The Distribution of 14C–Chloramphenicol in the Japanese Quail (Coturnix coturnix japonica)

Abstract: The distribution of ¹⁴C–labelled chloramphenicol after oral and intravenous administration to egg laying Japanese quail was studied by whole–body autoradiography. In the liver, kidneys, gizzard, intestinal contents (bile) and oviduct, the ¹⁴C–concentration was higher than that of the blood short time after injection and remained higher than the blood up to 4 days. From 4 hrs, the concentration of ¹⁴C in the egg yolks was higher than that of the blood and from 24 hrs the radioactivity in the albumen of the eggs in the oviduct was also higher than that of the blood. The peak concentration in the egg yolk was found in the second egg laid 2–4 days after administration of ¹⁴C–chloramphenicol. In the albumen the maximum concentration was found in the first laid egg 24–48 hrs after administration. In the egg yolks, about 30% of the radioactivity represented unchanged chloramphenicol up to 5 days after administration. It was also shown that about 5% of the injected ¹⁴C–chloramphenicol was exhaled as ¹⁴CO₂ during the first 12 hrs and about 37% of the dose was excreted in the combined faeces and urine during the same period of time     

3H-莪术醇在正常大鼠及肿瘤小鼠体内的代谢研究

³H-莪术醇自大鼠胃肠道吸收迅速且完全。灌胃后5分钟血中即有放射性,15分钟达高峰,1小时仍保持较高浓度,放射性自血中消失的生物半衰期为11.5小时(t_(1/2)β)。静脉注射后血中放射性的消失分快、慢两相,生物半衰期分别为33分钟(t_(1/2)α)及12.5小时(t_(1/2)β)。放射性在正常大鼠体内分布情况与肿瘤小鼠者相似。肝及肾组织含量约为其它组织的2～2.5倍。肿瘤组织中的分布与其它组织无明显差别;组织中放射性的消失与血浆中者略呈平行关系。放射性与脂肪组织似有较强的亲和力,给药后4小时仍维持较高水平。放射性主要自尿排泄,口服或静脉注射后24小时分别自大鼠尿排出剂量的45.38%及51.91%。胆汁为另一排泄途径,大鼠口服或静脉注射后24小时,分别自胆汁排出36.47%及56.43%,而口服或静脉注射后72小时仅从粪回收6.77%及14.35%,可见,自胆汁排出的放射性大部分均又被重吸收入血。     

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。     

Tissue Distribution of 14C-Rifampicin I. Whole Body Autoradiography of Albino Mice

Abstract: Whole body autoradiography of albino mice 5, 20, 60 min., 4, 24 hrs and 4 days after a single intravenous injection of ¹⁴C-rifampicin showed that rifampicin and/or its metabolites were rapidly distributed into most organs. As early as 5 min. after the injection, the lung, myocardium, brown fat, salivary glands, gastrointestinal mucosa, pancreas, kidney and liver showed higher uptake than the blood. A blood-brain barrier was apparent. A very high uptake was initially observed in the liver. Most of the radioactivity had disappeared after 24 hrs, although slight activity was still seen in the liver and thyroid after 4 days. No other specific retention of toxicological interest was observed.     

The distribution of 14C-chloramphenicol in the Japanese quail (Coturnix coturnix japonica)

The distribution of 14C-labelled chloramphenicol after oral and intravenous administration to egg laying Japanese quail was studied by whole-body autoradiography. In the liver, kidneys, gizzard, intestinal contents (bile) and oviduct, the 14C-concentration was higher than that of the blood short time after injection and remained higher than the blood up to 4 days. From 4 hrs, the concentration of 14C in the egg yolks was higher than that of the blood and from 24 hrs the radioactivity in the albumen of the eggs in the oviduct was also higher than that of the blood. The peak concentration in the egg yolk was found in the second egg laid 2-4 days after administration of 14C-chloramphenicol. In the albumen the maximum concentration was found in the first laid egg 24-48 hrs after administration. In the egg yolks, about 30% of the radioactivity represented unchanged chloramphenicol up to 5 days after administration. It was also shown that about 5% of the injected 14C-chloramphenicol was exhaled as 14CO2 during the first 12 hrs and about 37% of the dose was excreted in the combined faeces and urine during the same period of time.     

Accumulation in Murine Amniotic Fluid of Halothane and its Metabolites

Abstract: The distribution of radioactivity in pregnant mice was registered at 0, 1, 4, and 24 hrs after a 10 min. period of inhalation of ¹⁴C-halothane. Autoradiographic methods were used to allow to distinguish between the distribution of volatile (non-metabolized) halothane, water-soluble metabolites, and firmly tissue-bound metabolites. While volatile radioactivity was seen predominantly at short survival intervals, e.g. in body fat, blood, brain and liver, metabolites accumulated with time. Peak values occurred at 4 hrs in most organs (measured with liquid scintillation as well). The most remarkable findings were the high concentrations of radioactivity in amniotic fluid (and the ocular fluids of adults) with peak values at 4 hrs and rather high concentrations still prevailing at 24 hrs after inhalation. It is assumed that this activity represents only partly volaile halothane and mostly non-volatile metabolites. High activity of metabolites was seen in the neuroepithelium of the embryo in early gestation. Firmly tissue-bound metabolites, still remaining after washing the tissues with trichloroacetic acid and organic solvents, were found in the nasal mucosa, trachea and bronchial tree and in (presumably centrilobular) zones of the liver of adults after inhalation and 5-day old mice after intraperitoneal injection, indicating the formation of reactive metabolites in these organs. Firmly tissue-bound activity was not observed in the corresponding foetal organs.     

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.     

Absorption,distribution and excretion of the anti‐tuberculosis drug delamanid in rats: Extensive tissue distribution suggests potential therapeutic value for extrapulmonary tuberculosis

Delamanid (OPC‐67683, Deltyba™, nitro‐dihydro‐imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug‐resistant tuberculosis. The absorption, distribution and excretion of delamanid‐derived radioactivity were investigated after a single oral administration of ¹⁴C–delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 h post‐dose, and thereafter decreased slowly. Radioactivity levels were 3‐ to 5‐fold higher in lung tissue at time to maximum concentration compared with plasma. In addition, radioactivity was broadly distributed in various tissues, including the central nervous system, eyeball, placenta and fetus, indicating that ¹⁴C–delamanid permeated the brain, retinal and placental blood barriers. By 168 h post‐dose, radioactivity in almost all the tissues was higher than that in the plasma. Radioactivity was also transferred into the milk of lactating rats. Approximately 6% and 92% of radioactivity was excreted in the urine and feces, respectively, indicating that the absorbed radioactivity was primarily excreted via the biliary route. No significant differences in the absorption, distribution and excretion of ¹⁴C–delamanid were observed between male and female rats. The pharmacokinetic results suggested that delamanid was broadly distributed to the lungs and various tissues for a prolonged duration of time at concentrations expected to effectively target tuberculosis bacteria. These data indicate that delamanid, in addition to its previously demonstrated efficacy in pulmonary tuberculosis, might be an effective therapeutic approach to treating extrapulmonary tuberculosis. Copyright © 2017 John Wiley & Sons, Ltd.     

Autoradiographic study of the distribution of an anticholinesterase agent, 1-naphthyl-N-methyl[14C]carbamate, in the pregnant rat]

1-Naphthyl-N-methyl [¹⁴C]carbamate (carbaryl), an anticholinesterase, was given orally to pregnant female rats (Day 18). Each rat received 13.5 μCi and was killed 1, 5, 8, 24, 48, 72, and 96 hr later. Whole-body autoradiography was performed. We noted a placental transfer of radioactivity beginning with the first hr. The ¹⁴C concentration in the fetus was relatively constant from 8 to 96 hr. There was localization in the eye, liver, and brain of the fetus. In the mother, ¹⁴C activity was seen in the excretory organs. We noted a localization in bones (medullar), in the digestive tract (wall), and in the brain. Although the major portion of the carbaryl was quickly eliminated, some areas of radioactivity remained in the pregnant rat after oral administration of [¹⁴C]carbaryl. This localization occurred particularly in highly active protein building organs (fetus, digestive tract, medullar part of bones).     

S-adenosyl- -methionine N-ole-1-oyltaurate: pharmacokinetic of the orally administered salt in rats

A pharmacokinetic study based on the distribution of radioactivity from the double labelled S-adenosyl- -methionine (SAM) has been carried out by oral administration of the liposoluble stable salt [methyl-¹⁴C, 8-³H]SAM N-ole-1-oyltaurate to rats. The SAM sulfate p-toluensulfonate salt, the only SAM salt at present commercialized as drug, was chosen as reference compound to have a comparative pharmacokinetic analysis. The metabolism of the SAM is characterised by a differential use of the two labelled moieties by the various organs, liver being the most active in metabolizing the sulfonium compound with a preferential uptake of the methyl-¹⁴C fragment. The radioactivity detected after the administration of [methyl-¹⁴C, 8-³H]SAM N-ole-1-oyltaurate is, in all the organs examined, two times higher than the [methyl-¹⁴C, 8-³H]SAM sulfate p-toluensulfonate compound, attesting that the liposoluble [methyl-¹⁴C, 8-³H]SAM N-ole-1-oyltaurate is provided with better bioavailability.     

14C-棉酚在四种动物体内吸收、分布和排泄的比较研究

本文比较研究了¹⁴C-棉酚在小鼠、大鼠、犬和猴体内的吸收、分布和排泄过程。小鼠和大鼠于单次口服¹⁴C-棉酚后6～9小时,血内放射性达高峰,生物半衰期分别为31和16.5小时。口服¹⁴C-棉酚48小时后,以胃肠道内容物及肝、肾内放射性最高。睾丸内放射性大鼠比小鼠要高。进入体内¹⁴C-棉酚,放射性排出主要通过粪便,少部分从尿排出。以犬和猴(各1只)进行比较研究,也获得类似结果。它们睾丸内放射性均比大鼠低。与其它三种动物比较,犬心脏内放射性最高,猴体内放射性从粪便中排出最快。本文结果提示棉酚对不同动物的抗生育作用与毒性作用之间的差异,可能与它在相应脏器内的分布、蓄积及排泄速度的不同有关。     

Disposition and metabolism of a novel diurea inhibitor of acyl CoA: cholesterol acyltransferase (YM17E) in the rat and dog

We have investigated the disposition and metabolism of YM17E after intravenous and oral administration in the rat and dog.

2. Unavailability of YM17E was 5–9% at oral doses of 3–30 mg/kg in rat, and 9 and 13% at oral doses of 10 and 30mg/kg in dog.

3. Five N-demethylated metabolites, which have significant pharmacological activity, were found in rat and dog plasma after oral administration. Plasma concentrations of each of these metabolites were comparable with (hat of unchanged drug.

4. When ¹⁴C-YM17E was administered to rat, AUC of unchanged drug was 7% of that of radioactivity. However, AUC of the combined concentration of unchanged drug and five active metabolites was about 50% of that of radioactivity, indicating that the pharmacological activity of the agent was maintained in spite of its biotransformation.

5. After oral administration of ¹⁴C-YM17E at a dose of 10 mg/kg to rat, radioactivity was distributed widely to almost all tissues except the brain. The concentration of radioactivity in the liver, one of the target organs, was 65 times higher than that in plasma at 1 h after administration.

6. A significant amount of radioactivity in the liver was located in the microsomal subfraction, which contains much acyl CoA: cholesterol acyl transferase activity. More than 50% of this microsomal radioactivity was derived from unchanged YM17E and five active metabolites.

7. From excretion data in the bile duct-cannulated rat, the absorption ratio of YM17E from the gastrointestinal tract in this species was estimated to be at least 40%, suggesting that the low bioavailability of the drug is due to extensive first-pass metabolism.

8. Some 95% of the administered radioactivity was excreted in the faeces of rat following iv or po doses of ¹⁴C-YM17E.     

Absorption,Distribution, Metabolism,and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Orally to Rats

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [hexyl-1-¹⁴C] N-octylbicycloheptene dicarboximide (MGK 264).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered fhexyl-1-¹⁴C] MGK 264 at a single oral dose of 100 mg/kg, at a single oral dose of 1000 mg/kg, and at a daily oral dose of 100 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 100 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 100 mg/kg. Each animal was administered 18-30 μCi radioactivity.

Urine and feces were collected for all groups at predetermined time intervals. Seven days after dose administration, the rats were euthanized and selected tissues and organs were harvested. Samples of urine, feces, and tissues were subsequently analyzed for ¹⁴C content.

In the blood kinetics study, radioactivity peaked at approximately 4 h for the males and 6 h for the females. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity was approximately 8 h for males and 6 h for females.

Female rats excreted 71.45-73.05% of the radioactivity in urine and 20.87-25.28% in feces, whereas male rats excreted 49.49-63.49% of the administered radioactivity in urine and 31.76-46.67% in feces. Total tissue residues of radioactivity at 7 days ranged from 0.13 to 0.43% of the administered dose for all dosage regimens. The only tissues with ¹⁴C residues consistently higher than that of plasma were the liver, stomach, intestines, and carcass. The total mean recovered radioactivity of the administered dose in the studies ranged between 93.1 and 97.4%. No parent compound was detected in the urine.

Four major metabolites and one minor metabolite were isolated from the urine by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS). The four major metabolites were shown to be carboxylic acids produced by either ω-1 oxidation or β-oxidation of the side chain and oxidation of the norbornene ring double bond. The minor metabolite was the carboxylic acid of the intact norbornene ring.

The gender of the animals affected the rate, route of excretion, and metabolic profile. The urinary excretion rate was faster in females than in males and the amount excreted was also greater in female rats.     

The Metabolism of Biphenyl. I. Metabolic Disposition of 14C–Biphenyl in the Rat

Abstract The metabolic disposition of ¹⁴C–biphenyl in the rat was studied by liquid scintillation counting. The rats were given an oral dose of ¹⁴C–biphenyl (100 mg/kg, 0.7–1.0 μci) and the total excretion of radioactivity after 96 hrs was 92.2 % of the dose. Urinary excretion accounted for 84.8 % and faecal excretion for 7.3% of the dose. Most of this radioactivity, 75.8 % and 5.8% respectively, was excreted within 24 hrs. Only trace amounts of ¹⁴CO₂ were detected in the expired air and 0.6% of the dose was found to be still present in the rats 96 hrs after biphenyl administration. Extraction and fractionation of the 24 hrs urine samples showed that the largest fraction (nearly 30% of the dose) consisted of conjugated phenolic metabolites. Acidic metabolites accounted for a quarter of the dose and the low levels of expired ¹⁴CO₂ indicated that these were not products resulting from extensive degradation and decarboxylation.     

Disposition and Oxidative Metabolism of Antipyrine in the Rat

Abstract The main routes of excretion of antipyrine-N-methyl-¹⁴C and the role of oxidation in the metabolism of antipyrine were studied in the rat. After an intraperitoneal dose of 15 mg/kg ¹⁴C-antipyrine (1.0-1.5 uCi ¹⁴C), 74.2% of the radioactivity was found in the urine, 2.5% appeared in the faeces and 2.6% was recovered from expired CO₂ after 48 hrs. Most of the radioactivity (98%) was excreted during the first 24-hrs. The cumulative excretion of radioactivity in the bile amounted to 18% of the dose in 24 hrs. Only 1-2% of the radio activity in the urine represented unchanged antipyrine. Antipyrine was extensively metabolized by oxidation followed by conjugation. In urine 3-CH₂OH-antipyrine and 4-OH-antipyrine (unconjugated and conjugated) accounted for 35 and 18% of the radioactivity, respectively. 3-carboxy antipyrine represented 17% of the radioactivity. The corresponding figures for bile were 51,19 and 9%. In addition, the non-radioactive N-demethylated metabolite, nor-antipyrine, was found. The quantitation of N-demethylation based on radioactivity recovered from expired CO₂ suggested that at least 2.6% of antipyrine was metabolized by this pathway. The results show that antipyrine was extensively oxidized in the rat. Thus, in this species, antipyrine meets a fundamental requirement of a model compound for the study of factors influencing drug oxidation in vivo.     

Fate of 109Cd-labeled metallothionein in rats.

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

Studies on the Metabolism of d-Limonene (p-Mentha-1,8-diene): I. The Absorption,Distribution and Excretion of d-Limonene in Rats

Abstract

1. The absorption, distribution and excretion of d-limonene were investigated in rats using the ¹⁴C-labelled compound.

2. The highest concentration of radioactivity in blood was obtained 2 h after oral administration of [¹⁴C]d-limonene and most occurred in the serum fraction. Radioactivity in the tissues reached maximum 1 or 2 h after administration. Radioactivity in liver, kidney and blood was higher than in other tissues, but was negligible 48 h after administration. An autoradiographic study confirmed these findings of tissue distribution.

3. About 60% of administered radioactivity was recovered from urine, 5% from faeces and 2% from expired CO₂ within 48 h. In bile duct cannulated rats, about 25% of the dose was excreted in bile within 24 h.     

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.     

Absorption,distribution, metabolism and excretion of telmesteine,amucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of ¹⁴C-telmesteine in the Sprague–Dawley rat.

2. ¹⁴C-telmesteine was rapidly absorbed after oral dosing (20 and 50mg kg^-1) with an oral bioavailability of > 90% both in male and female rats. The C_max and area under the curve of the radioactivity in plasma increased proportionally to the administered dose and those values in female rats were 30% higher than in male rats.

3. Telmesteine was distributed over all organs except for brain and the tissue/plasma ratio of the radioactivity 30min after dosing was relatively low with a range of 0.1–0.8 except for excretory organs.

4. Excretion of the radioactivity was 86% of the dose in the urine and 0.6% in the faeces up to 7 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 3% for the first 24 h. The unchanged compound mainly accounted for the radioactivity in the urine and plasma.

5. Telmesteine was hardly metabolized in microsomal incubations. A glucuronide conjugate was detected in the urine and bile, but the amount of glucuronide was less than 6% of excreted radioactivity.     

Synthesesteigerung und Abbauhemmung bei der Vermehrung der mikrosomalen Cytochrome P-450 und b-5 durch Phenobarbital

Summary Heme moieties of microsomal rat liver cytochromes P-450 and b-5 were labeled with.¹⁴C-Aminolevulini cacid. The half life of the b-5 heme radioactivity was found to be 45 hrs, that of the P-450 heme radioactivity was 22 hrs.Treatment of fed rats with Phenobarbital (80 mg/kg i.p. and 1 PB in the drinking water) for 48 hrs increased the concentration of cytochrome P-450 up to 200%, only by induced synthesis. In starved rats treated with Phenobarbital, P-450 concentration was increased up to 400%, by both induced synthesis and inhibition of breakdown.Microsomal P-450 cytochrome was determined in rat liver homogenate and in suspensions of rat liver microsomes. The amount of P-450 obtained in the isolated microsomal fraction was compared with the P-450 content in the liver homogenate. Since P-450 is a microsomal hemoprotein this relation can be correlated with the microsomal protein, in order to to calculate the real content of microsomal protein in the liver homogenate. It was found to be 65 mg/g of liver, demonstrating, that 31% of the 209 mg of total protein/g of liver consists if microsomal protein.