Intratumoral injection of norcantharidin liposome emulsion hybrid delivery system amplifies the cancer-fighting effects of oral sorafenib against hepatocellular carcinoma.

Interventional therapies are increasingly used in clinical trials for hepatocellular carcinoma (HCC). Sorafenib is the front-line remedy for HCC, however, chemoresistance occurs immutably and affects the effectiveness of treatment. In a previous study, a norcantharidin liposome emulsion hybrid (NLEH) delivery system for HCC was developed. This study aims to examine the therapeutic effects of the combination of intratumoral injection of NLEH and sorafenib in treating HCC. Sorafenib combined with NLEH activated the apoptosis pathway by synergistically upregulating caspase-9, promoting cytotoxicity, apoptosis (64.57%), and G2/M cell cycle arrest (48.96%). Norcantharidin could alleviate sorafenib resistance by counteracting sorafenib-induced phosphorylation of Akt. Additionally, intratumoral injection of NLEH exhibited a sustained accumulation in the tumor within 24 h and didn't distribute to other major organs. Intratumoral injection of NLEH in combination with oral sorafenib displayed the most potent tumor growth inhibitory effect (77.91%) in vivo. H&E staining results and the indicators of the renal and liver function tests demonstrated the safety of this combination therapy. Overall, these results showed that intratumoral injection of NLEH in combination with oral sorafenib treatment represented a rational potential therapeutic option for HCC.

[Effects of Nano Material on Cadmium Accumulation Capacity and Grain Yield of Indica Hybrid Rice Under Wetting-drying Alternation Irrigation].

Wetting-drying alternation irrigation (WDI) can harvest high grain yield under effective irrigation water saving conditions. However, the kernel cadmium (Cd) content usually exceeds the national standard of 0.20 mg Cd per kg kernel in WDI. Applying a passivating agent with high-efficient repairing capabilities could be a feasible approach to reduce Cd content lower than 0.20 mg·kg-1 in WDI. Therefore, a field experiment was conducted with different irrigation regimes and passivating agents in a mildly Cd-polluted paddy field, of which the irrigation regimes were WDI and traditional flooded irrigation (FI) and the six passivating agents treatments were CK (no passivating agent; T1), slaked lime with 1125 kg·hm-2(T2), 1125 kg slaked lime and 3000 kg biochar per hectare (T3), 1125 kg slaked lime and 3000 kg organic fertilizer per hectare (T4), 1500 kg porous Nano stupalith per hectare (T5), and 1125 kg slaked lime combined with 1500 kg porous Nano stupalith per hectare (T6). Two typical Indica hybrid rice varieties with a high accumulated capacity named cultivar Shenliangyou 1813 and a low accumulated trait named cultivar Liangyou 6206 were utilized. The main reason that Indica hybrid rice cultivars were selected was their higher absorbed and accumulated characteristics than that of Japonica rice. The results indicated that available Cd content of the soil significantly declined with 17.13%-61.01% decreasing amplitude at maturity when compared with pre-transplanting in WDI; however, the reduction was in the range of -43.45%-21.07% for the FI treatment across cultivars and passivating agents treatments. The available Cd content at maturity was significantly greater in FI than in WDI (P<0.05). In contrast, WDI had higher Cd content on stem, leaf, and kernel organs at maturity than with FI treatment of both cultivars and all of the passivating agents (P<0.05). Generally, the T1 treatment had the maximum available Cd content in the soil layer and highest accumulated Cd content on different aboveground organs, followed by the T2, T3, T4, T5, and T6 treatments considering both cultivars and irrigation regimes. The Cd kernel contents were 0.23-0.24 mg·kg-1 and 0.16-0.21 mg·kg-1 for cultivars Shenliangyou 1813 and Liangyou 6206, respectively, in the T6 treatment. The higher Cd kernel content was generally related to a larger Cd content in the stem organ. For the grain yield, no significant differences were observed among cultivars, irrigation regimes, or passivating agents treatments (P>0.05). Under WDI, the kernel Cd content was still slightly higher than 0.20 mg·kg-1 in the T6 treatment (0.24 mg·kg-1 for cultivar Shenliangyou 1813 and 0.21 mg·kg-1 for cultivar Liangyou 6206); however, there is a predictability potential to produce lower than 0.20 mg·kg-1 kernel content in the T6 treatment if a cultivar with low accumulated capacity is used. Thus, the combined mode of the WDI+T6+cultivar with accumulated low Cd content could be considered an optimized cultivation scheme to obtain no Cd contaminated kernels with high grain yield and water-use efficiency in mildly polluted paddy fields.

[Preparation and evaluation of risperidone-loaded microsphere/sucrose acetate isobutyrate in situ forming complex depot with double diffusion barriers].

In the present study, a risperidone loaded microsphere/sucrose acetate isobutyrate (SAIB) in situ forming complex depot was designed to reduce the burst release of SAIB in situ forming depot and to continuously release risperidone for a long-term period without lagime. The model drug risperidone (Ris) was first encapsulated into microspheres and then the Ris-microspheres were embedded into SAIB depot to reduce the amount of dissolved drug in the depot. The effects of different types of microsphere matrix, including chitosan and poly(lactide-coglycolide) (PLGA), matrix/Ris ratios in microspheres and morphology of microspheres on the drug release behavior of complex depot were investigated. In comparison with the Ris-loaded SAIB depot (Ris-SAIB), the complex depot containing chitosan microspheres (in which chitosan/Ris = 1 : 1, w/w) (Ris-Cm-SAIB) decreased the burst release from 12.16% to 5.80%. However, increased drug release rate after 4 days was observed in Ris-Cm-SAIB, which was caused by the high penetration of the medium to Ris-Cm-SAIB due to the hydrophilie of chitosan. By encapsulation of risperidone in PLGA microspheres, most drugs can be prevented from dissolving in the depot and meanwhile the hydrophobic PLGA can reduce the media penetration effect on the depot. The complex depot containing PLGA microspheres (in which PLGA/ drug=4 : 2, w/w) (Ris-Pm-SAIB) showed a significant effectiveness on reducing the burst release both in vitro and in vivo whereby only 0.64% drug was released on the first day in vitro and a low AUC0-4d value [(105.2± 24.4) ng.mL-1.d] was detected over the first 4 days in vivo. In addition, drug release from Ris-Pm-SAIB can be modified by varying the morphology of microspheres. The porous PLGA microspheres could be prepared by adding medium chain triglyceride (MCT) in the organic phase which served as pore agents during the preparation of PLGA microspheres. The complex depot containing porous PLGA microspheres (which were prepared by co-encapsulation of 20% MCT) (Ris-PPm-SAIB) exhibited a slightly increased AUC0-4d of (194.6±15.8) ng.mL-1d and high plasma concentration levels from 4 to 78 days [Cs(4-78d)=(7.8±1.2) ng.mL-1]. The plasma concentration on 78 day C78d was (9.0 2.5) ng.mL-1 which was higher than that of Ris-Pm-SAIB [C78d= (1.6 ± 0.6) ng.mL-1]. In comparison with Ris-Pm-SAIB, the AUC4-78d of Ris-PPm-SAIB increased from (379.0±114.3) ng.mL-1.d to (465.0 ±149.2) ng.mL-1.d, indicating sufficient drug release from the Ris-PPm-SAIB. These results demonstrate that the risperidone loaded porous PLGA microsphere/SAIB in situ forming complex depot could not only efficiently reduce the burst release of SAIB depot both in vitro and in vivo, but also release the drug sufficiently in vivo, and be capable to continuously release the drug for 78 days.

[Dynamics simulation on plant growth, N accumulation and utilization of processing tomato at different N fertilization rates].

Three field experiments were conducted to simulate the dynamics of aboveground biomass, N accumulation and utilization of drip-irrigated processing tomatoes at different N fertilization rates (0, 75, 150, 300, 450, or 600 kg x hm(-2)). The results showed that Logistic models best described the changes in aboveground biomass, N accumulation, and utilization of accumulated N efficiency with the physiological development time (PDT). Rapid accumulation of N began about 4-6 d (PDT) earlier than the rapid accumulation of aboveground biomass. The momentary utilization rate of N (NMUR) increased after emergence, reached a single peak, and then decreased. The N accumulation, aboveground biomass and yield were highest in the 300 kg x hm(-2) treatment. The quadratic model indicated that application rate of 349 to 382 kg N x hm(-2) was optimum for drip-irrigated processing tomatoes in northern Xinjiang.

Synthesis and structure-activity relationship of non-phosphorus-based fructose-1,6-bisphosphatase inhibitors: 2,5-Diphenyl-1,3,4-oxadiazoles.

With the aim of discovering a novel class of non-phosphorus-based fructose-1,6-bisphosphatase (FBPase) inhibitors, a series of 2,5-diphenyl-1,3,4-oxadiazoles were synthesized based on the hit compound (1) resulting from a high-throughput screening (HTS). Structure-activity relationship (SAR) studies led to the identification of several compounds with comparable inhibitory activities to AMP, the natural allosteric inhibitor of FBPase. Notably, compound 22 and 27b, bearing a terminal carboxyl or 1H-tetrazole, demonstrated remarkable inhibition to gluconeogenesis (GNG). In addition, both inhibition and binding mode to the enzyme were investigated by enzymatic kinetics and in silico experiments for representative compounds 16 and 22.

Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals. For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2 diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B (IC(50)=12.74 µM) by a vertical screen for the first time. Further SAR research was carried out by synthesizing and evaluating a series of compounds bearing two methyls at C-4 position and a fused heterocycle to ring A. Among them, compound 14b achieved a PTP1B inhibitory activity about eightfold than LCA and a 14-fold selectivity over the homogenous enzyme TCPTP.

Polymeric micelles based on poly(ethylene glycol) block poly(racemic amino acids) hybrid polypeptides: conformation-facilitated drug-loading behavior and potential application as effective anticancer drug carriers.

In this work, racemic hybrid polypeptides poly(ethylene glycol) (PEG)-b-poly(racemic-leucine) (PRL) copolymers with different leucine residues have been synthesized and characterized. Using docetaxel as a model molecule, the high drug-loaded spherical micelles based on PEG-PRL were prepared successfully using dialysis, with a tunable particle size from 170 nm to 250 nm obtained by changing the length of the hydrophobic blocks. Facilitated drug-loading behavior (higher drug-loading ability and easier drug-loading process) of PEG-PRL compared with their corresponding levo forms (PEG-b-poly[levo leucine]) was observed and clarified for the first time. With this facilitation, the highest drug-loading content and efficiency of PEG-PRL micelles can achieve 11.2% ± 0.4% and 67.2% ± 2.4%, respectively. All drug-loaded PEG-PRL micelles exhibit a similar release behavior with a sustained release up to 72 hours. The PEG-PRL was shown to be nontoxic against MCF-7 and human umbilical vein endothelial cells up to a concentration of 100 µg/mL, displaying a good biocompatibility. Also, the docetaxel-loaded PEG-PRL micelles were more toxic than the free drug against MCF-7 human breast cancer cells - both dose and time dependent. Therefore, these high docetaxel-loaded micelles based on racemic hybrid polypeptides appear to be a novel promising nanomedicine for anticancer therapy.

Preparation of gel-core-solid lipid nanoparticle: a novel way to improve the encapsulation of protein and peptide.

Using thymopentin and insulin as the model protein-drugs, novel Gel-Core-solid lipid nanoparticle (SLN) with the hydrogel core and lipid shell were prepared by double emulsion and thermal sensitive gel technology, with the intention to improve the entrapment efficiency. Pluronic F127 and Glyceryl palmitostearate were selected as hydrogel material and lipid material, respectively. The particle sizes and zeta-potential were characterized by dynamic light scattering and electrophoretic light scattering. Transmission electron microscopy (TEM) was employed to investigate the structure of this Gel-Core-SLN. The Gel-Core-SLN was successfully prepared and the particle size was 305.2 nm with zeta potential of -17.15 mV. Observations by TEM confirmed that most solidified hydrogel particles were dispersed in the central of Gel-Core-SLN as a form of single core, which effectively prevented the diffusion of proteins to the external water phase during preparation process. The entrapment efficiency of thymopentin-loaded Gel-Core-SLN and insulin-loaded Gel-Core-SLN were 61.97% and 57.36%, respectively. Both the two drug-loaded Gel-Core-SLNs showed relatively low burst release. The pharmacological availability of insulin-loaded Gel-Core-SLN was 6.02%. It was suggested that the Gel-Core-SLN could be a promising drug delivery system with the outstanding encapsulation efficiency, low burst release and relatively high pharmacological availability.

Ethyl 2-(3-chloro-2-pyridyl)-5-oxopyrazolidine-3-carboxylate.

In the mol-ecule of the title compound, C(11)H(12)ClN(3)O(3), the five membered ring adopts an envelope conformation. In the crystal structure, inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers.

Preparation and bioavailability of sustained-release doxofylline pellets in beagle dogs.

The objective of this study was to develop doxofylline-loaded sustained-release pellets coated with Eudragit NE30D alone (F1) or blend of Eudragit RL30D/RS30D (F2) and further evaluate their in vitro release and in vivo absorption in beagle dogs. Doxofylline-loaded cores with a drug loading of 70% (w/w) were prepared by layering drug-MCC powder onto seed cores in a centrifugal granulator and then coating them with different kinds of polymethacrylates in a bottom-spray fluidized bed coater. Dissolution behaviour of these formulations was studied in vitro under various pH conditions (from pH 1.2 to pH 7.4) to evaluate the effect of pH on drug release profiles. It was found that F2 produced a better release profile than F1 did and two different release mechanisms were assumed for F1 and F2, respectively. The relative bioavailability of the sustained-release pellets was studied in six beagle dogs after oral administration in a fast state using a commercially available immediate release tablet as a reference. Coated with Eudragit NE30D and a blend of Eudragit RL30D/RS30D (1:12), at 5% and 8% coating level, respectively, the pellets acquired perfect sustained-release properties and good relative bioavailability, with small fluctuation of drug concentration in plasma. But combined use of mixed Eudragit RL30D/RS30D polymers with proper features as coating materials produced a longer T(max), a lower C(max) and a little higher bioavailability compared to F1 (coated with Eudragit NE30D alone). The C(max), T(max) and relative bioavailability of F1 and F2 coated pellets were 15.16 microg/ml, 4.17 h, 97.69% and 11.41 microg/ml, 5 h, 101.59%, respectively. Also a good linear correlation between in vivo absorption and in vitro release was established for F1 and F2, so from the dissolution test, formulations in vivo absorption can be properly predicted.

Ethyl 3-bromo-1-(3-chloro-pyridin-2-yl)-1H-pyrazole-5-carboxyl-ate.

The title compound, C(11)H(9)BrClN(3)O(2), is an inter-mediate in the synthesis of Rynaxypyre, a new insecticidal anthranilic diamide used as a potent and selective ryanodine receptor activator. The dihedral angle between the aromatic ring planes is 78.7 (2)°.

The properties of bufadienolides-loaded nano-emulsion and submicro-emulsion during lyophilization.

The aim of this study was to prepare two types of emulsions, bufadienolides-loaded nano-emulsion (BU-NE) and submicro-emulsion (BU-SE) which were separately prepared by ultrasonic-high-pressure homogenization (UHPH) and high-pressure homogenization (HPH) methods, and to try to stabilize the colloid systems by lyophilization. The lyoprotective effects of cryoprotectant carbohydrates during the freeze-thawing and freeze-drying cycles on the emulsions were investigated in detail. The lyophilized products were characterized with regard to their appearance and particle size by transmission electron microscopy (TEM), scanning electron microscopy (SEM), photon correlation spectroscopy (PCS) and zeta potential. The median diameter, polydispersity index (PI) and zeta potential of BU-NE and BU-SE were 43.5 nm versus 161.4 nm, 0.100 versus 0.143 and -19.7 to -26.2 mV versus -29.4 to -35.3 mV, respectively. With the same drug content (0.28 mg mL(-1)) BU-SE exhibited a higher entrapment efficiency than BU-NE. The optimum cryoprotectant for BU-NE and BU-SE was maltose (20%) and trehalose (20%), respectively. The median diameters (95.7 and 168.5 nm) of the rehydrated BU-NE and BU-SE were slightly increased. For both of them, the bufadienolides entrapment efficiency was reduced whereas the drug content was not. The lyophilized BU-NE and BU-SE powders were stable over a period up to 3 months with no change in visual appearance, reconstitution ability, particle size distribution and drug concentration. This shows that freeze-drying could be a promising method to stabilize the emulsions.

[Preparation and in vitro and in vivo evaluation of etoposide submicro-emulsion for intravenous injection].

The aim of this thesis is to prepare etoposide submicro-emulsion (ESE) for intravenous injection and investigate its characteristics in vitro and in vivo. High-pressure homogenization was used to prepare ESE, using 10% (w/w) soybean oil and 10% (w/w) medium-chain triglyceride as mixed oil phase, and 1.8% (w/w) fabaceous lecithin as emulsifier. The pH was adjusted to 5.5 with 0.1 mol x L(-1) NaOH to keep the most stability of ESE. The particle size distribution and zeta potential were measured using photon correlation spectroscopy. Ultrafiltration was used to estimate the relative percentages of etoposide in each phase. Long-term storage test and accelerated isothermal test-Weibull distribution method were used to estimate the physical and chemical stability of ESE. Plasma pharmacokinetics in rats was monitored by high performance liquid chromatography by comparison with etoposide nonaqueous solution at the same time. The mean particle size, zeta potential and entrapment efficiency of ESE were (189.9 +/- 54.6) nm, - 32.6 mV and 91.7%, respectively. The emulsion was stable during 9 month storage at 4 degrees C. The shelf life (T0.9) of etoposide in lipid emulsion was estimated to be about 665 days at 4 degrees C. The drug concentration-time curves of ESE and solution were similar and could be described by two compartment model. The area under the curve of concentration versus time from zero to the last time point and the mean residence time of ESE and solution were (18.30 +/- 8.74) and (19.32 +/- 6.45) microg x h x mL(-1), and (1.46 +/- 0.32) and (1.71 +/- 0.52) h, respectively. Etoposide was incorporated in submicro-emulsion to improve its physical and chemical stability without addition of organic solvents with insignificant different characteristics in vivo when compared with solution.

[Rheological properties of sucrose acetate isobutyrate in situ gel].

To study the rheological properties of sucrose acetate isobutyrate (SAIB) in situ gel and the influencing factors. Measurements of shear stress and viscosity were carried out at different shear rate. The rheological properties of SAIB solution were similar to those of Newtonian fluid. The factors such as the type of solvent, concentration, additive, drug and temperature had effect on the rheological properties. Ethanol was a suitable solvent compared with ethyl lactate and N-methylpyrrolidone (NMP). The solution viscosity of SAIB was reduced from 1.29 to 0.11 Pa x s with only increasing the content of ethanol from 10% to 20%. Polylactic acid (PLA) and risperidone could increase the intermolecular force and viscosity. However, adding 10% (w/w) PLA, the initial release of risperidone was reduced from 20.2% to 3.5%. The solution viscosity reduced significantly by stepping up the temperature. The results obtained support the using of SAIB is satisfactorily injectable in situ gel formulation.

Formulation, preparation and evaluation of flunarizine-loaded lipid microspheres.

The aim of this study was to investigate the feasibility of preparing flunarizine-loaded lipid microspheres. Lipid microspheres (LMs) are excellent drug carriers for drug delivery systems (DDS) and are relatively stable and easily mass-produced. They have no particular adverse effects. LMs have been widely studied as drug carriers for water-soluble drugs, lipid-soluble drugs and inadequately soluble (in water or in lipid) drugs, in that they have a lipid layer, a water layer and an emulsifier layer. Flunarizine (FZ), a poorly water-soluble drug, was incorporated in lipid microspheres to reduce side effects by avoiding the use of supplementary agents, compared with solution injection. After investigation, the final formulation was as follows: 10% oil phase (long-chain triglyceride (LCT); medium-chain fatty acid (MCT) = 50:50); 1.2% egg lecithin; 0.2% Tween-80; 2.5% glycerin; 0.3% dl-alpha-tocopherol; 0.02% EDTA; 0.03% sodium oleate; 0.1% FZ and double-distilled water to give a total volume of 100 mL. Homogenization was the main method of preparation and the best conditions were a temperature of 40 degrees C, a pressure of 700-800 bar and a suitable cycle frequency of about 10. The particle size distribution, zeta-potential and entrapment efficacy were found to be 198.7+/-54.0 nm, -26.4 mV and 96.2%, respectively. Its concentration in the preparation was 1.0 mg mL(-1). The lipid microspheres were stable during storage at 4 degrees C, 25 degrees C and 37 degrees C for 3 months. Pharmacokinetic studies were performed in rats using a dose of 1.0 mg kg(-1). The pharmacokinetic parameters were as follows: AUC(0-t) 6.13 mug.h mL(-1), t(1/2) 5.32 h and Ke 0.16 L h(-1). The preparation data fitted a two-compartment model estimated by using 3p87 analysis software. From the observed data, FZ encapsulated in LMs did not significantly alter the pharmacokinetic characteristic compared with the FZ solution injection and did not produce a delayed release effect, when it was released in-vivo in rats. However, the availability of the drug was increased. These results suggested that this LM system is a promising option for the preparation of the liquid form of FZ for intravenous administration.

Formulation and evaluation of nimodipine-loaded lipid microspheres.

The purpose of this study was to develop an alternative, improved and better tolerated formulation and investigate the pharmacokinetic profile of the new formulation of nimodipine (NM) compared with nimodipine ethanol solutions. Lipid microspheres (LMs) prepared using lecithin and vegetable oils have attracted a lot of interest owing to their versatile properties, such as non-immunogenicity, being easily biodegradable and exhibiting high entrapment efficiency. NM incorporated in LMs could reduce irritation by avoiding the use of ethanol as a solubilizer. The solubility of NM was also increased by dissolving it in the oil phase. The particle size distribution, zeta potential, entrapment efficacy and assay of the NM-loaded LMs were found to be 188.2+/-5.4 nm, -31.6 mV, 94.2% and 1.04 mg mL(-1), respectively. The preparation was stable for 1 year at 4-10 degrees C. The formulation and some physicochemical properties of NM-loaded LMs were investigated. The pharmacokinetic and biodistribution studies were performed in rats at a dose of 1.2 mg kg(-1). From the observed data, there is no obvious retention of NM-loaded LMs in plasma. Moreover, incorporation of NM in LMs did not alter the tissue distribution significantly except for the relatively greater drug accumulation in the liver and spleen. The stimulation studies demonstrate that LMs of NM reduce irritation markedly compared with NM solutions. These results suggest that the LM system is a promising option to replace NM ethanol solutions as an intravenous treatment.

[In vitro and in vivo assesemet of sodium norcantharidin lipid microsphere].

AIM: To prepare lipid microsphere of sodium norcantharidin (NCTD) and then study their characters and pharmacokinetic behavior. METHODS: Dynamic Light Scattering, HPLC and retrodialysis technique were used to determine the in vitro characters of the NCTD loaded lipid microsphere (LM), such as the particle size, xi-potential, content, incorporation ratio, release profile and changes after dilute. And the plasma concentration was determined by HPLC-MS, compared with NCTD aqueous solution at the same time. RESULTS: Every property showed that the LM was preferable. The average diameter was about 200 nm. The xi-potential was - 38 mV. The content was close to 100%. And the incorporation ratio exceeded 80%. After i. v. administration of single dose, the pharmacodynamic parameter of LM AUC was 111.28 microg x mL(-1) x h(-1). The data of plasma concentrations showed that the NCTD LM was of two compartment. There was no obvious difference between in vivo parameters of LM and reference solution. CONCLUSION: The NCTD LM was eligible and the character of it in vivo was not changed.

[Pharmacokinetic study of ketoprofen in rat by blood microdialysis technique].

AIM: To investigate the in vitro recovery and influencing factors of ketoprofen in microdialysis probe, and study the pharmacokinetic of unbound ketoprofen in rat after iv administration. METHODS: The recovery of ketoprofen was detected by a concentration difference method. After microdialysis probe was inserted into the jugular vein of male Wistar rats, the probe was infused with various concentrations perfusate. The in vivo recovery and the pharmacokinetics of unbound ketoprofen in rat were investigated. Dialysate samples were determined by HPLC. RESULTS: The recovery detected by gain was as the same as that by loss; the recovery was independent of the drug concentration surrounding the probe. The in vitro recovery was 28.75% by concentration difference method and the in vivo recovery was (40.3 +/- 2.7) % by retrodialysis method. After i.v. administration of ketoprofen in rat, T 1/2, AUC and CL of unbound ketoprofen were (181 +/- 16) min, (112 +/- 27) microg x min x mL(-1) and (0.22 +/- 0.05) L x min(-1), respectively. CONCLUSION: Microdialysis sampling can be used for the pharmacokinetic study of unbound ketoprofen in rat.