Pharmacokinetics and tissue distribution of the new gastrokinetic agent cisapride in rat, rabbit and dog

The plasma kinetics and tissue distribution of the gastrokinetic (+/-)-cis-4-amino-5-chloro-N-[1-(3-(4-fluorophenoxy)propyl]-3-methoxy-4- piperidinyl]-2-methoxybenzamide monohydrate (cisapride, R 51 619) have been studied in the rat, rabbit and dog. After intravenous administration to rats (5 mg/kg) and dogs (0.63 mg/kg) plasma level-time curves were adequately fitted to a two-compartmental model. The plasma clearance (ClT) and volume of distribution (Vdss) averaged 91 ml/min.kg and 4.7 l/kg in the rat and 4.2 ml/min.kg and 0.82 l/kg in the dog, respectively. Following oral administration, cisapride was rapidly and almost completely absorbed from the gastrointestinal tract in rats and rabbits. The absorption was somewhat slower in the dog. In male rats the plasma radioactivity was mainly due to metabolites, unaltered cisapride representing on average 10% of the total radioactivity. A markedly larger proportion of the parent drug was seen in female rats. Linear plasma kinetics were observed for cisapride in the dose range of 10 to 160 mg/kg. Similarly in the dog, linearity was observed after oral administration in the range of 0.31 to 10 mg/kg. The plasma kinetics remained unaltered on repeated oral doses of 10 mg/kg to rats and subchronic intravenous administration at 0.63 mg/kg to dogs. Compared with intravenous administration, the absolute bioavailability of oral cisapride was 23% in rats and 53% in the dog for the drug given in solution. The terminal plasma half-life of cisapride was about 1-2 h in the rat and about 4-10 h in the rabbit and dog.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man

1. Pharmacokinetics were studied in mouse, rat, rabbit, dog and man after single intravenous and/or oral doses of sildenafil or [14C]-sildenafil (Viagra). 2. In man, absorption from the gastrointestinal tract was essentially complete. With the exception of male rat, Tmax occurred at approximately 1 h or less. Bioavailability was attenuated by pre-systemic hepatic metabolism in all species. 3. The volume of distribution was similar in rodents and humans (1-2 l/kg) but was greater in dog (5.2 l/kg), due to lower plasma protein binding (84 versus 94-96% respectively). 4. High clearance was the principal determinant of short elimination half-lives in rodents (0.4-1.3 h), whereas moderate clearance in dog and man resulted in longer half-lives (6.1 and 3.7 h respectively). Clearances were in agreement with in vitro metabolism rates by liver microsomes from the various species. 5. After single oral or intravenous doses of [14C]-sildenafil, the majority of radioactivity was excreted in the faeces of all species. No unchanged drug was detected in the excreta of man. 6. Five principal pathways of metabolism in all species were piperazine N-demethylation, pyrazole N-demethylation, loss of a two-carbon fragment from the piperazine ring (N,N'-deethylation), oxidation of the piperazine ring and aliphatic hydroxylation. Additional metabolites arose through combinations of these pathways. 7. Sildenafil was the major component detected in human plasma. Following oral doses, AUC(infinity) for the piperazine N-desmethyl and piperazine N,N'-desethyl metabolites were 55 and 27% that of parent compound respectively.     

Pharmacokinetics and tissue distribution of the anticholinergics tiotropium and ipratropium in the rat and dog.

Ipratropium, a current treatment for chronic obstructive pulmonary disease (COPD) and tiotropium, a longer acting anticholinergic bronchodilator currently being developed for COPD are structurally related to atropine. In this study, the intravenous (i.v.), oral (p.o.) and intratracheal (i.tr.) single dose pharmacokinetics (PK) of tiotropium and ipratropium were determined in rat and dog. In rats, concentration-time profiles of tiotropium and ipratropium after single i.v. bolus administration of 7-8 mg kg(-1) are similar. Both drugs are highly cleared (Cl between 87 and 150 ml min(-1) kg(-1)) and extensively distributed into tissues (volume of distribution V(ss) between 3 and 15 l kg(-1)). In dogs, this holds also true for both drugs (Cl between 34 and 42 ml min(-1) kg(-1), V(ss) between 2 and 10 l kg(-1)), although different dose regimen were applied (i.v. bolus of 0.08 mg kg(-1) vs. infusion of 0.1 mg kg(-1) h(-1) for 3 h). Tiotropium plasma concentrations increased linearly in rats over a wide dose range following single i.v. administration. Both ipratropium and tiotropium showed a comparable terminal elimination half-life in rat urine (21-24 h) after single i.v. administration, which was much longer than the corresponding half-life in plasma (6-8 h). Whole body autoradiography in rats revealed a broad and rapid tissue distribution of [(14)C]tiotropium radioactivity after single i.v. administration. A comparable distribution pattern has also been reported earlier for ipratropium.     

Pharmacokinetics of rose bengal in the rat,rabbit, dog,and guinea pig

Rose bengal is a dye that is not biotransformed before excretion into the bile and can be used as a measure of hepatic excretory function. Rose bengal disappeared from the blood with time in a biexponential manner. Blood disappearance curves of rose bengal after doses between 0.01 and 10 mg/kg in the rat were almost identical, having an initial biological half-life of 2 min and a terminal half-life of 100 min. With higher doses, rose bengal disappeared from the blood at a much slower rate, apparently due to saturation of hepatic excretory processes. Rose bengal was excreted into bile by a mechanism that is consistent with a first-order process which exhibits a biological half-life of about 30 min unless a high dose that saturated the process was given. Since the terminal half-life of the plasma disappearance is much different than the biliary excretory half-life, the two compartment model cannot be used to quantitate hepatic uptake and biliary excretion of rose bengal. Species variation in the biliary excretion of rose bengal was observed. The biological half-life for excretion of rose bengal into the bile of rats and rabbits was similar (30 min), that of the guinea pig shorter (17 min), and that of the dog longer (46 min). Rose bengal clearance was slower in the bile duct-ligated rat, the rat with two-thirds of its liver removed, and in newborn rats, conditions which are known to alter hepatic excretory function. The blood concentration of rose bengal was higher in the two-thirds hepatectomized rats only during the first 30 min after administration and not at later times; thus, if rose bengal is used as a measure of hepatic function and if only one blood sample is taken, the time interval chosen is critical.     

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.     

Pharmacokinetics,toxicokinetics, distribution,metabolism and excretion of linezolid in mouse,rat and dog

1. Linezolid (ZYVOX?), the first of a new class of antibiotics, the oxazolidinones, is approved for treatment of Gram-positive bacterial infections. 2. The aim was to determine the absorption, distribution, metabolism and excretion (ADME) of linezolid in mouse, rat and dog in support of preclinical safety studies and clinical development. 3. Conventional replicate study designs were employed in animal experiments, and biofluids were assayed by HPLC or HPLC-MS. 4. Linezolid was rapidly absorbed after p.o. dosing with an p.o. bioavailability of > 95% in rat and dog, and > 70% in mouse. Twenty-eight-day i.v./p.o. toxicokinetic studies in rat (20-200mg kg^?1 day^?1) and dog (10-80mg kg^?1 day^?1) revealed neither a meaningful increase in clearance nor accumulation upon multiple dosing. 5. Linezolid had limited protein binding (<35%) and was very well distributed to most extravascular sites, with a volume of distribution at steady-state (V_ss) approximately equal to total body water. 6. Linezolid circulated mainly as parent drug and was excreted mainly as parent drug and two inactive carboxylic acids, PNU-142586 and PNU-142300. Minor secondary metabolites were also characterized. In all species, the clearance rate was determined by metabolism. 7. Radioactivity recovery was essentially complete within 24-48h. Renal excretion of parent drug and metabolites was a major elimination route. Parent drug underwent renal tubular reabsorption, significantly slowing parent drug excretion and allowing a slow metabolic process to become rate-limiting in overall clearance. 8. It is concluded that ADME data were relatively consistent across species and supported the rat and dog as the principal non-clinical safety species.     

Pharmacokinetics,toxicokinetics, distribution,metabolism and excretion of linezolid in mouse,rat and dog

1. Linezolid (ZYVOX), the first of a new class of antibiotics, the oxazolidinones, is approved for treatment of Gram-positive bacterial infections. 2. The aim was to determine the absorption, distribution, metabolism and excretion (ADME) of linezolid in mouse, rat and dog in support of preclinical safety studies and clinical development. 3. Conventional replicate study designs were employed in animal experiments, and biofluids were assayed by HPLC or HPLC-MS. 4. Linezolid was rapidly absorbed after p.o. dosing with an p.o. bioavailability of > 95% in rat and dog, and > 70% in mouse. Twenty-eight-day i.v./p.o. toxicokinetic studies in rat (20-200mg kg(-1) day(-1)) and dog (10-80 mg kg(-1) day(-1)) revealed neither a meaningful increase in clearance nor accumulation upon multiple dosing. 5. Linezolid had limited protein binding (<35%) and was very well distributed to most extravascular sites, with a volume of distribution at steady-state (V(ss)) approximately equal to total body water. 6. Linezolid circulated mainly as parent drug and was excreted mainly as parent drug and two inactive carboxylic acids, PNU-142586 and PNU-142300. Minor secondary metabolites were also characterized. In all species, the clearance rate was determined by metabolism. 7. Radioactivity recovery was essentially complete within 24-48 h. Renal excretion of parent drug and metabolites was a major elimination route. Parent drug underwent renal tubular reabsorption, significantly slowing parent drug excretion and allowing a slow metabolic process to become rate-limiting in overall clearance. 8. It is concluded that ADME data were relatively consistent across species and supported the rat and dog as the principal non-clinical safety species.     

Pharmacokinetics of a novel surface-active agent,purified poloxamer 188, in rat,rabbit, dog and man

Purified poloxamer 188 (PP188) is a non-ionic, block copolymer surfactant that is currently being evaluated clinically in sickle cell disease vaso-occlusive crisis and acute chest syndrome and preclinically in spinal cord injury and muscular dystrophy. This paper describes the pharmacokinetics of PP188 in rats, pregnant rats, pregnant rabbits, dogs and humans. Plasma protein binding interaction studies demonstrated no clinically significant effects on narcotic analgesics, hydroxyurea, warfarin, diazepam or digitoxin, but an increase in free fraction for propranolol. The plasma concentrations increased proportionate with increasing dose in all species tested. Renal clearance accounted for 90% of total plasma clearance in man. A single metabolite was detected and quantified in the plasma from dogs and humans that was cleared more slowly than parent drug. Allometric scaling of plasma clearance and volume of distribution at steady-state (Vss) across species provided good predictions of the pharmacokinetic parameters in humans. Based on the comparative pharmacokinetics of PP188 in rat, rabbit, dog and man, all three animal species were appropriate models for evaluating various aspects of PP188's toxicological profile.     

Pharmacokinetics of cyanamide in dog and rat

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (E.C. 1.2.1.3) has been made in the beagle dog and Sprague-Dawley rat. Cyanamide plasma levels were determined by a sensitive high performance liquid chromatographic assay, specific for cyanamide. In the dog, i.v. administration of cyanamide at 1, 2 and 4 mg kg-1, produced a dose-dependent pharmacokinetic behaviour. Statistically significant changes were observed in plasma clearance values (12.6 to 19.7 mL kg-1 min-1), half life values (39 to 61 min) and mean residence times (50 to 79 min). Peak plasma concentrations, after oral administration of 4 mg kg-1 were achieved at 30 min and oral bioavailability was about 65%. In the rat after i.v. or oral administration, cyanamide (2 mg kg-1) had a half life of 30 min, a total plasma clearance of 117 mL kg-1 min-1 and a mean residence time of 26 min. Oral bioavailability was about 69%.     

Pharmacokinetics, bioavailability, metabolism, tissue distribution and urinary excretion of gamma-L-glutamyl-L-dopa in the rat

gamma-L-Glutamyl-L-dopa (gludopa) is believed to be a dopamine prodrug specific for the kidney. Its pharmacokinetics have been studied in the rat given 50 mg kg-1 intravenously (i.v.) and 60 mg kg-1 intraperitoneally (i.p.). By the i.v. route, elimination followed apparent first order kinetics and was biphasic with a t 1/2 alpha of 7 min and terminal half-life of 67 min. After i.p. administration absorption was rapid (t 1/2 ab 6 min), elimination was monophasic with a terminal half-life almost identical following i.v. dosing (65 min), and bioavailability was 40%. In tissues (liver and kidney) gludopa was biotransformed to four intact catecholic products (L-dopa, dopamine, DOPAC and gamma-L-glutamyl-dopamine) which appeared quickly (peaks at 15 min) and which were almost completely cleared by 4 h. Dopamine was the major kidney metabolite accounting for 69% of total catechol content with an AUC 31 times greater than in liver where it accounted for only 34% of total catechols. In rat urine eight major metabolites (5.7% of the dose) and at least 12 minor metabolites were detected of all of which 85% was dopamine. A higher percentage of the dose was excreted as intact catechols in man (15.7%) but fewer metabolites were detected (L-dopa, dopamine, DOPAC). It is confirmed that gludopa is kidney specific in rat but that the pharmacological effects of dopamine are likely to be short lived due to rapid clearance. Gludopa appears to be less dopamine specific in man.     

Pharmacokinetics of droxicam in rat and dog

A study was made of the oral absorption of droxicam in the rat. Five minutes after administration of 1 mg/kg droxicam, only piroxicam levels (its active metabolite) were detected at the portal vein and caudal vena cava. The transformation of droxicam into piroxicam takes place in the gastrointestional tract. A pharmacokinetic test to compare the plasma levels of piroxicam obtained in rat and dog was then made after oral administration of droxicam and piroxicam. In both animal species the oral absorption of droxicam was not dose-related. However, droxicam given at therapeutic doses (0.2-0.3 mg/kg) was bioequivalent to piroxicam. The elimination half-life of piroxicam after oral administration of droxicam and piroxicam was 8 +/- 2 h in the male rat, 27 +/- 12 h in the female rat and 38 +/- 18 h in the male dog, whilst the half-life of oral absorption of piroxicam did not vary from one animal species to another. In the case of droxicam, however, this value was higher than that after oral administration of piroxicam, as a consequence of the process of transformation of droxicam into piroxicam. It is concluded that droxicam is a prodrug of piroxicam with a slower rate of absorption, but with the same bioavailability within the range of therapeutic doses.     

Pharmacokinetics and tissue distribution study of orientin in rat by liquid chromatography

A simple HPLC–UV method was established for the determination of orientin in plasma and different tissues of rat (heart, liver, spleen, lung, kidney, brain, stomach and small intestine). The separation was achieved by HPLC on a C₁₈ column with a mobile phase composed of acetonitrile–0.1% acetic acid (20:80, v/v), UV detection was used at 348 nm. Good linearity was found between 0.250–50.0 μg/ml (r² = 0.9966) for plasma samples and 0.050–50.0 μg/ml (r² ≥ 0.9937) for the tissue samples, respectively. Within- and between-day precisions expressed as the relative standard deviation (R.S.D.) for the method were 2.3–9.6% and 3.0–7.4%, respectively. The relative recoveries of orientin ranged from 95.4 to 100.6% for plasma and 93.1 to 107.9% for tissue homogenates. The developed method was successfully applied to the pharmacokinetics and tissue distribution research after intravenous administration of a 20 mg/kg dose of orientin to healthy Sprague–Dawley rats. The main pharmacokinetics parameters obtained presented that orientin was quickly distributed and eliminated within 90 min after intravenous administration. The tissue distribution results showed that liver, lung and kidney were the major distribution tissues of orientin in rats, and that orientin had difficulty in crossing the blood–brain barrier. It was also found that there was no long-term accumulation of orientin in rat tissues.     

Pharmacokinetics and metabolism of gabapentin in rat, dog and man

This paper describes the pharmacokinetic studies of 1-(aminomethyl)-cyclohexane acetic acid (gabapentin, G? 3450, CI-945) conducted with the 14C-labelled substance following intravenous and intragastric administration to rats and dogs and oral administration to humans. Gabapentin is well absorbed in rats, dogs and in humans, with maximum blood levels, reached within 1-3 h after peroral administration. Following i.v. administration to rats, similar blood and brain levels of gabapentin are observed after a short distribution phase, whereby concentrations in cerebrum and cerebellum are comparable. The highest concentrations are found in the pancreas and kidneys and the lowest values in adipose tissue. No binding of gabapentin to human plasma proteins or human serum albumin is observed. The distribution coefficient (octanol/buffer pH 7.4) is 7.5 X 10(-2). In man, no biotransformation of gabapentin is observed. In rats, biotransformation is only minor. In dogs, however, a remarkable formation of N-methyl-gabapentin is found. Elimination half-lives range between 2-3 h in rats, 3-4 h in dogs, and 5-6 h in man. Gabapentin is nearly exclusively eliminated via the kidneys. Renal elimination was up to 99.8% in rats and approx. 80% in man following oral administration. The blood level-time course after i.v. administration to rats can well be described by a three-compartment open model. Experiments in rats and dogs demonstrate that pharmacokinetics are not sex-dependent and are not changed after multiple dosage. Pharmacokinetics are shown to be linear in the range tested of 4 to 500 mg/kg i.v. in rats.     

Pharmacokinetics of iododoxorubicin in the rat, dog, and monkey.

The pharmacokinetics of iododoxorubicin (I-DOX) have been studied after single dose administration in the rat (iv and po), dog (iv and po), and monkey (iv). Plasma levels and amounts in urine were monitored by HPLC for both I-DOX and its biologically active metabolite, iododoxorubicinol (I-DOXOL). Plasma levels of I-DOX after iv administration could be described by a three-exponential curve with extremely fast initial phase. Terminal elimination half-lives of I-DOX were similar, 6-7 hr, in all three species. Body weight-normalized clearance (CL) and distribution volumes (Vd) of I-DOX were lower in the dog, but were similar in rat and monkey. The pharmacokinetic parameters also implied metabolic differences between species. Mean I-DOXOL/I-DOX AUC ratios were 0.02, 0.47, and 0.58, respectively, in rat, dog, and monkey, values considerably lower than reported in human studies. I-DOXOL remained slightly longer in the body than I-DOX, as seen both from terminal half-lives (9-11 hr) and mean residence times. In all species, renal excretion was virtually negligible: the amount of I-DOX + I-DOXOL in urine was less than 2% of dose. Mean bioavailabilities of I-DOX were 0.23 and 0.46 in rat and dog, respectively, and, in the latter, about half of I-DOXOL formation occurred during or before the first pass.     

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.     

南强菌素在大鼠体内的药动学、组织分布及排泄研究

目的研究海洋新骨架小分子南强菌素经单次静脉注射后在Wistar大鼠体内的药动学、组织分布及排泄特征。方法 48只Wistar大鼠(雌雄各半)分为8组(每组雌雄各三只),3组分别尾静脉注射南强菌素10、20、30 mg·kg-1,液相色谱-串联质谱法(LC-MS/MS)测定其血药浓度,DAS2.0计算药动学参数;其余5组单次尾静脉给予南强菌素20 mg·kg-1,其中3组大鼠给药后0.5、2、3 h麻醉处死、解剖测定南强菌素组织分布,1组给药后收集0² h、>22 h、>2⁴ h、>44 h、>4⁸ h、>88 h、>8²4 h的尿液粪便评价南强菌素的排泄过程,1组麻醉后插管收取024 h的尿液粪便评价南强菌素的排泄过程,1组麻醉后插管收取0² h、>22 h、>2¹6 h、>1616 h、>16²4 h胆汁评价胆汁排泄。结果大鼠分别静脉单次注射10、20、30 mg·kg-1南强菌素后,t蚝虔z分别为(2.09±0.68)、(2.44±0.35)、(2.57±1.33)h,AUC0-8 h分别为(3 378±544)、(3 492±460)、(4 451±573)μg·h·L-1;单次静脉给药20 mg·kg-1,0.5 h后肾脏组织中的南强菌素含量最高(1 736.8 ng·g-1),肺脏及脾脏次之;给药2 h后,多数组织中已经检测不到或仅能检测到极少量南强菌素;原型药物经尿样和胆汁的排泄率分别为1.87%和0.91%,粪便的排泄率极低,低于总给药量的0.01%。结论单次给予南强菌素,各剂量组的AUC0-8 h、ρmax和t蚝虔z用SPSS进行相关检验,无显著差异(P>0.05),表明在置信度(单双侧)0.05水平上剂量与AUC0-8 h、ρmax和t蚝虔z均不相关;原型药物经粪便和尿样排泄率较低,124 h胆汁评价胆汁排泄。结果大鼠分别静脉单次注射10、20、30 mg·kg-1南强菌素后,t蚝虔z分别为(2.09±0.68)、(2.44±0.35)、(2.57±1.33)h,AUC0-8 h分别为(3 378±544)、(3 492±460)、(4 451±573)μg·h·L-1;单次静脉给药20 mg·kg-1,0.5 h后肾脏组织中的南强菌素含量最高(1 736.8 ng·g-1),肺脏及脾脏次之;给药2 h后,多数组织中已经检测不到或仅能检测到极少量南强菌素;原型药物经尿样和胆汁的排泄率分别为1.87%和0.91%,粪便的排泄率极低,低于总给药量的0.01%。结论单次给予南强菌素,各剂量组的AUC0-8 h、ρmax和t蚝虔z用SPSS进行相关检验,无显著差异(P>0.05),表明在置信度(单双侧)0.05水平上剂量与AUC0-8 h、ρmax和t蚝虔z均不相关;原型药物经粪便和尿样排泄率较低,1²4 h内仅有1.87%从尿液中排出。     

Pharmacokinetics, tissue distribution and excretion of vinflunine.

The plasma pharmacokinetics, tissue distribution, excretion and binding to plasma proteins of vinflunine, were investigated after intravenous (iv) administration. We obtained plasma profiles after iv administration of vinflunine at the doses of 3.5, 7 and 14 mg/kg in rats. The t1/2 values for vinflunine were estimated to be 18.38+/-1.20, 17.05+/-0.77, 18.35+/-1.57 h, and the mean AUC0-t values were 3.48+/-0.38, 6.54+/-0.68, 12.79+/-2.93 microg x h/ml, respectively. Of the various tissues tested, vinflunine was widely distributed into tissues, with the highest concentrations of vinflunine being found in well perfused organs. Maximal concentration of vinflunine was reached at 0.5 h postdose in the majority of tissues. In tumor-bearing mice, the similar pattern of tissue distribution was observable, except that vinflunine can be distributed into tumor. The binding of vinflunine in human and rat plasma proteins were 39.6% and 58.4% respectively. Within 96 h after administration, 9.58%, 15.36% and 0.71% of the given dose was excreted in urine, feces and bile, respectively. In conclusion, Vinflunine had a longer terminal half-life, a wide tissue distribution and less than 25% of the given dose was excreted as unchanged drug, suggesting metabolism as a major style of elimination.     

Pharmacokinetics and tissue distribution of crotonoside

1.?Crotonoside is a bioactive ingredient from Croton Herba with a strong antitumour activity. This study aimed to develop a highly sensitive and selective high-performance liquid chromatography (HPLC) method to quantify crotonoside in biological samples for pharmacokinetics and distribution studies.

2.?Protein precipitation by perchloric acid was used to separate crotonoside from the biological samples, and the recovery rates for crotonoside and the internal standard (luteoloside) were >80%. All calibration curves examining the crotonoside levels in plasma and tissues were linear (all correlation coefficients >?0.99).

3.?The response to crotonoside appeared to be dose disproportional to the maximum plasma concentration and the area under the time–concentration curve in plasma over the range of 12.5–50.0?mg/kg, and crotonoside was highly distributed in tissues after intravenous administration. The highest crotonoside level was detected in the liver (28.79?±?14.96?μg/g), whereas crotonoside was undetected in the brain.