Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats
Zhiyuan ZhangHua ZhangDan LiuYingyuan LuXin WangPu LiYa‐Qing LouBaoxue YangYaxin LouChuang LuQiang ZhangGuoliang Zhang
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Abstract:
Methyl 3-amino-6-methoxythieno [2,3-b] quinoline-2-carboxylate (PU-48) is a novel diuretic urea transporter inhibitor. The aim of this study is to investigate the profile of plasma pharmacokinetics, tissue distribution, and excretion by oral dosing of PU-48 in rats. Concentrations of PU-48 within biological samples are determined using a validated high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. After oral administration of PU-48 (3, 6, and 12 mg/kg, respectively) in self-nanomicroemulsifying drug delivery system (SNEDDS) formulation, the peak plasma concentrations (Cmax), and the area under the curve (AUC0⁻∞) were increased by the dose-dependent and linear manner, but the marked different of plasma half-life (t1/2) were not observed. This suggests that the pharmacokinetic profile of PU-48 prototype was first-order elimination kinetic characteristics within the oral three doses range in rat plasma. Moreover, the prototype of PU-48 was rapidly and extensively distributed into thirteen tissues, especially higher concentrations were detected in stomach, intestine, liver, kidney, and bladder. The total accumulative excretion of PU-48 in the urine, feces, and bile was less than 2%. This research is the first report on disposition via oral administration of PU-48 in rats, and it provides important information for further development of PU-48 as a diuretic drug candidate.Keywords:
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Objective To study the distribution and pharmacokinetics of Gd-DTPA and Lip Gd-DTPA in mice.Methods The tissue and blood concentration of Gd-DTPA and Lip Gd-DTPA in mice were determined by ICP-AES.Results The concentration time curves of them in mice could be fitted to two compartment open models.LipGd-DTPA maintained a higher level of blood drug concentration compared with that of Gd-DTPA,and the distribution of it in the liver and spleen were enhanced evidently.Conclusion LipGd-DTPA has targeting to the liver and spleen evidently.
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Background: Flos Magnoliae is a frequently-used Chinese herbal medicine, from which Fargesin is isolated with extensive pharmacological activities. Objective: To develop a reliable high performance liquid chromatography (HPLC) method of fargesin and explore pharmacokinetics and tissue distribution profile of fargesin in Sprague Dawley rats after oral administration of 50 mg/kg. Methods and Results: The chromatographic analysis was conducted on a Shimadzu 2010-ODS-3 C18 column (4.6 mmx150 mm, 5 µm), and the mobile phase consisted of methanol and water (58:42 v/v) with a flow rate of 1.0 mL/min. Linearity of fargesin in all biological samples was good (R>0.9990) within the corresponding concentration range and the method was verified to be sensitive, accuracy and precision. The pharmacokinetic results of fargesin after oral administration (50 mg/kg) in rats showed that two absorption peaks were observed in rat plasma at 60min and 290 min, with the highest plasma concentration (Cmax) being 464.38±32.75 ng/mL at 290 min. The tissue distribution results showed that the main tissue depots for fargesin were heart, liver, kidney and lung. Conclusion: This study established a sensitive and reliable HPLC method for the content determinations of fargesin. The pharmacokinetics and tissue distribution results may provide practical information for further study of pharmacological actions and clinical application. Keywords: Double-peak, Fargesin, HPLC, oral administration, pharmacokinetics, tissue distribution.
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Objective: To evaluate the pharmacokinetics and tissue distribution of liposomal brucine (LB) for dermal application. Methods: Pharmacokinetics and tissue distribution were studied by in vivo animal testing. High performance liquid chromatography (HPLC) was used to detect the concentration of brucine in rats’ skin, plasma and various tissues. Results: After dermal administration, LB was absorbed rapidly in the skin and could be detected after 0.5 hours. After 36 hours, levels were too low to be detected. In plasma, levels were also too low to be detected after 36 hours. The concentration of LB reached 50% of the maximum in all tissues except the brain, peaking after 1.5 hours but still detectable after 12 hours. Conclusion: The concentration of LB was high in skin at the application site. LB was quickly absorbed into tissues through the blood circulation and widely distributed throughout the whole body. There was no obvious toxicity and LB did not readily accumulate in tissues and organs. It showed local potency but low overall systemic toxicity. Keywords: liposomal brucine, dermal administration, pharmacokinetics, tissue distribution
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OBJECTIVE:To study the pharmacokinetics and tissue distribution of hydroxycamptothecine(HCPT) capsules in mice METHODS:The contents of HCPT in mouse plasma and tissues were determined by fluorescence spectrophotometry The pharmacokinetic parameters were measured RESULTS:The calibration curves of HCPT revealed linearity in the range 0 01～0 5μg/ml The plasma concentration-time curves of HCPT capsules conformed to two-conpartment model of pharmacokinetics The major pharmacokinetic parameters were:T1/2α 0 29h,T1/2β 1 64h,AUC0～24 14 73μg/ml and CL 12 53ml/h HCPT in gastrointestinal tissue AUCpoAUCiv,P0 05,but in whole body blood AUCpoAUCiv,P0 05 CONCLUSION:The oral administration of drug can increase the local-concentration in gastrointestinal tissue,which can raise the index of chemotherapy and reduce the systemic side-effects
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OBJECTIVE To study the pharmacokinetics and tissue distribution of pCFTRinh-A in mice.METHODS 20 mg·kg-1 pCFTRinh-A was given by intraperitoneal injection.HPLC method for the determination of pCFTRinh-A in plasma and tissues was established and applied to determine pCFTRinh-A in plasma and tissue samples.RESULTS The plasma concentration of pCFTRinh-A was found after 5 min of administration.The main pharmacokinetic parameters were as follows: t1/2ka(2.089±0.481) min,t1/2a(21.576±0.761) min,t1/2β(155.424±28.723) min,AUC(489.055±12.538) μg·min·mL-1,tmax(11.32±1.006) min,ρmax(7.461±0.143) μg·mL-1,CL(s)(0.041±0.001) L·min-1.The absorption and distribution of pCFTRinh-A was quick while elimination was slow with high bioavailability.The distribution of pCFTRinh-A was high in liver,kidney and lung,while lower in heart,spleen and intestines and lowest in brain.CONCLUSION The pharmacokinetics and tissue-distribution characters of pCFTRinh-A will be helpful for building cystic fibrosis phenotype in large animals.
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Objective To study the pharmacokinetics and tissue distribution of Chuanhuning-emulsion( CHE) in rats. Methods The commercial ordinary Chuanhuning injection was used as the reference( CHR) to evaluate the pharmacokinetics and tissue distribution of CHE. After intravenous administration of CHE or CHR( 40 mg / kg) in rats,the concentration of dehydroandrographolide succinate( DAS,the active ingredients of CHE in vivo) was detected by LC-MS / MS. Pharmacokinetic analysis was performed using WinNolin 6. 2. Tissue distribution and targeting were evaluated through tissue concentrations. Results First,a suitable detection method was set up to study the pharmacokinetics of DAS. Second,there was no significant difference between CHR and CHE in the pharmacokinetic parameters. However,the concentrations of DAS in lungs of CHE group were higher than those in CHR group even at 2 h after iv administration of CHE or CHR. Conclusion CHE has a similar pharmacokinetic profile as CHR in rats. Furthermore,the cumulation of DAS in lungs is increased,which illustrates that CHE could enhance DAS targeted in lungs.
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AIM To investigate the tissue distribution of exendin-4 after administration in healthy rats. METHODS Exendin-4 was radioiodinated by the Iodo-GenTMmethod. Tissue distribution of [125I]exendin-4 was investigated after sc administration of [125I]exendin-4 at 3 μg·kg-1 in rats. Both total radioactivity and trichloroacetic acid (TCA) precipitated radioactivity were used to calculate the levels of [125I]exendin-4 in rats plasma and tissue samples after sc administration. RESULTS The tissue distribution of [125I]exendin-4 after sc injection showed substantial disposition in kidneys, lungs, bladder and pancreas. The rank order of normalized tissue distribution was kidneyslungsbladderpancreasintestineplasmaadrenalsjejunumlymphliverspleenheartmarrowthymustesticlesbrainmuscleadipose. CONCLUSION [125I]Exendin-4 underwent a rapid and wide distribution in the tissues throughout the whole body within the time course examined. TCA precipitated radioactivity in kidneys was the highest, however, only trace amounts of [125I]exendin-4 was detected in the brain.
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OBJECTIVE To establish a HPLC method for the determination of protocatechuic acid(PA)in rat plasma and tissue.METHODS A single oral dose of PA was performed in rats at 12.5,25,50 mg·kg-1,plasma concentrations at eachtime point were determined by HPLC and the data were analyzed by DAS 2.0.The concentrations of PA in the main tissues were determined at 10,30 and 60min after an oral administration of 25 mg·kg-1.RESULTS The pharmacokinetics of PA conformed to a two-compartment open model after ig administration.The main pharmacokinetic parameters were Cmax(mg·L-1):0.34±0.06,1.59±0.07,3.03±0.34;AUC(0-t)(mg·min·L-1):38.97±4.35,147.53±17.35,423.64±61.58.PA was mainly distributed in stomach,kidney,heart,less in liver,muscle and spleen,and least in brain and lung.CONCLUSION A simple,rapid,accurate and precise HPLC method for the analysis of PA in rat plasma was successfully developed and validated and successfully applied to a pharmacokinetic and tissue study of PA in rats.
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Objective To study the pharmacokinetics and tissue distribution of paclitaxel submicro-emulsion injection (PSME) in rats. Methods High pressure homogenization method was used to prepare PSME. The commercial paclitaxel injection was used as a reference to evaluate the pharmacokinetics and tissue distribution of PSME. The 3p87 computer program was used to analyze the pharmacokinetic model, and the pharmacokinetic parameters were calculated using the statistical moment method. The relative tissue exposure values (re) were used to evaluate the tissue targeting of PSME. Results The mean particle size and Zeta potential of PSME were (135.5±47.7) nm and -39.10 mV , respectively. The pharmacokinetic data obtained with both preparations fitted a two-compartment model, and the main pharmacokinetic parameters exhibit no statistically significant difference (n=6, P 0.05). Compared to the commercial paclitaxel group, the re values of liver, spleen, lung, kidney in PSME group were 1.25, 1.28, 1.24 and 1.33 , respectively. Conclusions The PSME had a similar pharmacokinetic characteristics as the commercial paclitaxel injection. There is only a little accumulation of PSME in liver, spleen, lung and kidney without remarkable influence on the tissue distribution of paclitaxel in rats.
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