Absorption, distribution and excretion of 3H-labeled cephaeline- and emetine-spiked ipecac syrup in rats.

The maximum plasma radioactivity levels of tritium (3H)-labeled cephaeline, (24.3, 28.7 and 40.6 ng eq./mL) were reached at 2.00-3.33 hours following oral dosing of ipecac syrup. The maximum plasma radioactivity levels of 3H-emetine (2.71, 6.47 and 9.62 ng eq./mL) were reached at 1.08-2.33 hours following ipecac syrup administration. The Cmax values of 3H-cephaeline were followed by a biexponential decrease with half-lives t 1/2(lambda z) of 3.45-9.40 hours. On the other hand, the t 1/2 (lambda z)of 3H-emetine were 65.4-163 hours, which revealed a biexponential decrease. The radioactivity of both tritium-labeled compounds was distrbuted maximally in most tissues at 24 hours. For 3H-cephaeline, the maximum radioactivity levels in tissues were approximately 100-150 times greater than in plasma. For 3H-emetine, the radioactivity levels in tissues were approximately 1000-3000 times greater than in plasma. Tissue radioactivity levels decreased at a substantially slower rate than that observed in plasma. Tissue radioactivity of 3H-emetine decreased more slowly than that of 3H-cephaeline. For 3H-cephaeline, the cumulative biliary excretion of radioactivity was 57.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity in these rats was 16.5% and 29.1%, respectively, of the dose at 48 hours following dosing. For 3H-emetine, the cumulative biliary excretion of radioactivity was 12.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity was 9.4% and 34.1%, respectively, of the administered dose at 48 hours. The radioactivity level of 3H-emetine remaining in the carcasses at 48 hours was equivalent to approximately 50% of the dose. A portion of each tritium-labeled compound was subjected to entero-hepatic circulation. Thus, the absorption rate of 3H-cephaeline and 3H-emetine was estimated to be approximately 70% on the basis of the data obtained from excretion studies. There was no difference in the absorption process between these two compounds. However, the difference was admitted in the biliary clearance, which is the main excretion route of both compounds. Delayed excretion of 3H-emetine may be primarily due to its resorption as related to entero-hepatic circulation and tissue retention. This study has determined the absorption, distribution and excretion of 3H-cephaeline and 3H-emetine in rats.     

Absorption, distribution, metabolism, and excretion of 1,2-dihydro-2,2,4-trimethylquinoline in the male F344 rat

1,2-Dihydro-2,2,4-trimethylquinoline (TMQ), an antioxidant used in the rubber industry, was readily absorbed from the gastrointestinal tract of the male Fischer 344/N rat and rapidly distributed throughout the body tissues. Absorption, distribution, metabolism, and excretion were not significantly affected by dose in the range 11.5-1150 mumol/kg. Following iv administration, the greatest amounts of TMQ-derived radioactivity were present in the high volume tissues including muscle, adipose, skin, liver, and blood. TMQ had no particular affinity for any tissue. TMQ-derived radioactivity was excreted primarily in urine (60-70%) and feces (20-30%) within 3 days after administration. Greater than 99% of the TMQ dose excreted in urine and feces was in the form of metabolites. Urine contained two major and ten minor metabolites while feces contained two major and four minor metabolites. The two major TMQ metabolites in urine were identified by NMR and mass spectroscopy as the O-sulfate conjugate of 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline and the monosulfate conjugate of 1,2-dihydro-1,6-dihydroxy-2,2,4-trimethylquinoline. In vitro studies with liver subcellular fractions suggest that most of the metabolites present in urine, feces, and bile are the products of mixed function oxidase activity and conjugates of these metabolites. Multiple exposure of rats to high TMQ doses (1150 mumol/kg) resulted in some bioaccumulation of TMQ-derived radioactivity in all tissues examined, but these residues did not persist when dosing was discontinued.     

Absorption,distribution, metabolism and excretion of p-bromophenylacetylurea in the female rat

1. This study has investigated absorption, distribution, metabolism and excretion of p-bromophenylacetylurea (BPAU) in the F344 female rat. BPAU and its metabolites were determined by HPLC. 2. Following a single p.o. dose of 150?mg/kg BPAU, the absorbed fraction of dosed BPAU was 65.9% and its half-life in the blood was 9.4 h. The relative distribution of BPAU (tissue/serum ratio) at 6 h (peak time point) after a single i.p. dose of 150?mg/kg BPAU was spinal cord (4.6 +/- 0.2) &;gt; liver (3.7 +/- 0.1) &;gt; brain (2.9 +/- 0.1) (mean +/- SD, n = 5), and they were significantly different from each other (p&;lt;0.05). BPAU in spinal cord reached the highest level. 3. Absorbed BPAU was metabolized in vivo into three major metabolites. N'-hydroxy- p-bromophenylacetylurea (M1) was a dominant metabolite in tissues, whereas 4-(4-bromophenyl)-3-oxapyrrolidine-2,5-dione (M2) reached a high concentration in blood. N'-methyl-p-bromophenylacetylurea (M3) was mainly found in the urine. All three metabolites were excreted via the urine and together accounted for 87% of absorbed BPAU. 4. This study provides a basic understanding of BPAU absorption, distribution, metabolism and elimination in rat.     

Absorption, distribution, metabolism and excretion of p-bromophenylacetylurea in the female rat

1. This study has investigated absorption, distribution, metabolism and excretion of p-bromophenylacetylurea (BPAU) in the F344 female rat. BPAU and its metabolites were determined by HPLC. 2. Following a single p.o. dose of 150 mg/kg BPAU, the absorbed fraction of dosed BPAU was 65.9% and its half-life in the blood was 9.4 h. The relative distribution of BPAU (tissue/serum ratio) at 6 h (peak time point) after a single i.p. dose of 150 mg/kg BPAU was spinal cord (4.6+/-0.2) > liver (3.7+/-0.1) > brain (2.9+/-0.1) (mean+/-SD, n = 5), and they were significantly different from each other (p < 0.05). BPAU in spinal cord reached the highest level. 3. Absorbed BPAU was metabolized in vivo into three major metabolites. N'-hydroxy-p-bromophenylacetylurea (M1) was a dominant metabolite in tissues, whereas 4-(4-bromophenyl)-3-oxapyrrolidine-2,5-dione (M2) reached a high concentration in blood. N'-methyl-p-bromophenylacetylurea (M3) was mainly found in the urine. All three metabolites were excreted via the urine and together accounted for 87% of absorbed BPAU. 4. This study provides a basic understanding of BPAU absorption, distribution, metabolism and elimination in rat.     

醋己氨酸锌在大鼠体内的吸收、组织分布和排泄

目的:研究醋己氨酸锌(zinc acexamate,ZA)在大鼠体内的吸收、组织分布、排泄等药代动力学特点。方法:用薄层色谱分离原形药后再用放射性定量。结果:大鼠iv[~3H]ZA(2.07MBq·kg~(-1)),血中分布相半衰期T_(1/2α)为0.8h,消除相半衰期T_(1/2β)11.0h,分布容积(V_d)为2.16L·kg~(-1)。ig[~3H]ZA(4.44MBq·kg~(-1)),灌胃给药后吸收迅速,血药浓度达峰时间为40min。结论:ZA经口给药吸收迅速,并能广泛分布于器官组织中。     

Metabolism of 3-(hydroxymethyl)-8-methoxychromone in the rat. I. Absorption, tissue distribution and excretion.

1. Two 14C-labelled preparations of 3-(hydroxymethyl)-8-methoxychromone were used to study the absorption, tissue distribution and excretion of isotope after oral administration to rats (20 mg/kg). 2. 14C, presumably from the labelled hydroxymethyl side-chain, was eliminated extensively as 14CO2. This excretion was triphasic; kinetic constants were calculated for each phase. 3. The major excretion route was via the kidney although significant quantities of isotope were excreted with the faeces. Isotope did not accumulate in tissues.     

The tissue distribution, metabolism, and excretion of octachlorostyrene in the rat

The tissue distribution, metabolism, and elimination of 14C-octachlorostyrene (OCS) were studied in the rat. OCS was absorbed in the gastrointestinal tract after oral administration and distributed in all tissues examined. The highest concentrations were found in fat followed by adrenal glands, skin, and lungs. Decay of radioactivity in the tissues followed first-order kinetics. Approximately 8% of an iv dose was excreted in feces during 7 days after administration, while negligible amounts were found in the urine. More than 90% of the radioactivity in feces was due to the unchanged compound, while pentachlorophenyldichloroacetic acid and heptachlorostyrene in equal proportions accounted for the remaining 10%. A small amount (1%) of the dose was detected in the expired air as carbon dioxide.     

Pharmacokinetics,bioavailability, tissue distribution and excretion of tangeretin in rat

Tangeretin, 4′,5,6,7,8-pentamethoxyflavone, is one of the major polymethoxyflavones (PMFs) existing in citrus fruits, particularly in the peels of sweet oranges and mandarins. Tangeretin has been reported to possess several beneficial bioactivities including anti-inflammatory, anti-proliferative and neuroprotective effects. To achieve a thorough understanding of the biological actions of tangeretin in vivo, our current study is designed to investigate the pharmacokinetics, bioavailability, distribution and excretion of tangeretin in rats. After oral administration of 50 mg/kg bw tangeretin to rats, the C_max, T_max and t_1/2 were 0.87 ± 0.33 μg/mL, 340.00 ± 48.99 min and 342.43 ± 71.27 min, respectively. Based on the area under the curves (AUC) of oral and intravenous administration of tangeretin, calculated absolute oral bioavailability was 27.11%. During tissue distribution, maximum concentrations of tangeretin in the vital organs occurred at 4 or 8 h after oral administration. The highest accumulation of tangeretin was found in the kidney, lung and liver, followed by spleen and heart. In the gastrointestinal tract, maximum concentrations of tangeretin in the stomach and small intestine were found at 4 h, while in the cecum, colon and rectum, tangeretin reached the maximum concentrations at 12 h. Tangeretin excreted in the urine and feces was recovered within 48 h after oral administration, concentrations were only 0.0026% and 7.54%, respectively. These results suggest that tangeretin was mainly eliminated as metabolites. In conclusion, our study provides useful information regarding absorption, distribution, as well as excretion of tangeretin, which will provide a good base for studying the mechanism of its biological effects.     

Absorption, distribution, excretion and metabolism of orally administered 14C-beta-cyclodextrin in rat

The absorption, distribution, excretion and metabolism of orally administered universally labelled 14C-beta-cyclodextrin and 14C-glucose were compared in rat. The maximum radioactivity of the blood derived from 14C-beta-cyclodextrin was observed between 4th and 11th h and the value of the maximum in different experiments ranged between 5 and 17 0/00 of the total administered radioactivity. Following 14C-glucose treatment radioactivity reached the maximum within half-an-hour, with values of 15 to 82 0/00. In the 8th h after a high dose (313.5 mg/kg) of beta-cyclodextrin no more than 3-50 ppm beta-cyclodextrin was detectable in the blood by HPLC. After 14C-beta-cyclodextrin treatment 4.2-4.8% of the administered total radioactivity was excreted by the urine and about the same quantity (2-3.6%) in case of 14C-glucose. No specific accumulation was observed after 14C-beta-cyclodextrin treatment in the different organs. The large intestine contained 10-15% of the cyclodextrin radioactivity while this value was only 2% in case of 14C-glucose. Following p.o. administration of different doses of 14C-beta-cyclodextrin the radioactivity peak was detected in the exhaled air between the 4-6th and 6-8th h, respectively, depending on the administered doses, while in case of 14C-glucose treatment it was observed within 2 h. The total radioactivity exhaled by 14C-beta-cyclodextrin treated animals in 24 h was 55 to 64% of the administered radioactivity and 58% in case of 14C-glucose. It is assumed that beta-cyclodextrin is metabolized in rats slower but similarly to glucose, therefore p.o. administered beta-cyclodextrin cannot induce toxic symptoms.     

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.     

Absorption, distribution, metabolism and excretion of an inhalation dose of [14C] 4,4'-methylenediphenyl diisocyanate in the male rat

The received dose, tissue distribution, metabolism, routes and rates of excretion of [(14)C]-4, 4(')-methylenediphenyl diisocyanate (MDI) were investigated in the male rat following a 6-h inhalation exposure to [(14)C]-MDI at a target concentration of 2 mg m(-3). The mean dose received was equivalent to 0.078 mg MDI per animal, of this between 25 and 32% of radiolabelled material was available systemically. Radioactivity was distributed to all tissues examined with the highest proportions present in the respiratory and gastrointestinal tracts, suggesting that both oral ingestion and pulmonary absorption contributed to the systemic dose of [(14)C]-MDI derived material, with the oral ingestion and the majority of the internal dose resulting from ingestion of radiolabelled material by grooming the pelt after exposure. Radioactivity was excreted mainly via faeces (about 80% of the received dose). Excretion in bile and urine each accounted for less than 15% of the dose. MDI was extensively metabolized after uptake, with two routes of transformation evident; the proposed spontaneous formation of mixed molecular weight polyureas and the enzyme catalysed metabolism of systemically available MDI or MDI derivatives to give N-acetylated and N-acetylated hydroxylated products. No free MDA was detected in any of the biomatrices (urine, faeces, bile) investigated.     

Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the rat.

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in rats, and eliminated more slowly by females than by males. The respective half-lives were about 4.9 and 2.1 h. Following single intravenous doses, dexloxiglumide was characterised as a drug having a low clearance (6.01 and about 1.96 ml/min/kg in males and females respectively), a moderate volume of distribution (Vss, 0.98 and about 1.1 L/kg in males and females respectively) and a high systemic availability. It was extensively bound to plasma proteins (97%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. Peak 14C concentrations generally occurred at 1-2 h in males and at 2-4 h in females. Tissue 14C concentrations then declined by severalfold during 24 h although still present in most tissues at 24 h but only in a few tissues (such as the liver and gastrointestinal tract) at 168 h. Decline of 14C was less rapid in the tissues of females than in those of males. Single intravenous or oral doses were mainly excreted in the faeces (87-92%), mostly during 24 h and more slowly from females than from males. Urines contained less than 11% dose. Mean recoveries during 7 days when 14C was not detectable in the carcass except in one female rat ranged between 93-101%. Biliary excretion of 14C was prominent (84-91% dose during 24 h) in the disposition of 14C which was also subjected to facile enterohepatic circulation (74% dose). Metabolite profiles in plasma and selected tissues differed. In the former, unchanged dexloxiglumide was the major component whereas in the latter, a polar component was dominant. Urine, bile and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. up to 63% dose in bile). LC-MS/MS showed that dexloxiglumide was metabolised mainly by hydroxylation in the N-(3-methoxypropyl)pentyl sidechain and by O-demethylation followed by subsequent oxidation of the resulting alcohol to a carboxylic acid.     

Absorption,distribution, metabolism and excretion of telmesteine,a mucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of (14)C-telmesteine in the Sprague-Dawley rat. 2. (14)C-telmesteine was rapidly absorbed after oral dosing (20 and 50 mg 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 30 min 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.