| Rosiglitazone (RGZ), a member of the thiazolidinedione class, is a potent synthetic agonist for peroxisome proliferator-activated receptor PPARy and an effective oral anti-diabetic agent. Many researches show that it also can improve cognition in patients with Alzheimer's disease (AD), thus implicating a possible role of the drug in the central nervous system. However, its underlying mechanism is not known clearly. Especially, there is still controversy on whether RGZ can permeate blood brain barrier. In present study, a simple and fast HPLC-UV method is established and a simple sample preparation method is also explored. They were applied in the analysis of pharmacokinetics, tissues distribution and determination of rosiglitazone in cerebrospinal fluid in rats.The peptide deformylase (PDF) inhibitors are a novel and unique class of antimicrobial agents in development for the treatment of respiratory tract and skin infections. LBM415 is the first such compound to enter clinical development. Its activity has been widely evaluated in preclinical and clinical studies against multiple pathogens. SW1210 and SW1204, new compounds synthesized according to the structure of LBM415, displayed as good antibacterial activity and potency as LBM415 in the test of Minimum Inhibitory Concentration (MIC) in vitro and antibacterial activity in KM mice in vivo. In present study, we evaluated the pharmacokinetic parameters and bioavailability to support its continued development.1. HPLC determination of pharmacokinetics, distribution of rosiglitazone, and permeability across blood brain barrier in ratsA simple, rapid and accurate method was established to analyze RGZ in rat plasma, tissue and cerebrospinal fluid. The method was applied in the pharmacokinetics, tissue distribution of rosiglitazone. RGZ was rapidly absorbed (Tmax 0.5-1 h) with an elimination half-life of 2.5 h. The highest levels of the drug were observed in liver and fat while the lowest levels in the brain and spleen. The method was also used for the determination of rosiglitazone in cerebrospinal fluid. The result showed that rosiglitazone can be detected in cerebrospinal fluid, thus providing direct evidence that rosiglitazone can permeate cross blood brain barrier.2. Establishment of RP-HPLC method for determination of LBM415 and SW1210 in rat plasmaWe established and validated a RP-HPLC method for determination of LBM415 and SW1210 in rat plasma. A Shimadzu VP-ODS C18 column (250mmx4.6mm I.D., 5μm) was used, with methanol:KH2PO4 (pH=3.0) as the mobile phase (gradient elution). The UV detection wavelength was set at 240 nm, and they acted to be the internal standard for each other. The method exhibited good extraction recovery, intra-and inter-day accuracies and linearity for these two compounds.3. Pharmacokinetics and bioavailability of LBM415 in ratThe research aimed to investigate the pharmacokinetics and absolute bioavailability of LBM415 in male SD rats.Three male SD rats took single oral dose and intravenous of 100 mg/kg and 25 mg/kg LBM415 respectively. The concentrations of LBM415 in plasma were determined by high performance liquid chromatogram-UV method. The pharmacokinetic parameters following single oral dose of 100 mg/kg are as follows:the mean cmax was (46.44±4.23)μg/mL, tmax was only (16.67±3.33) min, t1/2 (34.23±1.72) min, AUC0-∞(3457.51±460.14) mg min/L. The absolute bioavailability was 20.19%.4. Pharmacokinetics and bioavailability of SW1210 in rat plasmaThe research aimed to investigate the pharmacokinetics and absolute bioavailability of SW1210 in male SD rats.Three male SD rats took single oral dose and intravenous of 100 mg/kg and 25 mg/kg SW1210 respectively. The concentrations of SW1210 in plasma were determined by high performance liquid chromatogram-UV method. The pharmacokinetic parameters following single oral dose of 100 mg/kg are as follows:the mean cmax was (12.57±0.62)μg/mL, tmax was only (33.33±3.33) min, t1/2 (39.92±5.25) min, AUC0-∞(1052.80±37.66) mg min/L. The absolute bioavailability was 3.83%. Compared with LBM415, SW1210 has a relatively slow absorption rate and a lower absolute bioavilability.5. LC/MS analysis of pharmacokinetics of SW1204 in rat plasmaA simple and reliable LC/MS method was developed and validated for the determination of SW1204 in rat plasma. Then the method was applied in pharmacokinetics of SW1204 in rat plasma. Three male SD rats took single oral dose of 25 mg/kg SW1204, and the concentrations of SW1204 in plasma were determined by LC/MS. The mean of cmax was (1.23±0.11)μg/mL, tmax was (26.67±7.27) min, t1/2 (87.87±24.60) min, AUC0-∞(134.96±11.63) mg min/L.The result showed that SW1204 was absorbed rapidly and had a longer t1/2 than LBM415.
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