetics fitted well with a two compartment open model and showed a long lasting elimination phase with a half-life ranging from 2.0 to 2.6 days for the two doses and the two administration routes. Absorption of cytidine diphosphate choline radioactivity was complete after oral treatment with the low dose and accounted for 94.5% of the dose when 300 mg/kg of cytidine diphosphate [methyl-14C]choline were administered. However the distribution of radioactivity in tissues, urine and expired air suggest metabolic differences, at least from a quantitative point of view, between the oral and intravenous treatments. In particular, the higher excretion of radioactivity associated with trimethylamine in urine found when cytidine diphosphate [methyl-14C]choline was given orally, suggest that the compound may be metabolized, at least in part, previous to its gastrointestinal absorption.     

Disposition of 3,3′-dichlorobenzidine in the rat

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

Metabolism of 2- and 3-tert-butyl-4-hydroxyanisole in the rat (III): Metabolites in the urine and feces

The urinary and fecal metabolites of orally administered 2-tert-butyl-4-hydroxyanisole (2-BHA) and 3-tert-butyl-4-hydroxyanisole (3-BHA) in rats were identified. Samples of 2-day pooled urine and feces of rats given a single intragastric dose of 1 g/kg body wt of tert[butyl-14C]3-BHA (*Bu-3-BHA). tert[butyl-14C]2-BHA (*Bu-2-BHA), [methyl-14C]3-BHA (*Me-3-BHA) or [methyl-14C]-2-BHA (*Me-2-BHA) were analyzed by comparing thin-layer chromatography (TLC) retentions with authentic standards. Conjugated metabolites were identified after enzymatic hydrolysis. Proton magnetic resonance spectroscopy and electron impact mass spectrometry were used for confirmation of the authentic standards. In rats given 3-BHA, a major metabolite in the urine was 3-BHA-glucuronide with a smaller amount of tert-butylhydroquinone (TBHQ)-sulfate, while unchanged 3-BHA and 3-BHA-glucuronide were detected in the feces. In rats given 2-BHA, the main metabolites were the sulfate conjugates of 2-BHA, 4-tert-butyl-5-methoxy-1,2-benzoquinone (2-TBOQ) and the glucuronide of 2-BHA in the urine, while unchanged 2-BHA was found in the feces.     

Absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after low dose dermal exposure

Human dermal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) occurs through contact with soil and paper products. In a previous study, relative percutaneous absorption of TCDD increased as the dose decreased (Brewster et al., 1989). To determine the rate of absorption of a low dose of TCDD, absorption, distribution, and elimination were examined at 1, 4, 8, 12, 24, 48, 72, and 120 hr after dermal application of 200 pmol (111 pmol/cm2) [3H]TCDD to 10-week-old male Fischer 344 rats. The compound was applied over a 1.8 cm2 area of the interscapular region of the back in 60 microliters acetone and covered with a perforated cap; animals were held in individual metabolism cages. Within 120 hr after dosing, 82 pmol (26 ng) of TCDD was absorbed. Absorption kinetics appeared to be first-order; the absorption rate constant was 0.005 hr-1. At each time point, greater than 70% of the radioactivity detected in the application site could be removed by swabbing with acetone. The time-related increase in the amount of TCDD in liver and fat closely paralleled the amount absorbed, while the percentage of the administered dose detected in the blood was never greater than 0.3%. Thus, absorption of a low dose of TCDD through the skin is extremely slow and appears to be a first-order process.     

Disposition of flavodilol in laboratory animals

The disposition of flavodilol, a novel antihypertensive agent, was investigated in rats, rabbits, and dogs following iv or oral administration of 14C-flavodilol or unlabeled drug. Peak, plasma levels occurred within 6 hours of an oral dose in all three species. Following an iv dose, plasma elimination half-lives of flavodilol in rats, rabbits, and dogs were 3.0, 3.0, and 4.0 hr, respectively. Total body clearances were 0.71 liter/hr/kg for the rat, 1.89 liters/hr/kg for the rabbit, and 3.07 liters/hr/kg for the dog. Renal clearances were a small fraction of total clearance at 0.042, and 0.114 liter/hr/kg for the rat and dog, respectively, suggesting extensive nonrenal clearance. The volumes of distribution of 3.04 for the rat, 8.10 for rabbit, and 18.13 liters/kg for dog are large, suggesting significant extravascular distribution of flavodilol. Following 10 and 50 mg/kg po doses of 14C-flavodilol in rats, recovery of total radioactivity after 79 hr was 100.7% and 88.4% of the dose, respectively, most of which was recovered in the feces (77.5% and 66.6%, respectively). Tissue distribution studies of 14C in rats at 1.5, 5, 24, and 48 hr after a single po dose of 10 mg/kg 14C-flavodilol showed that the majority of the radioactivity was in the gastrointestinal tract and organs of elimination at all time points. Less than 1% of the dose remained in the body at 48 hr. 14C-Flavodilol was administered to rats iv at 1 mg/kg and orally at 10 mg/kg to assess comparative (label vs. nonlabel) absorption and distribution characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)     

葛根有效成分的代谢研究——Ⅱ.14C-黄豆甙元在大鼠体内的吸收、分布和消除

本文采用纸片液体闪烁计数法研究了¹⁴C-黄豆甙元在大鼠体内的吸收、分布和消除。大鼠口服¹⁴C-黄豆甙元30分钟,血液即可测出放射性,6～8小时达高峰,以后缓慢下降。口服给药吸收不完全,由实验推论约有64.6%放射性可被吸收。静脉注射后,血放射性消失曲线分为快、慢两个时相,其生物半衰期分别为13分钟和42分钟。放射性在肾、肝含量最高,血浆、肺、心次之,肌肉、脾、睾丸、脑较低。静脉注射后,¹⁴C主要自尿排出(24小时可排出剂量的71.2%),自粪排出17.4%。口服后24小时可自尿排出34.3%,自粪排出33.1%。胆汁也是一条重要排泄途径,静脉注射后24小时可自胆汁排出剂量的47.4%;口服后相应时间内排出39.1%。本文所得结果与前文应用化学方法所得结果进行比较,表明自消化道、尿、胆汁所回收的放射性主要是黄豆甙元的代谢产物,说明该药在体内的代谢很旺盛。     

Distribution and Elimination of 2–MethyI–4–Chlorophenoxyacetic Acid (MCPA) in Male Rats

Abstract The distribution and elimination of 2–methyl–4–chlorophenoxyacetic acid (MCPA) in male rats were studied. 3 mg of ¹⁴C–labelled and non–labelled MCPA in 50 % ethanol was injected into the stomach of male rats and urine, faeces and internal organs or tissues were analyzed for radioactivity. During the first 24 hrs 92.26 ± 5.36 % of the radioactivity was excreted in the urine and 6.76 ± 3.56 % in the faeces. Recovery in the urine and faeces after five days was 102.78 ± 1.10 % of the dose administered, indicating that practically all MCPA is eliminated in the urine and faeces. The maximum concentrations of MCPA in the tissues occurred between 2 to 8 hrs after administration. Thereafter the concentrations declined rapidly. The highest concentrations of MCPA were observed in the blood, kidney, lung, heart, suprarenal gland, liver, thyroid gland and bone marrow. The lowest concentrations were those in the brain, adipose tissue, testis and muscle.     

Distribution and elimination of the herbicide propanil in the Channel Catfish (Ictalurus punctatus)

1. The uptake, elimination and tissue distribution of total radioactivity derived from the herbicide, [¹⁴C]propanil (3,4-dichloropropionanilide) and its metabolites were examined in individual farm-raised Channel Catfish which were exposed for 24?h to water containing 1 ppm of ¹⁴C-propanil under static conditions. Uptake and elimination of total radioactivity was monitored in individual animals over time in respective exposure (24?h) and depurating (144?h) aquaria.

2. Maximal uptake was reached between 8 and 12?h with approx. 38% of the absorbed radioactivity remaining in the animal after 144?h of depuration. Whole body depuration of radioactivity was biphasic with a and β half-lives of 20 and 444?h, respectively.

3. Tissue distribution of total radioactivity was monitored at various time points in 12 tissues and bile over 48?h. Intestine, abdominal fat and liver possessed the greatest levels of radioactivity per gram of tissue over time. Radiolabel was shown to slowly increase in bile and intestine indicating biliary excretion as a possible pathway of metabolite elimination.

4. Bile possessed approx. 104 nmol (23%) of the remaining radioactivity in fish after 48?h. Other whole tissues possessing > 10% of radiolabel after 48?h were blood (83.5 nmol, 19% of the administered dose) and muscle (190 nmol, 43%).     

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.