Pharmacokinetics, tissue distribution, and excretion of buagafuran in rats

The pharmacokinetics, tissue distribution, and excretion of buagafuran (BF, 4-butyl-α-agarofuran), a promising antianxiety drug isolated from Gharu-wood (Aquilaria agallocha Roxb), were investigated in rats. BF plasma concentration was determined in rats after oral and intravenous doses by GC-TOF-MS. BF showed nonlinear pharmacokinetics after oral and intravenous administration of 4, 16, and 64 mg/kg. The AUC(0-∞) and C(max) did not increase proportionally with doses, indicating the saturation in absorption kinetics of BF in rats after oral dosage. BF absorption was extremely poor with an absolute bioavailability below 9.5%. After oral administration of (3)H-BF (4 mg/kg) to rats, radioactivity was well distributed to the tissues examined. The highest radioactivity was found in gastrointestinal tract, followed by liver and kidney. Radioactivity in brain, as a target organ, was about 20-40% of that in plasma at all time points. Total mean percent recovery of radioactive dose was about 80% in rats (51.2% in urine; 28.7% in feces). Bile elimination was also the major excretion route of BF, and 45.4% of the radioactive dose was recovered in bile.     

~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。     

Absorption,tissue distribution and elimination of 4-[(3)h]-epigallocatechin gallate in beagle dogs

Polyphenols found in tea are potent antioxidants and have inhibitory activity against tumorigenicity. The purpose of the described study was to assess the absorption, tissue distribution, and elimination of epigallocatechin gallate (EGCG), the principal catechin found in green tea, in a nonrodent species. 4-[(3)H]-EGCG was administered to beagle dogs by intravenous (IV) and oral routes. Following IV administration of 25 mg/kg, radioactivity in the bloodstream resided predominantly in the plasma. Distribution occurred during the first hour, and the plasma levels of total radioactivity declined with a mean half-life of approximately 7 hours. The apparent volume of distribution (0.65 l/kg) indicated wide distribution, and the total body clearance (1.01 ml/min-kg) was low. A subsequent single oral dose (250 mg/kg) was rapidly absorbed, with peak plasma levels at about 1 hour after administration, followed by elimination with a mean half-life of 8.61 hours. The mean area under the curve (AUC) for total radioactivity was approximately 20% of the value following IV administration (corrected for dose administered). Excretion of radioactivity in the feces predominated over urinary excretion following both IV and oral administration of [(3)H]-EGCG. Tissue distribution was determined 1 hour after an IV dose (25 mg/kg) administered after 27 days of oral treatment with EGCG (250 mg/kg/day) to mimic chronic consumption of tea. Radioactivity was distributed to a variety of epithelial tissues; the highest concentrations were observed in the liver and gastrointestinal tract tissues. Repeat dose oral administration of EGCG resulted in significantly lower blood radioactivity compared to the concentration following a single dose. These results are generally in accord with previous studies in rodents and indicate that, after oral administration, EGCG (as parent compound and metabolites) is widely distributed to tissues where it can exert a chemopreventive effect.     

Distribution and excretion of furobufen in rats and dogs

Groups of male rats and dogs were given single doses of 50 mg of 14C-furobufen per kg orally or intravenously. In rats, tissue radioactivity levels were generally lower than that of serum. Radioactivity accumulated in and was retained by white adipose tissue. The radioactivity in fat was due to a conjugate of dibenzofuranacetic acid, the major metabolite of furobufen. Approximately one-half of the dose was excreted each in the urine and feces of rats after oral and intravenous administration of 14C-furobufen. A similar excretion pattern was observed in dogs after an oral dose.     

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。     

Metabolic fate of the new anti-ulcer drug enprostil in animals. 1st communication: absorption, distribution and excretion in the mouse, rat and rabbit

Absorption, distribution and excretion of [3H]-enprostil ((+-)-11a,15a-dihydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorpr osta -4,5,13(t)-trienoic acid methyl ester, TA-84135), a new anti-ulcer prostaglandin, were studied in mice, rats and rabbits. Radioactivity associated with enprostil was rapidly absorbed from the gastrointestinal tract with Tmax values of 15 or 30 min. Absorption was also efficient inasmuch as approximately 80% of an oral dose was recovered in bile and urine in 24 h in bile duct-cannulated rats. Experiments in pylorus-ligated, bile duct-cannulated rats demonstrated that enprostil was mainly absorbed from the intestine, rather than from the stomach. In mice given oral doses of 2, 8 and 32 micrograms/kg, Cmax and AUC values of enprostil radioequivalents increased proportionately to the increase in dose, indicating linear kinetics over this dose range. Distribution of enprostil-associated radioactivity was investigated in rats by quantitating tritium in various tissues after the oral administration of [3H]-enprostil. Radioactivity in tissues was highest at 15 or 30 min after dosing. Highest levels of radioactivity were found in the stomach and intestines, the organs which came into direct contact with the dose, and the liver and kidney, the organs involved in excretion of enprostil. The rate of elimination of enprostil-associated radioactivity from all tissues and from plasma was similar. Enprostil-associated radioactivity did not accumulate in any tissue. Radioactivity was found in fetuses following oral administration of [3H]-enprostil to rats on the 12th or 19th day of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of glucosamine in the dog and in man

The pharmacokinetics, organ distribution, metabolism and excretion of glucosamine were studied in the dog giving uniformly labelled [14C]-glucosamine (sulfate), i.v. or orally, in single doses. Immediately after i.v. administration, the radioactivity in plasma is due to glucosamine, and freely diffuses into organs and tissues. This radioactivity disappears quickly from plasma (initial t1/2 = 13 min, terminal t1/2 = 118 min). After 30-60 min the radioactivity in plasma is no longer due to glucosamine, but is incorporated into alpha- and beta-globulins. The protein-incorporated radioactivity is found already 20-30 min after i.v. administration, reaches a peak after 8 h and then slowly disappears, with a t1/2 = 2.9 days. Of the administered radioactivity, more than 34% is excreted in the urine, mainly as glucosamine, and 1.7% is excreted in the feces. Radioactivity is excreted also as [14C]-CO2 in the expired air. The radioactivity, after i.v. administration, diffuses rapidly from blood into the body. Some organs show an active uptake of radioactivity, e.g. the liver and the kidney. Other tissues, such as the articular cartilage, also have an active uptake. In most other organs the radioactivity found can be explained by passive diffusion processes from plasma. After oral administration of a single dose of [14C]-glucosamine the radioactivity is quickly and almost completely absorbed from the gastrointestinal tract. The pattern of disappearance, metabolic transformation, tissue distribution and excretion of the radioactivity are consistent with those found after i.v. administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic studies on metiazinic acid I. Absorption, distribution, excretion and metabolism in rats and rabbits.

Absorption, distribution, excretion and metabolism after oral administration of 3-H-labelled metiazinic acid were studied. The administered radioactivity was excreted through both the urinary and fecal routes. The maximum levels of concentration in blood and most tissues were shown with 3 hr after dosing. The highest radioactivity was found in the kidney throughout all experiments. Relatively high radioactivity was observed in inflammatory-treated parts in rats. Unchanged compound, metiazinic acid S-oxide and these conjugates were found in urine and feces. Approximately 60% of the unchanged form was observed in plasma after 6 hr.     

Pharmacokinetics, tissue distribution, and excretion of sitafloxacin, a new fluoroquinolone antibiotic, in rats, dogs, and monkeys

The pharmacokinetics, tissue distribution and excretion of sitafloxacin (CAS 127254-12-0, DU-6859a) were investigated in rats, dogs, and monkeys following single intravenous or single oral administration of 14C-labelled sitafloxacin at a dose of 4.69 mg/kg. Following single administration of the oral dose, serum concentrations of radioactivity peaked at 0.5 h in rats, 2.3 h in dogs, and 2.5 h in monkeys. The apparent absorption ratios of 14C-sitafloxacin based on the AUC0-infinity were 31%, 51%, and 93% in rats, dogs, and monkeys, respectively. In rats, the drug-related radioactivity had been distributed to most organs and tissues 30 min after oral dosing, and had been essentially eliminated after 24 h. The highest levels of radioactivity were observed in the kidneys and liver, whereas the concentrations in the cerebrum and spinal cord were much lower than the serum value. The urinary recoveries of radioactivity after intravenous dosing were 45.5 % in rats, 32.3 % in dogs, and 77.8 % in monkeys. In bile duct-cannulated rats, 57.8 % of the orally administered radioactivity was excreted in the bile within 48 h, and at least 45 % of the sitafloxacin-related material secreted in the bile was re-absorbed from the gastrointestinal tract. These results indicate that sitafloxacin is rapidly absorbed and widely distributed into various tissues. Sitafloxacin-related material is eliminated primarily through both renal and biliary excretion in rats, and possibly in dogs, whereas renal excretion is the major route of elimination in monkeys.     

Disposition and metabolism of (2S,3S,4R)-N'-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N'-benzylguanidine, a novel neuroprotective agent for ischemia-reperfusion damage, in rats

The metabolism and disposition of KR31378 (a benzopyran derivative and a novel neuroprotective agent) were investigated following single oral or intravenous administration of [(14)C]-KR31378 to rats. [(14)C]-KR31378 was rapidly absorbed after oral dosing with an oral bioavailability of greater than 71%. The maximum plasma concentration and area under the curve of total radioactivity in rat plasma increased proportionally to the administered dose. KR31378 was distributed over all organs and tissues except for brain, eyeball and testis, and declined by first order kinetics up to 24 h after dosing. Excretion of the radioactivity was 29.5% of the dose in the urine and 58.5% in the feces within 2 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 66.0% for the first 24 h. KR31378 was extensively metabolized by ring hydroxylation, O-demethylation, oxidation and reduction with subsequent N-acetylation and O-glucuronide conjugation. N-acetylated conjugates (M2, M10, M11, M12, M14, and M15) were identified as the predominant metabolites in rats.     

Evidence for a different metabolic behaviour of cytidine diphosphate choline after oral and intravenous administration to rats

Radioactivity plasma decay was studied in rats after intravenous and oral administration of cytidine diphosphate [methyl-14C]choline at doses of 25 and 300 mg/kg. The kinetics fitted well with a two compartment open model and showed a long lasting elimination phase with a half-life ranging from 2.0 to 2.6 days for the two doses and the two administration routes. Absorption of cytidine diphosphate choline radioactivity was complete after oral treatment with the low dose and accounted for 94.5% of the dose when 300 mg/kg of cytidine diphosphate [methyl-14C]choline were administered. However the distribution of radioactivity in tissues, urine and expired air suggest metabolic differences, at least from a quantitative point of view, between the oral and intravenous treatments. In particular, the higher excretion of radioactivity associated with trimethylamine in urine found when cytidine diphosphate [methyl-14C]choline was given orally, suggest that the compound may be metabolized, at least in part, previous to its gastrointestinal absorption.     

Absorption,distribution, metabolism and excretion of gemigliptin,a novel dipeptidyl peptidase IV inhibitor,in rats

Abstract

1.?The absorption, distribution, metabolism and excretion of a novel dipeptidyl peptidase IV inhibitor, gemigliptin, were examined following single oral administration of ¹⁴C-labeled gemigliptin to rats.

2.?The ¹⁴C-labeled gemigliptin was rapidly absorbed after oral administration, and its bioavailability was 95.2% (by total radioactivity). Distribution to specific tissues other than the digestive organs was not observed. Within 7 days after oral administration, 43.6% of the administered dose was excreted via urine and 41.2% was excreted via feces. Biliary excretion of the radioactivity was about 17.7% for the first 24?h. After oral administration of gemigliptin to rats, the in vivo metabolism of gemigliptin was investigated with bile, urine, feces, plasma and liver samples.

3.?The major metabolic pathway was hydroxylation, and the major circulating metabolites were a dehydrated metabolite (LC15-0516) and hydroxylated metabolites (LC15-0635 and LC15-0636).     

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.     

Disposition of the hypolipidaemic agent, 2,3-dihydrophthalazine-1,4-dione, in Sprague Dawley rats

The disposition of [14C]2,3-dihydrophthalazine-1,4-dione, a potent hypolipidaemic agent, has been determined after both intravenous and oral administration. Both the routes of administration afforded multi-exponential disposition with an estimated t1/2 of approximately 75 h. After oral administration, the drug was observed to be absorbed rapidly from the intestine and distributed quickly to all tissues of the body. A large quantity of the 14C-radioactivity was found in the skin and carcass. Approximately 35% of the administered radioactivity was excreted in urine after oral administration and 11% in the faeces. Approximately 66% of the radioactivity excreted in urine was the parent drug. There was evidence of an additional metabolite which accounted for 28% of the urinary radioactive excretion. The parent drug has little serum protein binding, is highly water soluble, and is probably taken up by cells by passive diffusion.     

Biochemical studies on phthalic esters I. Elimination, distribution and metabolism of di-(2-ethylhexyl)phthalate in rats.

Elimination, distribution and metabolism of di-(2-ethylhexyl)phthalate (DEHP) were studied in the rat by the tracer technique. About 80% of the dose was excreted in the urine and faeces in 5 to 7 days following intravenous or oral administration. Excretion in the urine was generally slightly greater than that in the faeces. After intravenous administration of [14C] DEHP the radioactivity was preferentially localized in the liver for a short period. Delayed excretion of DEHP was observed in particular in adipose tissue. After oral dosing no significant retention was found in organs and tissues. Radioactivity measurements showed that affinity was lowest for testicles and brain regardless of whether [14C] DEHP was administered orally or intravenously. Orally ingested DEHP was excreted unchanged in the faeces and four major metabolites were detected in the urine.     

Absorption, distribution and excretion of the new thienopyridine agent prasugrel in rats

Prasugrel is converted to the pharmacologically active metabolite after oral dosing in vivo. In this study, (14)C-prasugrel or prasugrel was administered to rats at a dose of 5 mg kg(-1). After oral and intravenous dosing, the values of AUC(0-infinity) of total radioactivity were 36.2 and 47.1 microg eqx h ml(-1), respectively. Oral dosing of unlabeled prasugrel showed the second highest AUC(0-8) of the active metabolite of six metabolites analyzed. Quantitative whole body autoradiography showed high radioactivity concentrations in tissues for absorption and excretion at 1 h after oral administration, and were low at 72 h. The excretion of radioactivity in the urine and feces were 20.2% and 78.7%, respectively, after oral dosing. Most radioactivity after oral dosing was excreted in bile (90.1%), which was reabsorbed moderately (62.4%). The results showed that orally administered prasugrel was rapidly and fully absorbed and efficiently converted to the active metabolite with no marked distribution in a particular tissue.     

三尖杉酯碱的代谢

本文报告³H-三尖杉酯碱在正常及肿瘤鼠体内的吸收、分布和排泄。静脉注射³H-三尖杉酯碱后,大鼠血中放射性迅速降低,快、慢两相的生物半衰期分别为3.5分钟和50分钟。给大鼠静脉注射³H-三尖杉酯硷,注射后15分钟时,药物在各组织中的分布以肾脏为最高,肝、骨髓、肺、心脏、胃肠、脾、肌肉次之,睾丸、血及脑较低。两小时后各组织中的药物浓度均迅速下降,但骨髓的下降较慢,在所有组织中药物浓度居于首位。24小时后则在所测组织中药物浓度均降到相当低的水平。³H-三尖杉酯碱在肿瘤小鼠体内的分布情况与正常大鼠的分布趋势大致相仿。³H-三尖杉酯碱在静脉注射后24小时自大鼠体内排出的总放射性,在尿相当于注射剂量的30.2%,在粪相当于16.6%,其中原型药共占14.5%。此外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24.5%,其中原型药占17.1%。该硷口服给药可迅速吸收入血,但吸收不完全。     

Studies on absorption, distribution and excretion of 14C labeled (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluene-sulfonate hydrate (14C-T-3262) in rats and mice

Absorption, distribution and excretion of T-3262 were studied in rats and mice after oral administration of 14C-T-3262. The obtained results are summarized as follows. 1. 14C-T-3262 was absorbed from the upper small intestine such as duodenum in rats. 2. Serum levels of radioactivity in rats reached the highest concentration at 1 hour after an oral administration, then gradually diminished. 3. Urinary excretion was 35% and 42% of the dosed radioactivity in rats and mice, respectively, and fecal excretion was about 65% and 56% of the dosed radioactivity in rats and mice, respectively. 4. Biliary excretion in rats was about 27% of the dosed radioactivity after an oral administration of 14C-T-3262, and a half amount of excreted radioactivity was reabsorbed from the intestine. 5. Radioactivity was distributed the most into the kidney and the liver among all organs other the stomach and the intestine. Radioactivity was widely distributed into other organs such as spleen, adrenal, pancreas, lung, heart and thymus. But the distribution of radioactivity into the brain was little. 6. The distribution of 14C-T-3262 was also studied with whole body autoradiography in normal male mice and pregnant mice. The radioactivity was distributed widely to whole tissues except brain, spinal cord and eye ball. In pregnant mice, radioactivity levels in the fetuses were the same as the blood level of the mother mice. 7. The binding rate of 14C-T-3262 to rats and mice serum proteins was 63-66%. 8. Urinary and fecal excretion patterns of radioactivity in mice after multiple oral administration of 14C-T-3262 for 10 days were similar to those after a single administration. This result suggests that T-3262 did not accumulate in body. 9. After oral administration of 14C-T-3262 to nursing rats, the secreted radioactivity level in the milk was higher than the blood level.     

Absorption, distribution and excretion of neocarzinostatin (NCS) in mice after oral administration.

Distribution, excretion and toxicity of an antitumor protein, neocarzinostatin (NCS) were examined in mice after oral administration. The oral LD50 1 g/kg after intravenous injection. After oral administration of 200 mg/kg of NCS, the tissue level was low but detectable in lung, skin and pancreas in addition to the tissues of the gastrointestinal tract. The NCS level in lung and skin remained constant through 6 hours. In gastrointestinal tissues after oral administration the level was higher in the stomach than the large intestine or small intestine. The total recovery of orally administered NCS in feces of mice was 26.5% of the given dose during the first 12 hours. Inactivation of NCS by homogenates of small and large intestines (about 50%) was found in in vitro experiments.     

Disposition of radiolabeled FAVOR PAC in rats

FAVOR is the name for a family of superabsorbent cross-linked sodium polyacrylate polymers developed by Stockhausen GmbH & Co KG (Krefeld, Germany) that are known for their ability to absorb and retain large volumes of fluid. The absorption, distribution, rates and routes of excretion of radiolabeled FAVOR PAC (CAS Registry No. 9003-04-7; [14C]FAVOR PAC), one member of the FAVOR family, were evaluated following a single oral administration of the compound. Male Sprague-Dawley rats were administered single doses of 26 to 39 mg/kg [14C]FAVOR PAC by gavage. Approximately 98.8% (normalized mean) of the total administered dose was excreted in the feces within 5 days, and the majority ( approximately 88%) was excreted within the first 24 h. Urinary excretion accounted for 0.69% (normalized mean) of the total administered dose. Recovery of radioactivity in the organs, tissues, and carcass was generally less than 0.5% of the dose administered. Levels of total radioactivity in whole blood ranged from 0.75 to 1.20 microg equiv/g. Biliary elimination of total radioactivity accounted for less than 0.1% of the dose administered. The results indicate that FAVOR PAC is poorly absorbed and rapidly eliminated in feces following oral administration.