静脉注射9-硝基喜树碱脂质体后原形药物经大鼠胆汁的排泄

目的:考察静脉注射9-硝基喜树碱脂质体后原形药物经大鼠胆汁的排泄。方法:建立了利用HPLC法测定大鼠胆汁中9-硝基喜树碱浓度的方法;测定了9-硝基喜树碱在大鼠空白胆汁中的内酯型浓度、总浓度和内酯型比例的变化;测定了静脉注射3mg.kg-19-硝基喜树碱溶液和脂质体后大鼠胆汁中原形药物的排泄情况。结果:9-硝基喜树碱内酯型结构在胆汁中不稳定,内酯型浓度和比例迅速下降但总浓度保持恒定。静脉注射9-硝基喜树碱溶液和脂质体后12h胆汁中原形药物的累积排泄量分别为给药剂量的7.9%和8.1%。结论:脂质体包封对于9-硝基喜树碱静脉注射后的胆汁排泄没有显著影响     

Biliary excretion kinetics of phenolphthalein glucuronide after intravenous and retrograde biliary administration

Several organic compounds of large molecular weight have previously been shown to be rapidly and primarily excreted via the biliary system of the rat after intravenous or retrograde biliary infusion. Poor biliary reabsorption has been suggested to explain these findings. The kinetics of the biliary excretion of Phenolphthalein glucuronide have been examined with concurrent plasma data. A spectrophotometric method, capable of measuring Phenolphthalein glucuronide in amounts as small as 4 nmol per 100 μl of plasma, was developed. The glucuronide (20–40 μmol kg^?1) was administered to 14 rats intravenously and to 12 rats by retrograde biliary infusion. There was a significant concentration of Phenolphthalein glucuronide in the systemic blood after glucuronide administration by either route and the kinetics of elimination of the glucuronide were similar. The plasma availability of biliary infused doses was over 45 % of the availability from the intravenous doses based on area under the curve calculations for the average plasma level-time curves. The results demonstrate the need to sample the plasma as well as the bile before any conclusion can be made about reabsorption of a compound from the biliary ducts.     

Absorption, distribution, and excretion of arbekacin after intravenous and intramuscular administration in rats

Absorption, distribution, and excretion of arbekacin (HBK) were studied in rats after intravenous or intramuscular administration of HBK at a dose of 10 mg/kg or 20 mg/kg. Elimination half-lives of HBK were 0.69 hour for bolus intravenous administration, 0.55 hour for constant rate intravenous infusion, and 0.57 hour for intramuscular administration. Cumulative urinary excretions within 24 hours after administration were 74.7% of the dose for bolus intravenous administration, and 79.1% of the dose for intramuscular administration. No significant difference was observed in the cumulative urinary excretions between the 2 administration routes. Cumulative biliary excretions within 24 hours after administration were around 0.1% of doses regardless administration routes, bolus intravenous or intramuscular administration. The tissue or organ distribution of HBK after bolus intravenous administration was similar to that after intramuscular administration. The drug was distributed most abundantly into the kidney followed by plasma and the lung. The distribution of the drug into the liver was the least among the 6 tissues or organs examined in this study. The protein binding of HBK was studied by an equilibrium dialysis method at three different concentrations of HBK, 5, 10, and 20 micrograms/ml. Binding ratios of HBK to human serum, human serum albumin, and rat serum were less than 15%.     

Apparent two phase beryllium labelling of hepatic cell nuclei isolated after intravenous administration of beryllium compounds to rats

Cell nuclei are known to possess a high affinity in vitro for the toxic metal beryllium (Be) and the presence of Be in isolated rat liver nuclei has been demonstrated previously after hepatic accumulation of toxic doses of Be compounds. Changes in hepatic nuclear binding of Be has now been examined in rats injected with either particulate (Be phosphate) or soluble (BeSO₄) forms of Be and a common dose and time dependent two phase labelling pattern has been observed in nuclei prepared from both whole liver homogenates and isolated liver parenchymal cells. The initial phase, which is associated with the known acute parenchymal cell necrosis caused by Be, rapidly reaches a maximum at 1–2 days and then declines sharply to minimal levels within 7 days. This is followed by a slower second phase of comparable Be binding observed between 14–24 days which subsequently gradually declines and which occurs when the liver Be content has markedly decreased and no cellular necrosis is evident. These data support the view that nuclear binding of Be is probably not directly involved in the induction of acute cell necrosis and that the early nuclear labelling observed with hepatotoxic doses of Be may be an artefact of the isolation procedure.     

Salivary excretion of mexiletine after bolus intravenous administration in rats.

Salivary excretion of mexiletine was investigated following bolus intravenous administration (10 mg kg-1) in rats. Parotid and mandibular saliva was collected separately by stimulating salivation with constant rate infusion of pilocarpine (3 mg kg-1 h-1). The mexiletine levels in blood plasma and parotid and mandibular saliva declined biexponentially with time in almost parallel fashion. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva. Significant correlations were observed when all data relating mexiletine concentration in plasma and saliva were included (P less than 0.001). The saliva/plasma drug concentration ratios (S/P ratios) did not vary to a large extent (0.56 +/- 0.10 for parotid saliva, 0.21 +/- 0.06 for mandibular saliva), but there was a consistent tendency for the higher plasma drug levels in the distribution phase to produce relatively high S/P ratios for both parotid and mandibular saliva. Moreover, the plasma mexiletine levels calculated by the equation of Matin et al (1974) employing the observed values for the saliva drug level, saliva pH and free fraction of mexiletine in plasma were significantly higher than the observed drug levels. Therefore, it is suggested that the salivary excretion of mexiletine could not be explained quantitatively by simple, passive secretion based on pH-partition theory.     

Distribution, metabolism and excretion of 14C-MT-141 in rats. II. Distribution and excretion after multiple intravenous administration in male rats and after single intravenous administration in female rats

The distribution and tissue accumulation of the radioactivity were studied in male rats after the multiple intravenous administration of 14C-MT-141. The distribution and the placental transfer were also studied using pregnant rats or lactating rats after the single intravenous administration of 14C-MT-141. The radioactive concentration in the fetus was low and the radioactivity was distributed almost uniformly through the fetus body. The peak time of the milk level was 2 hours after the administration and the radioactivity in milk decreased gradually thereafter. The milk levels decreased more slowly than the blood levels did. The blood level after the last dose administered daily for 7 days tended to decrease more slowly, when compared with the single administration. However the blood concentration at 48 hours after the last administration was less than 3 times as high as that after the single administration.     

Biliary excretion of erythromycin after parenteral administration.

1 The biliary excretion of erythromycin has been studied following parenteral administration in 23 patients. 2 Mean bile levels of the drug were approximately ten times higher than corresponding serum concentrations 1 h after i.v. (erythromycin lactobionate) and i.m. (erythromycin ethylsuccinate) injection. 3 Thus, unlike many antimicrobial agents, these compounds are well concentrated in the bile.     

Pharmacokinetics and tissue distribution of spinosin after intravenous administration in rats

Spinosin is the major effective single constituent in the traditional Chinese herb Semen Ziziphi Spinosae, which is used for sedation and hypnosis. For the further use of spinosin in treating insomnia, the pharmacokinetics and tissue distribution of spinosin after intravenous administration to rats was investigated. An HPLC method with an ODS column (250 mm x 4.6 mm, i.d.) and a mobile phase of acetonitrile-water-acetic acid (23:77:1) was used for the determination of spinosin in the plasma and tissues of rats. Vanillin was used as an internal standard, and spinosin was detected at 334 nm. The calibration curve of spinosin in plasma showed good linearity over the concentration range of 1-300 microg/ml, and the quantitation of limit of plasma was 1 microg/ml. The linear range of concentrations of spinosin in the heart, spleen, stomach, lung, testis, brain, and intestine was 0.1-40 microg/ml and the quantitation limit was 0.1 microg/ml. The linear range of concentrations of spinosin in the liver and kidney was 1-150 microg/ml, and the quantitation limit was 1 microg/ml. The correlation coefficients of all calibration curves were between 0.9939 and 0.9980. The intra and interrun precision for all samples was less than < or =11.0%. The time-concentration curve of spinosin after the intravenous administration of a single dose of 20 mg/kg to rats corresponded to the two-compartment model. The main pharmacokinetic parameters T(0.5alpha), T(0.5beta), CLs, AUC(0-T), and V(c) were 6.66 min, 51.5 min, 1.42 l.min(-1), 2.83 mg.min.ml(-1), and 14.0 l.kg(-1), respectively. At 20 min, a concentration peak occurred in liver and brain tissues. The highest level of spinosin occurred in the liver, followed by the spleen and kidney. The lowest level of spinosin appeared in the testis, followed by the brain. Spinosin was not detected in smooth and skeletal muscle. After intravenous administration, the drug was distributed extensively and transferred quickly in rats in vivo.     

Pharmacokinetics and distribution of styrene monomer in rats after intravenous administration

An interest in the pharmacokinetics of styrene monomer in the rat, arising from the presence of the monomer in the industrial work place and in foods, necessitated an investigation of the dose dependency of the kinetics of styrene monomer when administered by the iv route. A rapid distribution of the monomer to the major organs was observed, and all of the rate coefficients describing the rates of distribution and elimination decreased with increasing dose. No change in the apparent volume of distribution with dose was observed. Some evidence for the involvement of saturable metabolic pathways was obtained.     

Biliary excretion of nitrazepam and its metabolites in rats

A single intravenous administration of nitrasepam (10 mg/kg) resulted in its excretion as free and conjugated metabolites in the bile of albino rats. The initial compounds, amino- and acetamido derivatives were deteced among free metabolits. Conjugated forms were recovered as N-glucoronides (5-nitro-2-aminobenzophenon and amine) and as O-glucoronides (C3-hydroxylated derivatives of nitrasepam and of acetamide). The presence of a considerable amount of nitrasepam and of its metabolites in the rats' bile is suggestive of their enterohepatic circulation.     

The absorption, distribution and excretion of pentazocine in man after oral and intravenous administration

Gas-liquid chromatography is a sensitive technique for the analysis of pentazocine in biological samples. Dose for dose, the concentration in blood and the urinary excretion rate of pentazocine are much lower after oral administration than after intravenous administration. The recovery of the unchanged drug in faeces is low whether it is given by mouth or intravenously.     

Distribution and excretion of methamphetamine and its metabolites in rats. III. Time-course of concentrations in blood and bile, and distribution after intravenous administration

The time-course of blood total radioactivity after i.v. administration of 3H-methamphetamine to rats showed a biphasic curve. The biological half-life of the alpha phase (t alpha 1/2) was 6.8 +/- 2.0 min, and that of the beta phase (t beta 1/2) was 11.3 +/- 0.8 h. The major metabolite in the blood was unconjugated p-hydroxymethamphetamine. The total radioactivity in bile peaked at 1.5 h after i.v. administration. The major metabolite in the bile was p-hydroxymethamphetamine glucuronide. The major compound excreted in urine was unchanged methamphetamine. Whole-body autoradiography was performed using 14C-methamphetamine, and tissue 3H concn. was determined after i.v. administration of 3H-methamphetamine to rats.     

大鼠口服东莨菪素后的组织分布和排泄特征研究(英文)

研究东莨菪素在大鼠体内的组织分布和排泄特征,SD大鼠灌胃东莨菪素(50mg/kg),分别于给药后5,15,30,60,120,240分钟取大鼠心、肝、脾、肺、肾、肌肉、脂肪、脑、睾丸、子宫、胃、小肠等组织器官测定其原形药物浓度。结果表明,东莨菪素广泛分布于各组织器官且于给药后15分钟浓度即达峰值,其中肝、肾、胃和小肠含量较高。此外,东莨菪素在胆汁、尿液、粪便的排泄研究显示,胆汁、尿液、粪便的累积排泄量分别为0.032%,3.752%和0.784%。表明东莨菪素在大鼠体内主要以代谢物的形式消除。     

Biliary excretion of chlorthalidone in humans

A single oral dose of the diuretic chlorthalidone (100 or 200 mg) was given to six cholecystectomized patients with T-tube drainage of the common bile duct, and the 24 h bile and urine were collected during 3–7 days. Urinary recovery of chlorthalidone was 23–27 per cent of the dose, which is in the range of that in healthy volunteers. Chlorthalidone concentration in bile was 11–44 times lower than urine concentration in corresponding periods, and biliary recovery was only 0·6–1·4 per cent of the dose. When compared from equal periods of sampling of bile and urine, the same relative amount of drug was found in bile, whether the 100 or 200 mg dose had been given (viz., a fraction of 2·5–4·7 per cent and 2·5–5·7 per cent of corresponding urinary amounts respectively). It was concluded that excretion into bile constitutes only a minor route of elimination for unchanged chlorthalidone. Bile samples treated with glucuronidase and sulphatase showed no increase of chlorthalidone concentration. The open acid analogue of chlorthalidone, 3-(4-chloro-3-sulphamoylbenzoyl)-benzoic acid, was apparently not formed as a human metabolite, as evidenced by gas chromatographic analysis of both urine and bile.     

Pharmacokinetics and body distribution of amiodarone and desethylamiodarone in rats after intravenous administration

The pharmacokinetics and body distribution of amiodarone and desethylamiodarone were investigated in rats following a single intravenous dose of 100 mg/kg and 150 mg/kg of amiodarone. The decline in serum and tissue concentrations of amiodarone and desethylamiodarone are described by biexponential functions. All aspects of the typical kinetic profile of the drug and its major metabolite, desethylamiodarone, are discussed. Amiodarone is preferentially distributed in decreasing order in thyroid gland, lung, kidney, liver, heart, adipose tissue, skeletal muscle and brain. The metabolite desethylamiodarone showed a distribution pattern which is similar to that observed for the parent drug. Our study indicates an extensive distribution of amiodarone, with the thyroid gland and lung as organs with specific binding sites or uptake mechanisms and adipose tissue as a depot with a large storage capacity. We also found a very extensive distribution of the metabolite desethylamiodarone with mainly lung and thyroid gland and to some lesser extent kidney, liver and heart as organs with sites of metabolism and/or specific binding sites or uptake mechanisms and fat as a reservoir for the drug. Our data demonstrate the advantages of intravenous loading dosages of amiodarone over oral doses, since considerably higher and longer lasting effective serum and tissue concentrations of amiodarone are reached while lower quantities of the less cardio-active metabolite are formed.     

Mammary excretion of cannabidiol in rabbits after intravenous administration

Abstract— The present study examined the distribution of cannabidiol into milk after an intravenous bolus injection (3 mg kg^?1) to lactating rabbits. Drug concentrations in milk and serum were measured by HPLC. Cannabidiol was excreted into milk rapidly and the drug levels in milk increased over a 4–24-h period following the maternal injection. The mean milk to serum concentration ratio was 25·9, indicating a significant accumulation of the drug in milk.     

Biliary excretion and tissue distribution of penta- and hexavalent molybdenum in rats

Biliary excretion, whole-body excretion, and distribution of pentavalent and hexavalent forms of molybdenum in blood, liver, and jejunoileocecum were studied in rats at 1, 2, 3, and 4 hr after iv administration of 0.08 and 4.6 mg of molybdenum/kg. The excretion of both valence forms of molybdenum was found to be dose dependent. No difference was observed between the two valence forms in the biliary and whole-body excretion after the dose of 0.08 mg Mo/kg, whereas after the administration of 4.6 mg Mo/kg the excretion of pentavalent molybdenum was considerably decreased. This was accompanied by a slower decline in the content of pentavalent molybdenum in all the analyzed tissues.     

Pharmacokinetic disposition and tissue distribution of bisphenol A in rats after intravenous administration

This study examined the dose-linearity pharmacokinetics of bisphenol A, a U.S. Environmental Protection Agency (EPA) classified endocrine disruptor, in rats following iv administration. Upon iv injection of 0.2, 0.5, 1, or 2 mg/kg, serum levels of bisphenol A declined biexponentially, with mean initial distribution and elimination half-life ranges of 4-8.2 min and 38.6-62.2 min, respectively. There were no significant alterations in the systemic clearance rate (mean range 90.1-123.6 ml/min/kg) and the steady-state volume of distribution (mean range 4.6-6.0 L/kg) as a function of the administered dose. In addition, the area under the serum concentration-time curve linearly rose as the dose was increased. In a second study, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state, and levels were measured in serum and various organs. When expressed in concentration terms (e.g., amount accumulated per gram organ weight), bisphenol A was found predominantly in the lung, followed by kidneys, thyroid, stomach, heart, spleen, testes, liver, and brain. Ratios of the organ to serum bisphenol A concentrations exceeded unity for all the organs examined (ratio range 2.0-5.8) except for brain (ratio 0.75). Given the high systemic clearance and short elimination half-life, bisphenol A is unlikely to accumulate significantly in the rat.     

Pharmacokinetic study of darbepoetin alfa: Absorption,distribution, and excretion after a single intravenous and subcutaneous administration to rats

KRN321 is a hyperglycosylated analogue of recombinant human erythropoietin (rHuEPO, epoetin alfa), and its absorption, distribution, and excretion have been studied after a single intravenous and subcutaneous administration of ¹²⁵I-KRN321 at a dose of 0.5?µg?kg^?1 to male rats. The half-lives of immunoreactive radioactivity in the terminal phase after intravenous and subcutaneous administration were 14.05 and 14.36?h, respectively, and the bioavailability rate after subcutaneous administration was 47%. The total radioactivity in tissues was lower than that in the serum in all tissues excluding the thyroid gland and skin at the injection site (subcutaneous administration). The maximum concentrations were observed in the bone marrow or skin at the injection site followed by the thyroid gland, kidneys, adrenal glands, spleen, lungs, stomach and bladder. The radioactivity found in trichloroacetic acid-precipitated fractions suggested that a high-molecular weight compound, unchanged or mixed with endogenous protein, distributed to the tissues after administration. The whole-body autoradiographic findings in both groups were in agreement with the tissue distribution mentioned above. The blood cell uptake of KRN321 was low for both groups. The excretion ratios of radioactivity into urine and faeces up to 168?h were 71.4 and 14.1% after the intravenous administration and 74.9 and 12.0% after the subcutaneous administration. There was no difference in the excretion profile of radioactivity between the two groups.