This study aimed to explore the impact of depression caused by chronic unpredictable mild stress (CUMS) on in vivo activity of six kinds of CYP450 isoforms in rats. According to 'Katz' method, the model of CUMS was established. Tolbutamide, chlorzoxazone, theophylline, midazolam, omeprazole and dextromethorphan were chosen as probe substrates of CYP2C6, CYP2E1, CYP1A2, CYP3A2, CYP2D1 and CYP2D2 of rats. Plasma concentration of six kinds of CYP450 in control group and model group were determined by LC-MS/MS and computed pharmacokinetic parameters. Consequently, metabolism of theophylline and chlorzoxazone accelerated significantly (P < 0.01), but tolbutamide, dextromethorphan, omeprazole and midazolam had no significant difference. The present study proved that depression caused by CUMS had strong induction to CYP1A2 and medium induction to CYP2E1.

Aim To establish a LC-MS/MS method for determination of 5-HT, NE, DA and observe the con-centration of 5-HT, NE, DA in rat plasma of CUMS. Methods Twenty-two male SD rats were divided into control group and model group. Model group was given 9 kinds chronic unpredictable mild stimulating factors every day. 21 days later, behavior and orbital blood were measured before and after modeling. Using benzo-yl chloride as a pre-column derivatization reagent, three analytes and IS were derivatized before LC-MS/MS detection. Change in three kinds of neurotransmit-ter concentration was measured in rat plasma before and after modeling. Results After modeling, com-pared with control group, the weight of rats in model group was declined significantly ( P<0. 05 ) . Horizon-tal scores, vertical scores and sugar consumption were declined significantly ( P <0. 01 ) . Calibration curves of 5-HT, NE, DA were linear between 1. 47 ~752, 1. 75 ~898 , 2. 05 ~1 053 μg · L-1 and LOQ were 1. 47, 1. 75, 2. 046μg·L-1 ,respectively. The recov-ery of 5-HT, NE, DA from plasma was over than 70%, and RSD of inter-day and intra-day assay was limited in 15%. Compared with control group, the con-centration of 5-HT, NE, DA in rat plasma of model group was declined to ( 3. 99 ± 1. 21 ) , ( 6. 24 ± 1. 94), (6. 07 ± 1. 98) μg·L-1(P <0. 01). Con-clusion After making CUMS model of depression, three kinds of neurotransmitters in rat plasma are de-creased.

Objective To investigate the effect of clopidogrel on the binding rate of ginsenosides with rat serum proteins (RSA). Methods Equilibrium dialysis and liquid chromatography-mass spectrometry were employed to quantify the concentration of ginsenoside Rg1 and Rb1. The protein-binding rates of Rg1 and Rb1 in the presence or absence of clopidogrel (1.0 mg/L) were determined. A molecular simulation model (consisting of homology modeling and molecular docking interaction) was used to reveal the target protein-compound interactions. Results The binding rates of ginsenosides Rg1 (0.4, 1.0, and 2.0 mg/L) with RSA were (30.16±2.82)%, (33.42±4.21)%, and (34.61±3.42)%, and those of and Rb1 were (50.13±2.34)%, (51.23±3.23)%, and (53.11± 3.26)%, respectively. In the presence of clopidogrel, the binding rates of Rg1 decreased to (22.13 ± 2.72)%, (21.42 ± 3.22)%, and (25.45 ± 3.52)%, and those of Rb1 to (40.13 ± 3.24)%, (41.25 ± 4.15)%, and (43.11 ± 3.31)%, receptively. The molecular docking suggested that these compounds competed to bind with RSA. Conclusion Clopidogrel can competitively bind to RSA with ginsenosides to lower the plasma protein binding rates of ginsenosides.

Objective To investigate the effect of clopidogrel on the binding rate of ginsenosides with rat serum proteins (RSA). Methods Equilibrium dialysis and liquid chromatography-mass spectrometry were employed to quantify the concentration of ginsenoside Rg1 and Rb1. The protein-binding rates of Rg1 and Rb1 in the presence or absence of clopidogrel (1.0 mg/L) were determined. A molecular simulation model (consisting of homology modeling and molecular docking interaction) was used to reveal the target protein-compound interactions. Results The binding rates of ginsenosides Rg1 (0.4, 1.0, and 2.0 mg/L) with RSA were (30.16±2.82)%, (33.42±4.21)%, and (34.61±3.42)%, and those of and Rb1 were (50.13±2.34)%, (51.23±3.23)%, and (53.11± 3.26)%, respectively. In the presence of clopidogrel, the binding rates of Rg1 decreased to (22.13 ± 2.72)%, (21.42 ± 3.22)%, and (25.45 ± 3.52)%, and those of Rb1 to (40.13 ± 3.24)%, (41.25 ± 4.15)%, and (43.11 ± 3.31)%, receptively. The molecular docking suggested that these compounds competed to bind with RSA. Conclusion Clopidogrel can competitively bind to RSA with ginsenosides to lower the plasma protein binding rates of ginsenosides.

Aim To investigate the pharmacokinetic effect of aspirin on caffeic acid in dengzhanxixin injec-tion( DI) . Methods Concentration of caffeic acid in rat plasma was detected by LC-MS/MS after rats were given intravenous administration of DI or DI combined with aspirin by gavage. Pharmacokinetic parameters were calculated by DAS 1. 0 pharmacokinetic software. Results In vivo pharmacokinetic models of caffeic acid were two-compartment open models in both the caffeic acid group and the caffeic acid combined with aspirin group. After compatibility, caffeic acid showed a significant increase in T 12β, with a slight decrease in CL. Conclusions Aspirin can reduce metabolic process of caffeic acid in vivo.

OBJECTIVETo detect pharmacokinetics of Danshensu Sodium in Danshen dripping solution in Beagles.

METHODDanshen dripping solution was dripped intravenously into healthy Beagles at a dose of 10 mL x kg(-1). Their plasma samples were extracted with acetic ether, the blood concentrations were determined by HPLC method.

RESULTDanshensu Sodium showed a good linear relationship within the range of 0.225-18.000 mg x L(-1), with the lowest detectable limit of 0.113 mg x L(-1). Its pharmacokinetic parameters were as follows: tmax was 30 min, Cmax was (9.5742 +/- 2.3715) mg x L(-1), t1/2 was (19.23 +/- 2.97) min, CL was (0.0127 +/- 0.0030) L x min(-1) x kg(-1), AUC(0-tn) was (474.954 +/- 95.483) mg x min x L(-1) and AUC(0-infinity) was (482.494 +/- 95.353) mg x min x L(-1).

CONCLUSIONThe accurate, stable and reliable blood concentration method shows a one-compartment mode of Danshensu Sodium in Beagles.

Animals ; Chromatography, High Pressure Liquid ; Dogs ; Drug Stability ; Drugs, Chinese Herbal ; pharmacokinetics ; Female ; Lactates ; pharmacokinetics ; Male ; Solutions

Aim To establish an UPLC-ESI-MS method for determination of asiaticoside and investigate its application to pharmacokinetic study in rats.Methods Eight rats were given 40 mg·kg~(-1) asiaticoside iv respectively.Drug plasma concentration was determined by UPLC-ESI-MS.Pharmacokinetic parameters were evaluated.Results Calibration curves were linear over 0.038～7.6 mg·L~(-1) and LLOQ was 38 μg·L~(-1),the recoveries of asiaticoside from plasma were larger than 95%,and RSD of inter-day and intra-day assay were below 10%.After iv administration of 40 mg·kg~(-1) asiaticoside,the pharmacokinetic parameters of AUC(0-t),T(1)/(2)β,CL,Vd were (81 443.67±57 156.81) μg·L~(-1)·min~(-1),(23.44±9.60) min,(0.19±0.07) L·min~(-1)·kg~(-1),(8.92±6.68) L·kg~(-1),respectively.Conclusion The method described in this report was sensitive and specific,and suitable for pharmacokinetic studies of asiaticoside in rats.

OBJECTIVETo establish a LC-MS-MS method for quantification of cinnamic acid in human plasma and study its pharmacokinetics after administration of Mailuoning injection at a single and the multiple doses to healthy volunteers.

METHODPlasma samples were acidified with hydrochloric acid and extracted with ethyl acetate-ether. Cinnamic acid was determined by LC-MS-MS using a ZOBAX SB C18 column with a mobile phase of methanol-water (containing 2 mmol x L(-1) ammonium acetic) (45: 55) at a flow rate of 0.5 mL x min(-1) and detected using ESI with negative ionization mode. Ions monitored in the multiple reaction monitoring (MRM) mode were m/z 146.8 /103.1 [M - H]- for cinnamic acid and m/z 245.6 /126.0 [M - H] - for tinidazole (IS). After administration of Mailuoning injection at a single and the multiple doses via intravenous guttae (ivgtt) to 10 healthy volunteers, the concentration of cinnamic acid in plasma was determined by LC-MS-MS method. The concentration-time curves were simulated by DASver 1.0 and the pharmacokinetic parameters were calculated.

RESULTThe calibration curve was linear within the range of 0.5400 microg x L(-1). The LLOQ was 0.5 microg x L(-1) and RSDs of intra and inter day were less than 10%. The concentration-time curves of cinnamic acid were consistent with the two-compartment model. The pharmacokinetic parameters after administration of Mailuoning Injection at a single and the multiple injections were as follows: C(max) (microg x L(-1)), 115.73 +/- 44.31 and 113.79 +/- 25.61; T1/2beta (h), 0.41 +/- 0.087 and 0.52 +/- 0.132; V(L x kg(-1)), 0.519 +/- 0.134 and 0.651 +/- 0.322; CL(L x kg(-1) x h(-1)), 0.899 +/- 0.295 and 0.830 +/- 0.222; AUC(0-tn) (microg x L(-1) x h), 158.64 +/- 56.019 and 166.49 +/- 46.788.

CONCLUSIONThe developed LC-MS/MS method was sensitive and selective, and there was no interference from endogenous substances. After administration of Mailuoning injection via ivgtt to healthy volunteers, the pharmacokinetic parameters of cinnamic acid between a single and the multiple doses, and between the male and female were no significant difference. There was no accumulation with multiple injections for cinnamic acid, but there were significant individual differences in the pharmacokinetics of cinnamic acid in volunteers.

Adult ; Chromatography, High Pressure Liquid ; methods ; Cinnamates ; blood ; pharmacokinetics ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Humans ; Injections ; Male ; Tandem Mass Spectrometry ; methods ; Young Adult

Objective Albumin is well known to decrease in response to sepsis, However, the.degradation and distribution in patients with severe sepsis to explore the mechanism of hypoalbuminemia in sepsis. Methods 10 volunteers and 10 patients with severe sepsis. 125I labeled albumin was administered intravenously to 10 healthy volunteers and 10 patients with severe sepsis. Each subject had frequent blood samples taken at 0,1,2,4,8,12,24 hours and on day 2, 3, 4, 5, 6, 7, 9, 11, 13, 15, 18, 22, 25 to measure 125I concentration and draw the curve of concentration over time. Plasma was regarded as the central pool and body fluid as side pool, The curve of albumin concentration vs time was expected to follow two compartment model. Results Radioactivity of blood samples was counted and the results were graphically expressed. The half-life time(t1/2), apparent volume of distribution(Vd) and transportation rate(K12) of albumin from the central pool to the side pool were calculated. The half-life time in sepsis was obviously shorter than that in control group (8.2 1.4 vs 12.5 1.7days, P<0.001). The transportation rate in sepsis group was quicklier than that in control group [(4.4±1.9)× 10-2/h vs (2.4±0.6)×10-2/h, P<0.005]. There was no significant difference in apparent volume of distribution between two groups. Conclusions In patients with severe sepsis, the distribution rate of albumin from plasma to body fluid was obviously elevated and the decomposition rate of albumin was markedly increased.

0.05).CONCLUSION:It is more economical to use domestic CsA in liver transplantation recipients.