Pharmacokinetics,tissue distribution and excretion of glufosfamide in animals
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Objective: To study the pharmacokinetics,distribution and excretion of glufosfamide in animals.Methods: 6 Beagle dogs were given 60,30,15 mg·kg-1 glufosfamide individually by iv.Plasma concentration was analyzed by LC-MS/MS.Pharmacokinetic parameters were calculated by 3P97 software.18 mouse were divided into 3 groups and given 300 mg·kg-1 glufosfamide by iv,and thereafter decapitated to determine the tissues distribution.10 rats were divided into 2 groups and given 100 mg·kg-1 300 mg·kg-1 glufosfamide individually.Samples of urine and feces were collected and determined for the excretion study.Results:The pharmacokinetics of glufosfamide in Beagle dogs was consistent with the two-compartment model.T1/2β and AUC of 60,30,15 mg·kg-1 group were 614.8,544.0,596.3 min and 37173.1,21760.0,10741.7 μg·mL-1·min.The maximum concentration appeared in the kidney(2780.2 μg·g-1),ovary(2684.5 μg·g-1)and uterus 2369.4 μg·g-1 of mouse 4 h after injection.For 300 mg·kg-1 glufosfamide in rats,26.9% prototype was excreted through urine,with a maximum excretion rate of 1.36 mg·h-15-8 h after injection;0.12% was excreted through feces,with a maximum excretion rate of 4.3 μg·h-1 2-5 h after injection.For 100 mg·kg-1 glufosfamide in rats,46.8% was excreted through urine,with a maximum excretion rate of 1.29 mg·h-1 8-12 h after injection;0.21% was excreted through feces,with a maximum excretion rate of 6.1 μg·h-1 5-8 h after injection.Conclusions: After intravenous injection of glufosfamide,plasma concentration,AUC demonstrate linear relationship with the dose.The drug is widely distributed in mouse,mainly in kidney,ovary,uterus,lung,spleen.25%-50% prototype is excreted through the urine within 1-24 h.Keywords:
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1. This study was designed to determine the absorption, metabolism and excretion of 1-phenoxy-2-propanol in Fischer 344 rats following oral administration in an effort to bridge data with other propylene glycol ethers. 2. Rats were administered a single oral dose of 10 or 100 mg kg(-1) 14C-1-phenoxy-2-propanol as a suspension in 0.5% methyl cellulose ether in water (w/w). Urine was collected at 0-12, 12-24 and 24-48 h and faeces at 0-24 and 24-48 h post-dosing and the radioactivity was determined. Urine samples were pooled by time point and dose level and analysed for metabolites using LC/ESI/MS and LC/ESI/MS/MS. 3. The administered doses were rapidly absorbed from the gastrointestinal tract and excreted. The major route of excretion was via the urine, accounting for 93 +/- 5% of the low and 96 +/- 3% of the high dose. Most of the urinary excretion of radioactivity occurred within 12 h after dosing; 85 +/- 2% of the low and 90 +/- 1% of the high dose. Total faecal excretion remained < 10%. Rats eliminated the entire administered dose within 48 h after dosing; recovery of the administered dose ranged from 100 to 106%. Metabolites tentatively identified in urine were conjugates of phenol (sulphate, glutathione) with very low levels (< 2%) of hydroquinone (glucuronide), conjugates of parent compound (glucuronide, sulphate) and a ring-hydroxylated metabolite of parent. There was no free parent compound or phenol in non-acid-hydrolysed urine. In acid-hydrolysed urine, 61% of the dose was identified as phenol and 13% as 1-phenoxy-2-propanol. Although the parent compound was stable to acid hydrolysis, some of the phenol in acid hydrolysed urine may have arisen from degradation of acid-labile metabolite(s) as well as hydrolysis of phenol conjugates. 4. Rapid oral absorption, metabolism and urinary excretion of 1-phenoxy-2-propanol in rats were similar to other propylene glycol ethers.
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1. The plasma pharmacokinetics, excretion and metabolism of DX-9065a were studied in the healthy male Caucasian volunteer after a single intravenous dose of 10 mg 14C-labelled DX-9065a. 2. At the end of a 1 h infusion, the mean plasma concentration of total radioactivity was 380 ng ml(-1) (equivalent to unchanged DX-9065). Thereafter, it decreased in a bi-exponential manner and was below the detection limit by 48 h after dosing. The half-life for the distribution phase was 6.93 h. 3. The total radioactivity recovered in urine and faeces by 336 h post-dose was 83.8% of the administered dose, with excretion ongoing at the end of the 14-day collection. The major route of excretion was via urine, accounting for a mean of 77.6% of the administered radioactivity. The urinary excretion profile was biphasic, consisting of rapid (0-24 h) and slow (24-336 h) phases. A large renal clearance suggested that renal tubular secretion might contribute to the excretion of DX-9065 via urine. 4. No metabolite peaks in the radio-HPLC chromatograms of urine samples were detected, indicating that biotransformation of DX-9065 does not play a significant role in the elimination of DX-9065 in man.
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To study the tissue distribution and excretion of bromotetrandrine (W198) in rats.The concentrations of W198 in biological samples were determined by an HPLC method with UV detection.After a single i.v. dose of 20 mg x kg(-1) W198 in rats, the parent drug concentrations in tissues were higher than those in blood at the same time. Parent drug was mainly distributed in lung, kidney, heart and liver, the peak levels were attained at 0.25 h and decreasing at 2 h after dosing in most tissues. After a single iv dose of 20 mg x kg(-1) W198 in rats, the excretion of the parent drug in urine, feces and bile amounted to 0. 150%, 2.1% and 0.063% of the dose, respectively.W198 was mostly distributed in lung. The parent drug excretion was less than 3% via urine, feces and bile.
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Objective To investigate distribution and excretion of N-Ile1Thr2-63-desulfatohirudin(rH)a recombinant hirudin newly developed in China,in rats for its development as a novel anticoagulant agent.Methods ELISA was used to determine the rH concentration in related tissues and body fluids.Tissues were collected at 15,60 and 180min respectively,after iv administration of rH 1.0 mg·kg-1 to 3 groups of 5 rats,and homogenized.Urine,bile and feces were collected at pre-selected intervals of time after iv dosing 1.0 mg·kg-1 to 3 groups of 5 rats and assayed.Results rH following iv dosing was distributed rapidly,the rH levels in all tissues being found to be the highest at 15 min post-injection,afterwards gradually reduced.The highest concentration of rH was found in blood,the next in lung and heart,the lowest in brain.With 15 min post dose as an example,the rH contents in tissues were ranked in order of plasmalungheart adiposeskeletal muscleskidneyliverspleenbrain.The 12 h-cumulative excretion amount of rH in urine and feces accounted for 0.03%and 0.001% of administered dose,respectively;the 6 h-cumulative excretion amount in bile was 0.02%of the dose.Conclusions The rH is distributed mainly in blood circulation system with very low content in other tissues.The drug is excreted from urine,feces and bile of rats in extremely minute amount(only 0.051% dose),suggesting that rH undergoes extensive metabolic elimination in rat body.
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DL-2-(4-(2-Thienylcarbonyl)phenyl)propionic acid (suprofen, S) was rapidly absorbed in rats after oral administration. Blood levels after a single oral dose of 2, 10, 50, or 100 mg/kg of 3H-S reached maxima within 30 min and were dose-dependent. The major portion of the drug was shown to be absorbed from the upper part of the small intestine and a portion from the stomach. The radioactivity in rat plasma was extensively bound to the plasma protein in vivo; this was found to be unchanged S and four metabolites. Elimination of S and its metabolites from blood was rapid; 3H was mostly excreted in the urine and feces within 24 hr after oral administration of 3H-S. No significant amounts of 14CO2 were excreted in expired air after administration of 14C-S. Rat urine contained S and four metabolites found in rat plasma, accounting for about 60% of the urinary radioactivity. After rats with biliary fistulas were given an oral dose of 2 mg/kg of 3H-S, 41% of the dose was excreted in the bile during 48 hr; there was significant enterohepatic circulation. When single or 21 consecutive daily doses of 3H-S were administered to rats, the blood levels after the multiple doses were higher than those after a single dose but no significant difference was found in excretion of 3H.
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The disposition, biliary excretion, and pharmacokinetics of ketoconazole in Sprague-Dawley rats were determined after intravenous administration. Greater than 80% of the radioactivity after a 5 mg/kg iv dose of 3H-ketoconazole was excreted in the feces. Urinary excretion was essentially complete after 48 hr; however, fecal excretion was prolonged over a 7-day period. Biliary excretion of radioactivity averaged 54.3 +/- 18.0% of the dose over a 7.5-8-hr period in pentobarbital-anesthesized rats. The possibility of enterohepatic recirculation was examined using a linked rat technique. Less than 2% of the radioactivity was found in the recipient bile over 9-12 hr. In eight male rats, the plasma pharmacokinetics of ketoconazole, as determined by an HPLC assay with fluorescence detection, were as follows: VD = 655 +/- 91 ml/kg, Cl = 14.4 +/- 5.1 ml/min/kg, and t 1/2 = 35.0 +/- 12.3 min. Three of the rats were given an additional oral dose to determine absolute bioavailability. The time to peak was 30-60 min, and the bioavailability was 35.8 +/- 3.55%. Previous studies have indicated that ketoconazole is well absorbed in rats; therefore, the poor bioavailability is probably due to first pass metabolism. The prolonged fecal excretion of radioactivity from an intravenous dose was probably caused by slow elimination of ketoconazole metabolites.
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The absorption, distribution, metabolism and excretion of 14C-KT1-32 were studied after a single oral and intravenous administrations in the doses of 4-100mg/kg to male and female rats, and male mice.1. The radioactivity in plasma reached a maximum concentration at 4.5hr (48μg equivalent KT1-32/ml) after oral administration of 14C-KT1-32 to male rats in a dose of 20mg/kg and then declined with half-life of 3.9hr.2. The levels of radioactivity in plasma reached a maximum concentration at 3.3hr after oral administration of 14C-KT1-32 to female rats in a dose of 20mg/kg and then declined with half-life of 3.7hr.3. The excretion of radioactivity amounted to 57% of the dose in urine and 43% of the dose in feces within 96hr after oral administration to male rats in a dose of 20mg/kg, while after intravenous administration to male rats, the excretion of radioactivity were found to be 81% and 17% of the dose in urine and feces, respectively.4. The biliary excretion within 48hr after oral administration of 20mg/kg corresponded to 7.7% of the administered dose to male rats, while the excretion of the radioactivity reabsorbed, amounted to 5.3% of the dose in the bile within 48hr after intraduodenal injection.5. After 20mg/kg oral administration, the female rats excreted during 96hr 73% and 28% of the dose in urine and feces, respectively.6. The radioactivities in the tissues, except the gastro -intestinal tract and fat, reached the maximum concentration at 3hr after oral administration of 20mg/kg to male rats and relatively high radioactivities were found in the blood, liver, kidney and lung. The radioactivities in all tissues were decreased to less than 17% of the highest concentration at 72hr after oral administration.7. In female rats, after oral administration of a dose of 20mg/kg, the concentrations in the tissues were lower than that in male rats.8. After oral administratrion of a dose of 20mg/kg, Ml, M2, M4 metabolites and the intact drug were the major components and M-3, M-5 and M-6 were also detected, however as the minor compounds, in the 0-24hr urine collected from male rats.9. The M1, M2 metabolites and intact drug were also found in the 0-24hr fractions of bile in male rats.
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雄性ビーグル犬にONO-1078(4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate)を投与後の体内動態について検討した． 1．8あるいは30mg/kgを経口投与後の血漿中未変化体濃度は，それぞれ投与後1.7および2.7時間に最高濃度69あるいは238ng/mlに達した．半減期に有意差は認められなかった．4mg/kgを静脈内投与後のAUCをもとにして求めたbioavailabilityは，それぞれ4.8および2.7%であった． 2．14C-ONO-1078を4mg/kg経口投与後の血漿中放射能は，投与後1.3時間に最高濃度28ng eq./mlに達し，半減期7.2時間で減少した．4mg/kgを静脈内投与後のAUCをもとにして求めたbioavailabilityは2.8%であった． 3．14C-ONO-1078を4mg/kg経口投与したとき，投与後120時間における組織内放射能は，肝臓，腎臓，甲状腺および血液にわずかに認められたが，他の組織では検出されなかった． 4．14C-ONO-1078を4mg/kg経口あるいは静脈内投与したとき，投与後120時間までに放射能はそれぞれ糞に99.7および99.6%，尿中に0.4および1.9%排泄され，いずれも糞が主排泄経路であった． 5．14C-ONO-1078を4mg/kg経口投与したとき，投与後48時間までに胆汁中に4.9%が，尿中には0.3%が排泄された． 6．以上のように，ONO-1078は消化管から長時間にわたって吸収され，主として胆汁を介して糞中へ排泄された．
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Tissue distribution and excretion of radioactivity in mice after intragastric admin- istration of ~3H-β,β-dimethylacrylshikonin were investigated.Tissues and feces were com- busted by sample Oxidizer,the subsequent radioactivity measurements were carried out af- ter addition of scintillator to the combusted samples and urine.The results showed that the radioactivity in gastrointestinal system was higher than that in the liver,lung,kidney and heart,while that in skeletal muscle,spinal cord,brain was lower.After single intragastric administration(chemical dose 84.0 mg/kg,radioactive dose 22.3 MBq/kg)ofβ,β-dimethy- lacrylshikonin to mice,the cumulative radioactivity excretion rate of urine and feces were (8.43±0.26)% and(72.87±9.92)% respectively within 336 h ,the total excretion rate was(81.30±9.79)%.The samples of plasma,feces and urine were also analyzed by HPLC.The rsult is that parent drug mainly existed in feces,not in plasma or urine.This study showed that ~3 H-β,β-dimethylacrylshikonin was distributed widely in mice,and excre- ted mostly through fecal route and secondarily via urine.
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The absorption, distribution, metabolism and excretion of tacrolimus (FK506) were studied in the rat after intravenous (i.v.) and oral administration of 14C-labeled FK506 (14C-FK506). 1. After i.v. injection at a dose level of 1.0 mg/kg, the pharmacokinetic parameters of FK506 in the whole blood were as follows: elimination half life, 6.4 hours; total body clearance, 1.59 l/h ·kg; and volume of distribution at steady state, 11.8 l/kg. After oral administration at a dose level of 3.2 mg/kg, the parameters in the whole blood were as follows: maximal blood concentration (Cmax), 41 ng/ml; time to reach Cmax, 0.25 hour; and area under the concentration-time curve (AUC0-24h), 255 ng·h/ml. Absorption of radioactivity and FK506 was 37 and 14%, respectively, calculated from the values of AUC0-24 h in the whole blood. Distribution of FK506 in the blood changed depending on its levels. The ratio of whole blood to plasma levels was more than 2.5 at less than the whole blood levels of 50 ng/ml but decreased above these levels. 2. Radioactivity was distributed throughout the body after i.v. injection of 14C-FK506 at a dose of 0.32 mg/kg. Radioactivity was highest in most of tissues at 5 minutes after injection, the first sampling point after injection, and the levels were higher than those in the plasma except that in the white fat, testis, cerebellum and cerebrum. At 72 hours after injection, radioactivity in most tissues decreased to less than 10% of the maximal concentrations except that in the cerebrum, testis and urinary bladder, in which about half of the concentration was detected. After oral administration at a dose of 1.0 mg/kg, radioactivity was distributed mainly in the gut and liver and was hardly detected in the other tissues. 3. During 72 hours after administration of 14C_ FK506 at a dose of 1.0 mg/kg, 8 and 95%of the dosed radioactivity were respectively excreted to the urine and feces after i.v. injection and 4 and 96% after oral administration. During 48 hours after i.v. injection to the bile duct-cannulated rats, 3, 8 and 82% of the dosed radioactivity were recovered in the urine, feces and bile, respectively, and 3, 6 and 35% during the same period after oral administration. 4. Less than 0.4% of the dosed radioactivity was excreted as unchanged FK506 in the urine, feces and bile, and the elution pattern of excreted radioactivity was very complex on high performance liquid chromatography and no major but many small radioactive peaks were observed. The major in vitro metabolite, 13-O-mono-demethylated metabolite, was detected in the urine, feces and bile but its portion to total radioactivity was very small.
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