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??OBJECTIVE To establish an UPLC-MS method for simultaneously determining the contents medical components of neohespiridin and naringin in rat plasma, meanwhile to investigate the pharmacokinetics for Daidai flavonoids lipid-lowering dropping pills and Daidai flavones extraction were compared in rats. METHODS We are established an UPLC-MS method to simultaneously determine the content of effective components(neohesperidin and naringin) of Daidai fruit flavones lipid-lowering dropping pills in rat plasma, measured blood drug concentration in rats, fitted medicine curve, analyzed and compared the pharmacokinetic process in vivo of Daidai fruit flavones lipid-lowering dropping pills and Daidai fruit flavonoids extracts, to evaluate the oral bioavailability improvement of Daidai fruit flavones lipid-lowering dropping pills. RESULTS The pharmacokinetics experimental results of rat gastric drug delivery with Daidai fruit flavonoids extract compared with that of rat with Daidai fruit flavones lipid-lowering dropping pills showed that the ??_max of neohesperidin in medicated serum is(1.68??0.02) _extract and(5.54??0.09) _{dropping pills}mg??L^-1, respectively; the ??_max of naringin is(1.50??0.05) _extract and(4.83??0.10) _{dropping pills}mg??L^-1, respectively; the ??_max and AUC_0~?? of Daidai fruit flavones lipid-lowering dropping pills were significantly higher than that of Daidai fruit flavonoids extraction(P<0.05), and MRT and t_1/2 of Daidai fruit flavones lipid-lowering dropping pills were significantly shorter than that of Daidai fruit flavonoids extracts.With Daidai fruit flavonoids extract as reference, the relative bioavailability of neohesperidin and naringin in dropping pills were 278.52% and 258.59%, respectively. CONCLUSION Daidai flavones dropping pill can significantly improve the medical components of neohespiridin and naringin oral bioavailability of Daidai flavones extraction.     

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??OBJECTIVE To investigate the pharmacokinetic characteristics of enteric-coated sodium mycophenolate(EC-MPS) or mycophenolate mofetil (MMF) dispersible tablets after multiple oral doses in early renal transplant patients, providing references for the rational use of the study drugs in clinical practice. METHODS Thirty-eight first-time renal transplant patients were selected and randomly divided into EC-MPS group (n=18) or MMF dispersible tablets group (n=19). The patients received EC-MPS (540 mg, q12h) or MMF dispersible tablets (750 mg, q12h), combined with tacrolimus and methylprednisolone to prevent acute rejection, respectively. Blood samples were collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 h after oral administration on the postoperative day 5. Enzyme multiplied immunoassay technique (EMIT) was employed to determine the plasma concentration of MPA. The main pharmacokinetic parameters of the two durgs were assessed. RESULTS Pharmacokinetic parameters on the postoperative day 5 of EC-MPS and MMF dispersible tablet were as follows: AUC_{0-12 h} were(43.62??16.20) and(42.02??14.40)mg??h??L^-1(P>0.05);??_max were (17.85??11.32) and (13.96??5.11) mg??L^-1(P>0.05);t_max were (2.72??1.74) and(1.32??0.42)h(P<0.05); ??₀ were (1.63??1.18) and (1.66??0.93) mg??L^-1(P>0.05); ??₁₂ were(1.84??2.09) and (1.81??1.76) mg??L^-1(P>0.05); CL were (14.12??5.30) and (19.66??5.99) L??h^-1(P<0.05). Most of the patients revealed a second small peak in the 4-12 h after taking MPA in the two study groups. CONCLUSION There are large individual differences of pharmacokinetic between EC-MPS and MMF dispersible tablets in early renal transplant patients. It is necessary to carry out therapeutic drug monitoring of MPA to guide the adjustment of drug dosage.     

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??OBJECTIVE To develop a highly sensitive and specific LC-MS/MS method to explore the pharmacokinetic properties of araloside A. METHODS Araloside A was administered in a dose of 50 mg??kg^-1 via gastric in fusion and 5 mg??kg^-1 by intravenous injection in rats.Araloside A was analyzed by a validated LC-MS/MS method in plasma after intravenous and intragastric administration. The pharmacokinetic parameters were evaluated by software DAS 3.0. RESULTS The RESULTS of pharmacokinetic study showed that the linear range of araloside A was good in 1.0-10 000.0 ??g??L^-1(r>0.994 8). The specificity, precision and accuracy, matrix effect and extraction recovery rate and stability all meet the requirements. The main pharmacokinetic parameters for intragastric administration with araloside A 50 mg??kg^-1 and intravenous injection of araloside A 5 mg??kg^-1 were as follows:t_1/2 was(8.65??3.22) and(2.00??0.21)h, AUC_0-t was(277.14??101.00) and (21 194.59??4 385.13)ng??h??L^-1, MRT_0-t was (7.88??0.64) and (1.21??0.11)h, Vd/F was (2 229.99??1 013.97) and (0.71??0.20)L??kg^-1, CL/F was(149.11??62.28) and (0.24??0.05) L??h^-1??kg^-1, respectively; ??_max was (32.68??10.74) ??g??L^-1 for intragastric administration and t_max reached(1.21??0.70) h, oral bioavailability of araloside A was about 0.14%. CONCLUSION The LC-MS/MS method established is specific and sensitive, and can be successfully applied in basic pharmacokinetic study of araloside A in rat plasma.     

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??OBJECTIVE To prepare compound aspirin and esomeprazole magnesium enteric-coated pellet capsules and evaluate the drug release in vitro/in vivo. METHODS The aspirin pellet cores were prepared by using extrusion-spheronization method, and the esomeprazole magnesium-containing drug pellets were prepared with fluidized bed. By using fluidized bed coating method, the two kinds of drug-containing pellets were respectively coated with enteric layer to obtain enteric-coated pellets. After determining the loading capacity by measuring drug content, the two kinds of drug-containing pellets were filled into No.1 capsules. In vitro release was evaluated by measuring release percentage. The in vivo release behavior was evaluated by determination of pharmacokinetic parameters in rats. RESULTS The cumulative release percentage of the two drugs was less than 5% in 2 h in 0.1 mol??L^-1 hydrochloric acid solution. The cumulative release percentage of aspirin was more than 70% in 45 min in pH 6.8 PBS and it was more than 80% in 30 min for esomeprazole magnesium. Aspirin was metabolized to salicylic acid in plasma and its main pharmacokinetic parameters were as follows:t_1/2=9.47 h, MRT_0-??=14.43 h, t_max=3.00 h, ??_max=51.34 mg??L^-1, AUC _0-24=703.39 mg??h??L^-1, AUC _0-??=860.52 mg??h??L^-1. The pharmacokinetic parameters for esomeprazole magnesium were as follows:t_1/2=3.72 h, MRT_0-??=7.44 h, t_max=1.50 h, ??_max=2.71 mg??L^-1, AUC_0-24=11.89 mg??h??L^-1, AUC_0-??=13.79 mg??h??L^-1. CONCLUSION The formulation of compound enteric-coated pellet capsules is reasonable, and the preparation technology has good reproducibility. The drug release is located in the intestinal tract, thus esomeprazole magnesium can antagonize the gastrointestinal side effects of aspirin and aspirin can produce better antithrombotic effect .     

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??OBJECTIVE To observe whether low concentration (1??10^-8 mol??L^-1) of ouabain (OUA)can increase the contractility in rat cardiocytes and investigate the Na/K pump signal transduction pathways related to positive inotropic action following the low concentration of OUA. METHODS On enzymatic isolation of rats ventricular myocytes, the Na⁺/K⁺ pump current (Ip) was by whole-cell patch-clamp, in order to observe the low concentration of OUA on Ip. The contraction of a single myocyte was assessed by a video-based motion edge-detection system. ??To detect and compare the potentiations of 1??10^-8-1??10^-3 mol??L^-1 OUA on the contractility in rat cardiocytes. ??The cardiocytes were pre-treated with PP2(1 ??mol??L^-1), NAC(100 ??mol??L^-1), PD98059(50 ??mol??L^-1)for 5 min, and the effects of the signals transduction inhibitors on the positive inotropic effect of 1??10^-8 mol??L^-1 OUA was recorded. RESULTS The 1??10^-8-1??10^-3 mol??L^-1 OUA increased the contractility of rat cardiocytes (P<0.01). Compared 1 ??mol??L^-1 PP2 +1??10^-8 mol??L^-1 OUA group with 1??10^-8 mol??L^-1 OUA group, the contraction amplitude decreased (P<0.05), and compared 100 ??mol??L^-1 NAC +1??10^-8 mol??L^-1 OUA group with 1??10^-8 mol??L^-1 OUA group, the contraction amplitude also decreased (P<0.01), no significant difference in contraction amplitudes between 50 ??mol??L^-1 PD98059+1??10^-8 mol??L^-1 OUA group and 1??10^-8 mol??L^-1 OUA group (P>0.05). CONCLUSION The 1??10^-8-1??10^-3 mol??L^-1 OUA could increase the contraction amplitude of cardiocytes in rats in concentration-dependent manner. Positive inotropic effect of OUA in low concentration is related to Na/K pump signal transduction. Multiple signal pathways regulate the positive inotropic effect of 1??10^-8 mol??L^-1 of OUA, including the Src/ROS signal pathway.     

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??OBJECTIVE To study the pharmacokinetics of pirfenidone in Chinese healthy volunteer after a single dose and multiple-dose administration. METHODS Twelve Chinese healthy volunteers were randomly divided into low, medium and high dose groups(200, 400, 600 mg). The multiple-dose group was administrated with pirfenidione 400 mg three times daily for 5 d. Intensive blood sampling was performed from 12 volunteers within 12 h after the single dosing and the last dose of the multiple dosing. HPLC-MS/MS was used to determine the plasma concentrations of pirfenidone. The pharmacokinetic parameters were calculated by DAS software. RESULTS The main pharmacokinetic parameters of pirfenidone after single-dose administration of 200,400,600 mg qd as follows: ??_max were(5.00??1.42),(9.43??2.74)and(14.14??3.36)mg??L^-1;t_max were(0.57??0.33),(0.60 ??0.30)and(0.60??0.38)h;t_1/2 were(2.16??0.77),(2.15??0.75)and(2.01??0.76)h; AUC_0-?? were(13.87??7.79),(29.26??12.02)and(45.85??20.25)mg??h??L^-1;AUC_0-12 were?(13.27??7.08),(27.92??10.56)and(43.98??18.14)mg??h??L^-1,respectively. The main pharmacokinetic parameters after 400 mg tid for 5 d were as follows: ??_max was(9.46??2.77)mg??L^-1,??_min was(1.14??1.11)mg??L^-1,t_max was(0.52??0.34)h,t_1/2 was(1.93??0.63)h,AUC_0-?? was(26.74??13.49)mg??h??L^-1,AUC_0-12 was (25.79 ??12.34)mg??h??L^-1,AUC_sswas(23.53??10.59)mg??h??L^-1.CONCLUSION The pharmacokinetic parameters of pirfenidone show that ??_max and AUC were linear in the dose range from 200-600 mg and the pharmacokinetic parameters were similar as reference.
     

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??OBJECTIVE To establish a LC-MS/MS method for determining F1 in rat plasma and study the pharmacokinetic properties of F1. METHODS Ten healthy SD rats were enrolled in this study. They were randomly divided into two groups and received intragastric(10 mg??kg^-1) and intravenous administration(5 mg??kg^-1) of F1. After receiving F1, the concentrations of F1 in plasma were determined. Blood samples(0.1 mL)were immediately collected into heparinized tubes before injection and at 0,0.08, 0.25,0.5,0.75,1,2,4,6,8,10,12,24 h after injection. The pharmacokinetic parameters were determined by DAS2.0 software, absolute bioavailability of F1 was calculated based on AUC and dose administered. RESULTS The main pharmacokinetic parameters after intragastric and intravenous administration of F1 were as follows: ACU_0-t(27.052??10.068),(153.878??88.777)ng??h??mL^-1;AUC_0-??(31.425??9.261),(179.054??116.794)ng??h??mL^-1;MRT_0-t(10.722??4.335), (2.398??1.344)h; MRT_0-?? (15.651??5.917),(6.925??7.013)h;t_1/2(4.294??1.534),(6.052??3.633)h;??_max(18.394??17.856),(219.079??142.207)ng??mL^-1,respectively. Absolute bioavailability value was 8.79%. CONCLUSION This method can be used to determine the content of F1 in rat plasma. The experimental results can guide the structural optimization of F1, improve the pharmacokinetics of F1 in vivo and provide experimental basis for improving bioavailability of F1.     

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??OBJECTIVE To develop an LC-MS/MS method for the quantitative analysis of ocotillol in rat plasma, and study the pharmacokinetic characteristics of ocotillol in rats after oral administration.METHODS Ocotillol was extracted from plasma sample by protein precipitation. The concentration of ocotillol in plasma was determined by LC-MS/MS and the plasma concentration-time curve and main pharmacokinetic parameters were calculated after a single oral administration of ocotillol at 40 mg??kg^-1 to SD rats.RESULTS Excellent linearity was found between 10-240 ng??mL^-1. Intra-and inter-day precision values (RSDs) of QC samples were both below 15% and the extraction recoveries of ocotillol from plasma were higher than 84.14%. Double peaks were observed in the mean plasma concentration versus time profile of ocotillol after oral administration. The main pharmacokinetic parameters of ocotillol were as follows:the mean maximum plasma concentration (??_max) was (156.60??51.84) ng??mL^-1 occurring at (0.83??0.26) h post dose, the mean elimination half-time (t_1/2) was (8.82??7.56) h, and the mean area under the plasma concentration versus time curve (AUC_0-t) was (687.15??144.08) ng??h??mL^-1.CONCLUSION The current data shows that ocotillol is rapidly absorbed in rats after oral administration and slowly eliminated from circulatory blood system, with low plasma exposure. Enterohepatic circulation may contribute to the atypical drug absorption profiles.     

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??OBJECTIVE To research population pharmacokinetics of biapenem in critical patients after repeated dosing. METHODS Blood samples were collected according to the different time points after intravenous administration of 300 mg for many times in the group of critical patients. High-performance liquid chromatography (HPLC) was used to determine the drug concentration in plasma.And pharmacokinetic parameters was caculated. RESULTS The main pharmacokinetic parameters for critical patients were as follows: ??_max was (6.66??2.93)mg??L^-1,T_maxwas (0.51??0.04) h,AUC_0-?? was (18.98??16.95) mg??h??L^-1,T_1/2 was (2.06??1.93) h,Cl was (20.9??17.4) L??h^-1,Vd was (46.43??3.5) L. CONCLUSION The pharmacokinetic parameters of biapenem in critical patients with a significant difference was found in healthy people. So need according to pharmacokinetic characteristics of patients to develop personalized anti-infection plan.     

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??OBJECTIVE To establish a robust, fast and convenient method for in vitro assay of rat liver CYP1A2 and CYP2D1, and explore their kinetic features.METHODS Two selective substrates including phenacetin and dextromethorphan, which are probes of CYP1A2 and CYP2D1, were chosen for liver microsomes incubation, respectively; the corresponding ultra performance liquid chromatography tandem mass spectrometry(UPLC-MS) methods were developed for kinetic studies.RESULTS The fast and convenient UPLC-MS methods with high resolution and short running time(4~5 min) were established and validated for two assays of CYP1A2 and CYP2D1 activities;both methods showed good accuracy and precision, and the values of LOQ for CYP1A2 and CYP2D1 assays could reach 0.267 and 0.007 ??mol??L^-1, respectively. The kinetic studies showed that the Michaelis constant(K_m) for CYP1A2 and CYP2D1 were (28.4??2.7) and (13.9??1.3) ??mol??L^-1, respectively. Their activities were determined to be (1.47??0.12) and (3.98??0.09) nmol??mg^-1, respectively,when the substrate concentration was 10 ??mol??L^-1.CONCLUSION UPLC Tandem MS technique is proved to be a rapid, convenient and efficient approach with high sensitivity and selectivity for the assays of CYP1A2 and CYP2D1 in drug metabolism.