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     

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.     

Acute and subacute effects of neuroleptics on dopamine synthesis and release in the rat striatum

Summary The effects of acute and subacute treatments with moderate doses of thioproperazine and haloperidol on dopamine synthesis and release have been examined in rat striatal slices. Synthesis and release of dopamine were determined by measuring the rate of formation of ³H-H₂O during the conversion of l-3,5-³H-tyrosine into ³H-Dopa and the accumulation of newly synthesized ³H-dopamine in striatal slices and their incubating medium. Possible effects of the treatments on tyrosine striatal levels or tyrosine specific activity were also investigated. Dopamine synthesis rate was markedly accelerated 2.5 hrs after the acute injection of thioproperazine, but was equal to control levels 24 hrs later. The effects of thioproperazine and haloperidol were thus determined 2.5 and 24 hrs after an acute injection and following the last injection of a repeated daily treatment of 11 days. Dopamine synthesis and release were still markedly increased 2.5 hrs after the last injection of the subacute neuroleptic treatments when compared to controls, but these effects were less pronounced than those observed 2.5 hrs after an acute injection of either drug. Conversely, dopamine synthesis and release were significantly decreased 24 hrs after the last injection of the subacute neuroleptic treatments when compared to controls. Two hypotheses are proposed to explain the ments when compared to controls. Two hypotheses are proposed to explain the changes in dopamine synthesis induced by repeated treatments with neuroleptics.     

Cellular localization of stable solid liposomes in the liver of rats

Small solid liposomes made from distearoylphosphatidyl choline and cholesterol (molar ratio 2 : 1) showed significant stability in plasma, with a half-life of about 24 hr after intravenous injection in rats. The major cellular uptake of intact liposomes was found in the liver and spleen, peaking after 2–4 hr in the liver and after 24 hr in the spleen. Isolation of parenchymal and non-parenchymal cells from rat livers at various intervals after injection of liposomes showed that both cell types adsorbed liposomal membranes and took up the liposomal contents. Our study has shown that most of the liposomal markers found in the liver shortly (< 40 min) after administration stemmed from the liposomes adsorbed to extracellular binding sites, and that uptake into the cells took place subsequently. In non-parenchymal cells, uptake was rapid and the intracellular level remained rather constant after 40 min and for up to 4 hr. The uptake of liposomes by parenchymal cells was slower, it showed a lag-phase of approx. $\text{1}\text{2}$ hr and peaked at 2 hr, whereupon the radioactivity in parenchymal cells dropped. The contents of liposomes behaved in a manner similar to the membranes. It is concluded that, in addition to a rapid uptake of liposomes in non-parenchymal liver cells, there is a significant degree of association with parenchymal cells, provided that the liposomes administered are small (< 100 nm in diameter) and stable.     

Metabolism of 2,4′,5-trichlorobiphenyl: tissue concentrations of methylsulphonyl-2,4′,5-trichlorobiphenyl in germfree and conventional mice

Whole-body autoradiography of 2,4′,5-[¹⁴C]trichlorobiphenyl ([¹⁴C]triCB) indicated that, whereas there was accumulation of radioactivity in the tracheobronchial mucosa of conventional (C) mice 1–7 days after injection, no such effect was observed in germfree (GF) mice 1 day after injection. At days 4 and 7 there was a low, but significant, uptake by the tracheobronchial mucosa of the GF mice. Chemical analysis showed that the concentrations of 4-methylsulphonyl-triCB (4-MeSO₂-triCB) in lung, kidney and liver 7 days after administration of triCB were 6.5, 14.7 and 3.7 times higher, respectively, in C than in GF mice. The results are interpreted as indicating the existence of a major metabolic route to triCB methyl sulphones involving the intestinal microflora, and a minor route, not requiring the flora. Abbreviations: C, conventional; GC, gas chromatography; GF, germfree; GSH, glutathione; MF, mass fragmentography; PCB, polychlorinated biphenyls; triCB, trichlorobiphenyl.     

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。     

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.     

Effect of cortisone,aldosterone and nialamide on “amphetamine stereotypies” and brain methamphetamine levels of adrenalectomized rats

Cortisone, aldosterone or nialamide was administered to adrenalectomized or sham-operated rats for 7 days, and methamphetamine was injected 24 hrs after the last injection of these compounds. Stereotyped head movement and licking activity were scored 5 min, 30 min and 60 min after methamphetamine injection and, in parallel brain methamphetamine levels in similarly treated rats were measured 5 min, 30 min and 60 min after the methamphetamine injection.Adrenalectomy depressed stereotyped head movements but enhanced the brain amphetamine accumulation. Nialamide but not the hormones further increased the amphetamine accumulation in adrenalectomized rats. No drugs had any effect on the amphetamine-induced head movement suppressed by adrenalectomy.     

Disposition of NICKEL-63 in the rat

The urinary and faecal excretion of nickel-63 (⁶³Ni) and the distribution of ⁶³Ni in kidneys, liver, heart and blood serum after an i.p. injection of radiolabelied nickel chloride (⁶³NiCl₂) have been investigated. Most of ⁶³Ni was excreted via urine within 24 h. The daily faecal excretion, though very low, was consistent up to 6 days. The uptake of ⁶³Ni was highest in kidneys and the order was kidneys 0 serum > heart > liver, 24 h after ⁶³NiCl₂ injection. However, ⁶³Ni was eliminated rapidly from the body and there was almost no radioactivity 6 days post administration.     

Tissue accumulation of lipoprotein associated toxaphene in normo- and hypolipidemic mice

Normo- and hypolipidemic mice were given a single i.v. injection of¹⁴C-toxaphene associated with low density lipoprotein (LDL), high density lipoprotein (HDL) or dimethyl sulfoxide (DMSO). The tissue distribution of radioactivity was studied 20 min and 4 h after the application. In the normolipidemic mice at 20 min postinjection there was high uptake of the¹⁴C-toxaphene preparations in the liver and adrenals followed after 4 h by a redistribution to the adipose tissues. In the hypolipidemic mice, proportionally less label accumulated initially in the liver and adrenals while more radioactivity was seen in the kidneys and heart. The radioactivity then redistributed to the liver with a very small uptake in the adipose tissue compared to the normolipidemic mice after 4 h. The results indicate that changes in the lipid pattern, e.g. hypolipidemic conditions, may influence the tissue distribution of lipophilic xenobiotics.     

Effects of Hydroxyethylstarch (HespanR), a Plasma Expander,on the Functional Activity of the Reticuloendothelial System. Comparison with Human Serum Albumin and Pyran Copolymer

ABSTRACT

The purpose of the present investigation was to determine if RES activity was altered after the infusion (bolus i.v. injection over ～3–5 min) of hydroxyethyl starch (HES). RES function was determined by vascular clearance of ⁵¹Chromium-labeled sheep erythrocytes and the subsequent uptake into the liver, spleen, lungs, and thymus at 1 hr, 3 hr, 6 hr, 1 day, 3 days, and 7 days post infusion. Infusion with the low doses of HES (20 and 40 ml/ kg) produced changes in vascular clearance which were comparable to physiological saline. Infusion with 80 ml/kg HES produced a biphasic response with a modest suppression of vascular clearance (i.e., 151% increase in half life) and hepatic phagocytosis (50%) during the first 6 hours after injection, followed by recovery at 24 hours and a stimulation in hepatic uptake (42%) after 3 days. These effects by HES were compared to those produced by infusion with 80 ml/kg HSA, a comparable colloid and with 80 ml/kg pyran copolymer, a positive control.     

PEG-coated Poly(lactic acid) Nanoparticles for the Delivery of Hexadecafluoro Zinc Phthalocyanine to EMT-6 Mouse Mammary Tumours

Hexadecafluoro zinc phthalocyanine (ZnPcF₁₆), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in three vehicles: poly(d,l -lactic acid) (PLA) nanoparticles, polyethylene glycol (PEG)-coated nanoparticles and a Cremophor EL (CRM) oil-water emulsion. Nanoparticles were prepared by the salting-out procedure. Biodistribution of the dye was assessed by fluorescence in EMT-6 mammary tumour bearing mice after intravenous injection of 1 μmol kg^?1 ZnPcF₁₆. Plain nanoparticles were rapidly retained by the reticuloendothelial system (RES) as reflected by the low area under the blood concentration-time curve (AUC_0–168, 57 μg h g^?1). Little tumour uptake of the dye was observed with this formulation. In contrast, PEG-coated nanoparticles displayed a reduced RES uptake, leading to significantly higher blood levels over an extended period (t1/2 30 h; AUC_0–168 227 μg h g^?1) and enhanced tumour uptake. At 48 h post injection, tumour to skin and tumour to muscle concentration ratios reached 3·5 and 10·8, respectively. Blood levels of ZnPcF₁₆ after administration as a CRM emulsion decreased faster than with PEG-coated nanoparticles (t1/2 12 h), but since no early liver uptake was observed, the AUC_0–168 and the tumour uptake were only slightly lower. However, with the CRM formulation, a late liver uptake was observed, reaching 51% of the injected dose after 7 days.     

Binding of antiparkinsonian ergot derivatives to the dopamine receptor

The effects of bromocriptine, lisuride and apomorphine on specific binding of ³H-spiroperidol to homogenates of rat caudate nucleus were studied. (+)-Butaclamol was used to define specific binding. Bromocriptine and lisuride inhibited binding markedly, in vitro and also 30 min after in vivo injection. Bromocriptine continued to inhibit binding 24 h after a single injection and also after 4 days of drug administration. Lisuride did not affect net specific binding at these periods. Apomorphine produced a mild reduction in binding after 30 min but none after 4 days. It appears that the ergot alkaloids inhibit binding of ³H-spiroperidol by binding strongly to the dopamine receptor.     

Autoradiographic Studies of 3H-estramustine in the Rat Ventral Prostate

Abstract The alkylating agent ³H-estramustine was administered to castrated male rats and found to accumulate in the epithelium of the ventral prostate 5 and 20 min. following intravenous administration, as judged from autoradiography. Four hrs. after intravenous injection of this isotope, the radioactivity was recovered in the secretion of the prostatic lobuli. A preferential accumulation of radioactivity in prostatic secretion was also observed 2 hrs. after intramuscular administration of ³H-estramustine to intact or castrated rats. In contrast, ³H-oestradiol and ³H-testosterone, which were also taken up by the ventral prostatic epithelium, were not recovered in prostatic secretion. The present results indicate that ³H-estramustine is secreted from the prostatic cells into the lumina of the prostatic lobuli. It is speculated that a recently detected estramustine-binding protein in rat ventral prostate may be involved in this process and that the present finding may be of relevance in the understanding of the mechanism of action of the chemotherapeutic agent Estracyt® (estramustine phosphate) used in the treatment of advanced prostatic carcinoma.     

斑蝥酸钠在小鼠体内抗癌作用的研究

斑螯Mylabris spp.体内抗癌有效成分为斑蝥素及斑蝥酸钠,已经北京及上海协作区五十多个医院临床试验肯定了效果。本文报告了³H-斑螯酸钠在艾氏腹水癌小鼠体内的吸收、分布和代谢。血液中的放射性代谢速率,以2小时最高,24小时在血中尚存留很少量,72小时测不到放射性。³H-斑蝥酸钠在组织中的代谢是4小时进入脑、胆、肾、肝四种组织的量最多,其他组织较少。³H-斑蝥酸钠用电镜放射自显影方法研究其对癌细胞的作用,曝光40天观察到³H-斑蝥酸钠进入细胞线粒体较多,由核孔进入细胞核及核仁也很多;对照组则没有。本实验进一步验证了临床的效果。     

Synthesis and bioevaluation of 4‐chloro‐2‐tert‐butyl‐5‐[2‐[[1‐[2‐[18F]fluroethyl]‐1H‐1,2,3‐triazol‐4‐yl]methyl]phenylmethoxy]‐3(2H)‐pyridazinone as potential myocardial perfusion imaging agent with PET

This study reports the synthesis and characterization of 4‐chloro‐2‐tert‐butyl‐5‐[2‐[[1‐[2‐[¹⁸F]fluroethyl]‐1H‐1,2,3‐triazol‐4‐yl]methyl]phenylmethoxy]‐3(2H)‐pyridazinone ([¹⁸F]Fmp2) for myocardial perfusion imaging (MPI). The tosylate precursor and non‐radioactive compound [¹⁹F]Fmp2 were synthesized and characterized by infrared, ¹H‐NMR, ¹³C‐NMR, and mass spectra (MS). The radiotracer [¹⁸F]Fmp2 was obtained by one‐step nucleophilic substitution of tosyl with ¹⁸F, and evaluated as an MPI agent in vitro and in vivo. Starting from [¹⁸F]KF/K₂₂₂ solution, the typical decay‐corrected radiochemical yield (RCY) was 38 ± 8.8% with high radiochemical purity (>98%). The specific activity was calculated as 10 GBq/µmol at the end of synthesis determined by HPLC analysis. In the mice biodistribution, [¹⁸F]Fmp2 showed very high initial heart uptake (53.35 ± 5.47 %ID/g at 2 min after injection) and remarkable retention. The heart/liver, heart/lung, and heart/blood ratios were 7.98, 8.20, and 53.13, respectively at 2 min post‐injection. In the Positron Emission Tomography (PET) imaging study of Chinese mini‐swine, the standardized uptake value of the liver decreased modestly during the 2 h post‐injection, while the heart uptake and heart/liver ratios continued to increase with time. [¹⁸F]Fmp2 exhibited good stability, high heart uptake and low lung uptake in mice and Chinese mini‐swine. It may be worthy of further modification to improve liver clearance for MPI in the future.     

Comparative Studies on the Metabolic Disposition of 8-Chloro-6-pheny1–4H-s-triazolo[4,3-a][1,4]benzo-diazepine (D-40TA) and Nitrazepam after Single and Repeated Administration in Rats

Abstract

1. Orally administered D-40TA was absorbed by rats with a maximum blood level at 30 min and a half-life of 60 min. The blood level of orally administered nitrazepam reached a plateau which persisted for 90 min and then declined with a half-life of 90 min.

2. Both D-40TA and nitrazepam crossed the blood-brain barrier of rats. The 1-oxo metabolite of D-40TA is pharmacologically active, and also readily entered the brain.

3. Orally administered D-40TA and nitrazepam were eliminated in urine and faeces over 3 days, the larger part in faeces. In both cases, about 90% of the dose of radioactivity was eliminated from the body during the first 2 days after administration.

4. After intravenous injection of either [¹⁴C]D-40TA or [¹⁴C]nitrazepam, the radioactivity was excreted in bile at the same rate, 69 and 64% of the dose being recovered from the 24 h-bile, respectively. The biliary metabolites of both benzodiazepines underwent entero-hepatic cycling.

5. After daily oral administration of [¹⁴C]D-40TA or [¹⁴C]nitrazepam, the cumulative excretion closely paralleled the dosage of radioactivity. For both drugs, excretion was complete within 3 days of discontinuing medication. During repeated administrations of the labelled drugs, no increase in concn. of blood radioactivity 1 h after dosing was observed. With [¹⁴C]D-40TA-treated rats, most of the radioactivity still in the body 24 h after administration was recovered from the gastro-intestinal contents; only small amounts were in tissues. Dosing of [¹⁴C]D-40TA for 7 days caused no increase in tissue levels of radioactivity, except in the liver, where the radioactivity increased to about twice the level noted after a single administration.     

Studies in tissue glycogen in acute stress

The glycogen was estimated in liver, cardiac and skeletal muscles during the recovery period after electro-shock. The supercompensation in the level of glycogen was observed in cardiac and skeletal muscles at 1 1/2 and 5 hrs respectively during the recovery period, after electro-shock. The liver glycogen level was lower than the control value after electro-shock at least upto 5 hrs of recovery period. Further, the glycogen level was observed to be minimum when the ventricular glycogen showed its supercompensation at 1 1/2 hr of recovery period. The glycogen level of those three tissues returned to control level after 24 hrs of electro-shock.     

Localization of colloidal particles (liposomes,hexylcyanoacrylate nanoparticles and albumin nanoparticles) by histology and autoradiography in mice

Distribution and uptake of 3 labeled colloidal carrier systems have been studied following i.v. injection in mice: [¹⁴C]diazepam liposomes, [¹⁴C]polyhexylcyanoacrylate nanoparticles and ¹²⁵I-albumin nanoparticles. All systems accumulated in the organs of the reticuloendothelial system (RES). Targeting to a specific organ was not achieved. Concentration kinetics revealed that [¹⁴C]diazepam was eliminated together with the lipids without any redistribution of the drug in the body. After 10 days, only radioactivity of the nanoparticle systems remained on a relatively high level in the organs of the RES. Whole-body and light microscopic autoradiographs of [¹⁴C]polyhexylcyanoacrylate and ¹²⁵I-albumin nanoparticles revealed an unusual spotted appearance of silver grains in liver, lungs and bone marrow. Ultrastructural investigations of liver and lung tissue demonstrated incorporation of polyhexylcyanoacrylate nanoparticles into hepatocytes and pulmonary cells 5 min after injection and possibly microembolism for albumin and cyanoacrylate nanoparticles.     

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。