10-羟基癸烯酸在动物体内吸收、分布、代谢和排泄

10-癸基癸烯酸(即10-HDA,定位标记为³H-10HDA),经小鼠和大鼠口服后,胃肠道吸收快,峰时均在1h,全身分布迅速广泛,与组织亲和力强,肝中放射性为最高,依次为肾、胰、脂肪、脑、脾、心和肺。平均Vd为9.71/kg。Ig和iv的T1/2β在12.6～22.7h。体内消除较缓慢,31 d内,尿粪中放射性累计排泄分别为给药量的85.4%和13.5%,提取尿和胆汁经分析结果主要以原形药物排出。血浆蛋白结合率为63%。血中放射—性时间曲线符合开放二室模型。     

Distribution of radioactivity and metabolite profiling in tumour and plasma following intravenous administration of a colchicine derivative (14C-ZD6126) to tumour-bearing mice

The main aim of the study was to investigate the distribution of radioactivity in the tissues and tumours using quantitative whole-body autoradiography (QWBA), together with a more detailed investigation of plasma and tumour samples, following administration of a single intravenous dose at 200?mg?kg^?1 of ¹⁴C-ZD6126 to mice bearing subcutaneous Hras5 tumour xenografts. The study also included an assessment of tumour necrosis following administration of a single intravenous dose of non-labelled ZD6126 at 200?mg?kg^?1. QWBA analysis showed that drug-related material was widely distributed to the tissues and tumour. In the majority of tissues, concentrations of radioactivity were highest at 15?min and declined rapidly thereafter. The tumour-to-plasma ratio was 0.6:1 at 0.25?h and increased to 6:1 at 48?h, indicating that drug-related material persisted in the tumour longer than in plasma. ZD6126, a phosphate ester, is rapidly hydrolysed to ZD6126 phenol, the active metabolite. The major metabolite in plasma (36% of the sample radioactivity) and all tumour samples (58–83% of the sample radioactivity) was confirmed as ZD6126 phenol. Extensive tumour necrosis was noted by 24?h, which was still evident at 48?h, although there was some evidence of tumour regrowth.     

Tissue distribution of dioxin-like compounds: Potential impacts on systemic relative potency estimates

Relative effect potencies (REPs) for dioxins and dioxin-like compounds based on tissue concentration or internal dose (^systemicREPs) can be considered of high relevance for human risk assessment. Within the EU-project SYSTEQ, ^systemicREPs for 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD), 2,3,4,7,8,-pentachlorodibenzofuran (4-PeCDF), 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), 2,3′,4,4′,5-pentachlorobiphenyl (PCB 118) and 2,3,3′,4,4′,5-hexachlorobiphenyl (PCB 156) were calculated based on a plasma, adipose tissue or liver concentration in Sprague Dawley rats and C57bl/6 mice three days after a single oral dose. Compound-specific distribution as well as differences in accumulation and elimination can influence the tissue concentration and thereby the relative potency estimate of a congener. Here, we show that distribution patterns are generally similar for the tested congeners between the SYSTEQ dataset and other studies using either a single dose or subchronic dosing. Furthermore, the responding concentration for TCDD in single dose studies is comparable to the responding concentrations reported in subchronic studies. In contrast with data for laboratory rodents, available distribution data for humans in the general population display little or no hepatic sequestration. Because hepatic sequestration due to CYP1A2 protein binding may affect the amount of congener that is bioavailable for the AhR to produce hepatic responses, estimates of relative potencies between congeners with differing degrees of hepatic sequestration based on hepatic responses may be misleading for application to human risk assessment. Therefore, extra-hepatic concentration in blood serum/plasma or adipose tissue together with a biological extra-hepatic response might give a more accurate prediction of the relative potency of a congener for human responses under environmental conditions.     

3H-乙炔雌二醇环戊醚的吸收、分布和排泄

给雌大鼠口服氚标记的乙炔雌二醇环戊醚(EECPE)后半小时血液中即可测出放射性,但10小时后才达高峰。在胃肠道的生物半衰期为13小时,说明³H-EECPE的吸收较慢。猴服³H-EECPE后1小时血液即可测出放射性,4小时达高峰。³H-EECPE被吸收后,在大鼠和猴体内的分布均以脂肪组织的浓度最高,脑组织的浓度也较高,而在靶器官—子宫、输卵管、乳腺—的浓度却不高。³H-EECPE在各组织中均有较长时间的储留,尤其在脂肪组织中储留的时间更长,这可以解释其口服后的长效作用。³H-EECPE的主要排泄途径为粪,自尿排出较少。由于在体内储留,所以排泄缓慢。     

吡喹酮对日本血吸虫雄虫的Ca2+,Mg2+,K+与Na+的含量及45Ca2+在虫体内分布的影响

日本血吸虫雄虫在4℃或37℃的HBS及无⁴⁵Ca²⁺的HBS中经吡喹酮1或30μg/ml作用0.5～2h后,未见虫的Ca²⁺,Mg²⁺含量有明显变化,但除4℃的HBS组外,余2组虫的K⁺含量明显减少,而虫的Na⁺含量的增加则不明显。在含30 mM Mg²⁺的HBS中,雄虫经吡喹酮作用1h后,虫的Mg²⁺含量明显增加。在37℃的HBS中,血吸虫雄虫经吡喹酮1μg/ml作用5～60min后,虫的皮层胞质中的⁴⁵²⁺含量的百分比较各相应对照组的明显减少,而虫体肌肉的则相反。在4℃的HBS或无⁴⁵Ca²⁺的HBS中,吡喹酮对⁴⁵²⁺在虫体内的分布无明显影响。     

A quantitative cerebral and whole body autoradiographic study of a intravenously administered benzodiazepine antagonist 3H-Ro 15-1788 in mice

³H-Ro 15-1788, a benzodiazepine receptor antagonist, was injected IV into male and pregnant mice. Autoradiograms were prepared from sagittal sections of animals killed after 30 s to 48 h. In the adult animal there was a rapid and high initial accumulation of radioactivity in the brain as compared to other organs and tissues. The highest accumulation was found in cortical brain areas, such as the olfactory bulb and the frontal cortex. Cerebellar cortex, globus pallidus, amygdala, substantia nigra, colliculus, hippocampus and pons followed in rank order. The rate of decline of radioactivity was highest in the pons and lowest in the olfactory bulb. The initial disappearance of radioactivity from the cerebellum was higher than from the other brain regions. Ro 15-1788 was rapidly eliminated; 4 h after drug administration there was an almost complete clearance of radioactivity from all tissues. After 24 h no trace of activity remained in the animal. The distribution of radioactivity at later time points indicates that metabolites of Ro 15-1788 are eliminated by fecal, urinary and nasal secretion. In the fetus also there was an early accumulation of radioactivity in the central nervous system. The radioactivity in fetal organs was lower than in the mother at all time intervals.     

Circadian variation in the head twitch response produced by 5-methoxy-N1,N1-dimethyltryptamine and p-chloroamphetamine in the mouse

Circadian fluctuations were measured in the head twitch response produced by 5-methoxy-N¹,N¹-dimethyltryptamine (5-MeODMT) and p-chloroamphetamine (PCA) in male BK. TO mice. The effects of depleting brain 5-hydroxytryptamine (5-HT) with p-chlorophenylalanine (PCPA) on the 5-MeODMT in the mouse were also studied. Changes in brain 5-HT and 5-hydroxyindoleacetic (5-HIAA) were concomitantly determined. PCPA (400 mg/kg IP twice on consecutive days) significantly increased the number of head twitches induced by 5-MeODMT (5 mg/kg IV) on days 3 and 5 after the initial injection of PCPA when 5-HT and 5-HIAA were also significantly reduced. On day 12, there was no significant difference in the number of head twitches between mice administered PCPA and those given saline, and 5-HT and 5-HIAA levels were nearly back to normal. PCPA, using the same dose schedule, significantly reduced the number of head twitches induced by PCA when PCA was administered 24h after the second injection of PCPA (day 3). Mice maintained on a 12-h light-dark cycle showed a maximum response to the direct 5-HT receptor agonist 5-MeODMT (5 mg/kg IV) towards the end of the dark period, when the 5-HT level was at its lowest. p-Chloroamphetamine, which causes release of 5-HT from pre-synaptic neurones, produced a peak head twitch response in the middle of the light period when 5-HT and 5-HIAA levels were maximal, while the response towards the end of the dark period was significantly less than that at other tines tested. It is concluded that 5-HT receptor response shows a circadian rhythm related to both pre-synaptic availability of 5-HT and post-synaptic receptor sensitivity.     

Pharmacokinetics,mass balance,and metabolism of [14C]vicagrel,a novel irreversible P2Y12 inhibitor in humans

Vicagrel, a novel irreversible P2Y₁₂ receptor inhibitor, is undergoing phase III trials for the treatment of acute coronary syndromes in China. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg [¹⁴C]vicagrel (120 µCi). Vicagrel absorption was fast (T_max = 0.625 h), and the mean t_1/2 of vicagrel-related components was ~38.0 h in both plasma and blood. The blood-to-plasma radioactivity AUC_inf ratio was 0.55, suggesting preferential distribution of drug-related material in plasma. At 168 h after oral administration, the mean cumulative excreted radioactivity was 96.71% of the dose, including 68.03% in urine and 28.67% in feces. A total of 22 metabolites were identified, and the parent vicagrel was not detected in plasma, urine, or feces. The most important metabolic spot of vicagrel was on the thiophene ring. In plasma pretreated with the derivatization reagent, M9-2, which is a methylated metabolite after thiophene ring opening, was the predominant drug-related component, accounting for 39.43% of the radioactivity in pooled AUC_0–8 h plasma. M4, a mono-oxidation metabolite upon ring-opening, was the most abundant metabolite in urine, accounting for 16.25% of the dose, followed by M3-1, accounting for 12.59% of the dose. By comparison, M21 was the major metabolite in feces, accounting for 6.81% of the dose. Overall, renal elimination plays a crucial role in vicagrel disposition, and the thiophene ring is the predominant metabolic site.     

Involvement of opioid receptors in phencyclidine-induced enhancement of brain histamine turnover in mice

Summary When the histamine (HA) turnover in the brain of mice was estimated on the basis of the pargyline-induced accumulation of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, the enhancing effect of phencyclidine (PCP) on the HA turnover was antagonized by a large dose of naloxone. However, a dopamine receptor antagonist haloperidol, which is also a potent receptor antagonist, did not inhibit the effect of PCP on the HA turnover. [abetd-Ala², abetd-Leu⁵]enkephalin, a prototypic opioid agonist, markedly enhanced the HA turnover. The effect of this peptide was demonstrated not only when the HA turnover was determined by the pargyline-induced t-MH accumulation but when it was estimated by the HA depletion induced by -fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. A agonist, SKF-10047, and a agonist, ethylketazocine, had no PCP-like enhancing effect on the HA turnover. These results suggest that PCP enhances the brain HA turnover in mice by stimulating, probably indireclty, endogenous opioid systems. Send offprint requests to K. Saeki at the above address     

Autoradiographische und radiochromatographische Untersuchungen der Verteilung und des Stoffwechsels von Thioacetamid

Summary The distribution of³⁵S-thioacetamide after a large dose (40 mg/100 g) was investigated in thirteen rats using whole-body autoradiography. Control experiments were made on six rats which were given³⁵S-sodium sulphate in order to differentiate the radioactivity due to³⁵S-thioacetamide from that due to metabolically formed sulphate. In addition, extracts of various organs, faeces and urine from five other rats were examined using Chromatographic separation methods.The results show that there is an accumulation of thioacetamide or thioacetamide sulphoxide in the centres of the liver lobules, in the outer medullary portion of the kidney, in the heart muscle, spleen and lymph nodes, in the mucous membranes of the stomach and the intestine and also in the gastric and intestinal contents. After the administration of a large dose of³⁵S-thioacetamide about 80% of the radioactivity is excreted in the urine as thioacetamide or its sulphoxide within 24 hours. A small fraction is eliminated through the gastro-intestinal tract.Our findings suggest that in thioacetamide poisoning there is a correlation between organ damage and the concentration of the poison in the organ, especially in the liver.

Die Autoradiographien wurden im Pharmakologischen Institut der Freien Universität (Direktor: Prof. Dr. Herken) hergestellt). Für die Unterstützung bei der Durchführung der Arbeiten haben wir Herrn Prof. Dr. Koransky sehr zu danken.Frl. C. Eulenstedt leistete hervorragende technische Assistenz.     

Stimulus-evoked release of tritiated monoamines from rat periaqueductal gray slices in vitro and its receptor-mediated modulation

Summary The periaqueductal gray is a brain region of considerable interest. It is innervated by monoamine-containing neurons as well as by a variety of peptidergic fiber systems, and it participates in the regulation of various functions. Virtually nothing is known about monoamine release in the periaqueductal gray and its receptor-mediated modulation. We therefore studied the release of radioactivity from periaqueductal gray slices preloaded with tritriated monoamines, using an in vitro superfusion method.The release of radioactivity from superfused periaqueductal gray slices after preloading of the tissue with [³H]noradrenaline increased upon electrical stimulation in a frequency-dependent manner. The stimulus-evoked release of radioactivity was Ca²⁺-dependent. Clonidine reduced and yohimbine enhanced the release. The inhibition curve for the effect of clonidine was shifted to the right in the presence of 10^–6 M yohimbine. While phenylephrine, isoprenaline, SK&F 38393, quinpirole, carbachol, [Arg⁸]vasopressin, -MSH and ACTH-(1-24), at a concentration of 10^–6 M, did not influence the electrically evoked release of radioactivity, [Leu⁵]enkephalin reduced it. The selective -opioid receptor agonists [d-Ala²,NMePhe⁴,Gly-ol⁵]enkephalin and [d-Arg²,Lys⁴]-dermorphin-(1–4)-amide reduced the release of radioactivity, whereas the selective opioid receptor agonist [d-Pen²,d-Pen⁵]enkephalin and the selective K opioid receptor agonist U-69593 had no effect. In the presence of naloxone, which by itself had no effect on the release of radioactivity, the effect of [d-Arg²,Lys⁴]dermorphin-(1–4)-amide was abolished. These results show that the release of noradrenaline from periaqueductal gray slices is via a Ca²⁺-dependent. exocytotic process, and that it is modulated through ₂-adrenoceptors as well as via -opioid receptors. Though the overflow of radioactivity from slices preloaded with [3H]dopamine in the presence of desipramine was measurable, there are reasons to assume that we are dealing here with the release of tritiated catecholamines from a population of nerve endings consisting of noradrenergic and dopaminergic terminals.The release of radioactivity from periaqueductal gray slices preloaded with [³H]5-hydroxytryptamine upon elevation of the K⁺ concentration in the superfusion medium was much more pronounced than that induced by electrical stimulation. The K⁺-evoked release of radioactivity was almost completely abolished in the absence of Cat²⁺; showing that the release is via a Ca²⁺-dependent process. 5-Hydrotryptamine reduced the K⁺-evoked release of radioactivity in a concentration-dependent manner.Some of these data were presented at the XIth International Congress of Pharmacology, 1–6 July 1990, Amsterdam, The Netherlands (Eur J Pharmacol 183:408) Send offprint requests to D. H. G. Versteeg at the above address     

Reactions of vinyl chloride with RNA and DNA of various mouse tissues in vivo

The irreversible binding of ¹⁴C-vinyl chloride metabolites to RNA and DNA of mouse brain, lung, liver, kidney, spleen, pancreas, and testes after a single i.p. injection has been studied. Hydrolysates of nucleic acids from selected organs were separated on Aminex A6 for quantitation of alkylation products.Radioactivity in nucleic acids was registered in all of the studied organs with the exception of brain. RNA from spleen, pancreas and liver, and DNA from spleen and liver contained the highest amounts of radioactivity. In nucleic acids from spleen and pancreas, both organs of high metabolic activity, the entire radioactivity was found metabolically incorporated as C₁-fragments. In RNA of kidney and liver, a large part of the radioactivity was also present as incorporated C₁-fragments, but 3,N⁴-ethenocytidine (in kidney) as well as 1,N⁶-ethenoadenosine and 1,N⁶-ethenoadenine (in kidney and liver) were identified as alkylation products. In liver DNA, incorporation of C₁-fragments was insignificant, indicating different interactions of vinyl chloride metabolites (C₁-fragments and alkylating products) with RNA and DNA. The elution profiles of radioactivity in hydrolysates of liver DNA were dominated by an alkylation product of unknown structure (probably a derivative of deoxyguanosine). Possibly, 1,N⁶-ethenodeoxyadenosine and 1,N⁶-ethenoadenine were also present in liver DNA.The results are consistent with the ability of vinyl chloride to act as a multipotent carcinogen by alkylation of DNA in several tissues.     

高三尖杉酯碱在大鼠及小鼠的代谢

本文报告³H-高三尖杉酯碱在正常大鼠、小鼠和荷瘤小鼠体内的吸收、分布和排泄。给大鼠静注后,t_1/2(α)和(β)分别为2.1和53.7分钟。静注后15分钟,以骨髓、肾和肝的放射性最高。荷瘤小鼠体内的放射性分布情况与正常大鼠的趋势相仿。静注后24小时,自大鼠尿排泄剂量的42.2%,在粪中排出6.3%,其中原形药放射性占剂量的15.9%。静注后48小时,自胆汁排泄剂量的57.7%,其中原形药放射性占剂量的20.2%。该碱经肌注也可被迅速吸收入血。     

Distribution and elimination of (14C)-2-ethylhexyl acrylate radioactivity in rats

The fate of (¹⁴C)-2-ethylhexyl acrylate was studied in adult male Wistar rats given an intravenous (i.v.) or intraperitoneal (i.p.) injection of 10 mg/kg (0.054 mmol/kg). The elimination of radioactivity from blood was bi-exponential, irrespective of the route of (¹⁴C)-2-EHA administration or the age (weight) of the rats. The first phase half-lives after i.v. and i.p. administration in 4-month-old rats were 30 and 60 min, in 7-month-old rats 115 and 130 min, respectively. The corresponding values for the slow-phase were 5 and 6 h, and 14 and 14h. Elimination of the radioactivity from tissues followed a pattern similar to that seen for blood. More than half of the administered radioactivity was exhaled as carbon dioxide. Exhalation of unchanged (¹⁴C)-2-EHA accounted for only 0.05% (i.v.) or 0.3% (i.p.) of the initial dose of radioactivity. The radioactivity excreted in the urine within the first 24 h posttreatment accounted for 7% (i.p.) or 14% (i.v.) of the initial dose, and only 2% was excreted as thioethers.     

Comparative Tissue Distribution and Elimination of Amphotericin B Colloidal Dispersion (Amphocil®) and Fungizone® After Repeated Dosing in Rats

The pharmacokinetic profiles of amphotericin B (AmB) after administration of Amphocil^®, an AmB/cholesteryl sulfate colloidal dispersion (ABCD) and the micellar AmB/deoxycholate (Fungizone^®) were compared after repeated dosing in rats. After administration of ABCD and Fungizone at an equal AmB dose (1 mg/kg), AmB concentrations in plasma and most tissues were lower for the ABCD dose, especially in the kidneys where reduced drug concentration correlated with reduced nephrotoxicity. In contrast, AmB concentrations in the liver were substantially higher when ABCD was administered; however, without an accompanying increase in hepato-toxicity. Daily administration of ABCD for 14 days did not lead to AmB accumulation in plasma; while a slight accumulation was observed after multiple administration of Fungizone. AmB was eliminated more slowly from the plasma and various tissues and urinary and fecal recoveries of AmB were reduced after ABCD administration. These results suggest that ABCD may be stored in tissues in a form that is less toxic and is eliminated from the systemic circulation by a different mechanism than the free and protein-bound AmB in plasma. AmB accumulation in the spleen was observed when higher doses of ABCD (5 mg/kg) were administered, which could be due to saturation of hepatic uptake of AmB. Comparison of spleen concentrations of AmB between ABCD and Fungizone^® at 5 mg/kg AmB doses was not possible because of Fungizone's toxicity in rats. In all other organs, AmB concentrations reached or approached a steady state within two weeks of dosing with ABCD. Urinary and fecal clearances of AmB were not different between ABCD and Fungizone administration. In summary, the distribution and elimination characteristics of AmB in rats were substantially altered when it was administered as ABCD in comparison to Fungizone. Nephrotoxicity of AmB in rats was reduced after administration of ABCD apparently because of the altered tissue distribution pattern. Thus, ABCD (Amphocil^®) may be a clinically beneficial formulation of AmB in patients with systemic fungal infections.     

UPLC-MS,HPLC-radiometric,and NMR-spectroscopic studies on the metabolic fate of 3-fluoro-[U-14C]-aniline in the bile-cannulated rat

1. A study of the rates and routes of excretion of 3-fluoro-[U-¹⁴C]aniline following intraperitoneal administration to male bile-cannulated rats by liquid scintillation counting (LSC) gave a total recovery of ～ 90% in the 48?h following dosing, with the majority of the dose being excreted in the urine during the first 24?h (～ 49%).

2. The total recovery as determined by ¹⁹F-nuclear magnetic resonance (¹⁹F-NMR) was ～ 49%, with the majority of the dose excreted in the first 24?h (～ 41%). The comparatively low recovery in comparison to that obtained from LSC was due to matrix effects in bile and a contribution from metabolic defluorination.

3. High-performance liquid chromatography with radiometric profiling of urine and bile revealed a complex pattern of metabolites with the bulk of the dose excreted as a single peak.

4. Ultra-performance liquid chromatography-orthogonal acceleration time of flight mass spectrometry profiling also showed a complex pattern of metabolites, detecting ～ 21 metabolites of 3-fluoroaniline (3-FA) with six of these detected only in urine and four solely in bile.

5. ¹⁹F-NMR revealed the presence of the parent compound and 15 metabolites in urine collected during the first 24?h after -dosing. The matrix effects of bile on ¹⁹F-NMR spectroscopy made metabolite profiling impractical for this biofluid.

6. The major metabolite of 3-FA was identified as 2-fluoro-4-acetamidophenol-sulfate.

     

The role of the liver and kidneys in the pharmacokinetics of subcutaneously administered teriparatide acetate in rats

1. Teriparatide acetate, a synthetic polypeptide fragment consisting of human parathyroid hormone residues 1-34 [hPTH(1-34)], is a bone anabolic agent used to treat osteoporosis.

2. The present study was conducted to characterise the pharmacokinetics of teriparatide acetate in rats after subcutaneous administration.

3. Teriparatide was rapidly absorbed into the circulation and eliminated immediately. No intact teriparatide was detected in the urine. To elucidate the mechanism of teriparatide metabolism, we performed in vivo and in vitro studies using the radiolabelled bioactive analogue, [¹²⁵I]-[Nle^8,18,Tyr³⁴]-hPTH(1-34). After subcutaneous administration, the concentration of analogue metabolites increased in the plasma time-dependently. The concentration in the kidneys was more than 3-fold the concentration in the liver. In vitro analyses suggested that kidney radioactivity was associated with degraded bioactive analogue. In model rats, renal failure, but not hepatic failure, affected the pharmacokinetics of teriparatide acetate, which accounted for the decrease in the clearance of teriparatide.

4. In conclusion, our results suggest that after subcutaneous administration of teriparatide acetate, teriparatide is rapidly absorbed and distributed to the liver or kidneys, where it is immediately degraded. The kidneys play a particularly important role in the distribution and metabolism of teriparatide, but not its excretion.

     

Distribution of 3H-soman in mice

³H-soman (specific activity 10 Ci/mMol), a potent irreversible cholinesterase inhibitor, was administered IV to mice in a dose of one LD-50, which corresponds to 0.25 mCi/mouse. Animals were sacrificed at 5 min, 2 h and 24 h, and whole body autoradiography was performed. High levels of radioactivity in lung and skin were observed at all time intervals after injection. The central nervous system showed very low concentrations of radioactivity, which remained so for 24 h post-injection. Considerable accumulation of ³H-soman in the urine and gallbladder, and in the intestinal lumen, may indicate these as pathways of soman excretion. Quantitative determinations of radioactivity in various tissue samples were consistent with the above-mentioned findings.It is concluded that the nature of the persistent binding of soman to lung and skin is striking, and may indicate the existence of specific sites for soman depots.     

The absorption,tissue distribution,and excretion of dodecyldimethylamine oxide (DDAO) in selected animal species and the absorption and excretion of DDAO in man

The absorption tissue distribution, and excretion pattern of [methyl-¹⁴C]DDAO and [1-dodecyl-¹⁴C]DDAO administered orally or cutaneously to rats, mice, and rabbits were investigated. The excretion pattern of radioactivity from [1-dodecyl-¹⁴C]DDAO administered orally and cutaneously to man was also investigated. An oral dose of DDAO is rapidly and extensively absorbed and excreted by rats and man. Peak tissue levels of radioactivity resulting from oral administration of [methyl-¹⁴C]DDAO to rats occur within 1 hr after dosing. Cutaneously administered DDAO is absorbed by man, rats, rabbits, and mice. In man, the rate of DDAO absorption through the skin is at least one order of magnitude less than that observed in rats, mice, and rabbits.     

125I标记外泌体在Pan02胰腺癌荷瘤小鼠体内的生物分布研究

目的 旨在开发用 ¹²⁵I-NaI标记外泌体的方法,并通过 γ 计数仪考察其在 Pan02 胰腺癌荷瘤小鼠体内的生物分布特征。方法 通过非放射性 NaI对用于治疗胰腺癌的工程化外泌体进行冷标记,采用透射电子显微镜、纳米粒子跟踪分析和Western blotting实验对标记前后外泌体进行表征。在此基础上采用Iodogen法进行外泌体的放射性 ¹²⁵I-NaI标记,分离纯化后测定 ¹²⁵I-NaI的标记率,Radio-HPLC法测定给药前后 ¹²⁵I-外泌体的放化纯度以考察其稳定性;将 ¹²⁵I-外泌体单次尾iv于Pan02胰腺癌荷瘤小鼠体内,分别于给药后2、6、24、72 h（每个时间点雌雄各3只）经CO₂麻醉后心脏放血处死小鼠,取血清、主要组织器官及肿瘤,γ计数仪测量其放射性计数,计算各组织/血清在不同时间点的蛋白沉淀率;并计算在不同时间点的每克组织（或每毫升血清）放射性计数占总注入放射性计数的百分比（%ID·g^-1或%ID·mL^-1）。结果 外泌体表征的结果显示,标记前后的外泌体形态一致,均成圆形或茶托样结构;标记前外泌体粒径峰值为 113 nm,标记后外泌体粒径峰值为 122 nm,粒径大小主要分布在 50～200 nm;均表达其标志性蛋白 CD63及 TSG101,符合外泌体特征。¹²⁵I-NaI标记外泌体的标记率为 27.82%,纯化后 HPLC法测得即时放化纯度为 100%,给药后放化纯度为（93.34±5.48）%。在小鼠尾 iv给药后 2 h,标记的外泌体主要分布在肝脏［（10.899 2±1.518 1）%ID·g^-1］和脾脏［（2.566 4±0.799 8）%ID·g^-1］,肿瘤中为［（0.291 0±0.056 0）%ID·g^-1］,脑、心脏、脂肪和肌肉组织摄取较少;给药后72 h,肝脏中仍有较高摄取,肿瘤中仍有放射性分布。给药后 2～6 h各组织脏器的蛋白沉淀率较低,表明 ¹²⁵I-NaI标记外泌体稳定性有所降低。结论 外泌体可以进行 ¹²⁵I标记,而且标记同位素前后对外泌体物理形态、生物学活性无明显影响;¹²⁵I标记外泌体的方法简便,标记率和放化纯度均较高;该外泌体产品在荷瘤小鼠体内大部分血流丰富的组织器官均有分布,且具有一定的肿瘤靶向定位能力。