In order to investigate the effect of ligustrazine (Lig) i.p. on peritoneal permeability in peritoneal dialysis and its side effects, creatinine was given intravenously and continuously to maintain the high plasma creatinine level. All the rabbits were divided into three groups: normal control group (group A), group B treated with 0.12% Lig and group C treated with 0.24% Lig. The peritoneal dialysis of all rabbits lasted 2 h. The plasma and dialysate levels of glucose, protein and creatinine were observed immediate, 30 min, 60 min, 90 min, 120 min after dialysis. Creastinine dialysate/plasma ratio (D/P), protein D/P ratio, glucose D/Do at different time points after dialysis and creatinine mass transfer area coefficient (MTAC) at 120 min were calculated. The structures of peritoneum were observed under optical microscope and electron microscope after continuously intraperitoneal injection of Lig for 14 days. The results showed that the 90-min and 120-min creatinine D/P ratios in the group C were higher than in the group A. The 120-min creatinine MATC in the group C was higher than in the group A. The rabbits treated with Lig did not show significant structure changes of peritoneum and signs of peritoneal irritation. It was suggested that Lig could increase mass transfer ability of peritoneum without significant side effects.
Biological Transport ; Cell Membrane Permeability ; Creatinine/blood ; Dialysis Solutions/chemistry ; Peritoneal Dialysis/*methods ; Peritoneum/*metabolism ; Pyrazines/*pharmacokinetics ; Pyrazines/pharmacology

OBJECTIVETo verify established the total quantum statistic moments model with astragaloside IV, paeoniflorin, tetramethylpyrazine in Buyanghuanwu injection, in order to establish a pharmacokinetic experimental method with multi-component traditional Chinese medicine (TCM) compound system.

METHODThe RP-HPLC was adopted, with the chromatographic column of C18, 4.6 mm x 250 mm, 5 microm. As for astragaloside IV, the ELSD detector was adopted with acetonitrile-water (35: 65) as the mobile phase at 1 mL x min(-1); the pressure of column was (15.0 +/- 0.408) MPa, the column temperature was 30 degrees C. Regarding paeoniflorin and tetramethylpyrazine, the detection of wavelengths was 254 nm, with acetonitrile-water (35:65) as the mobile phase at 1 mL x min(-1), the column pressure of (15.17 +/- 0.41) MPa. The pharmacokinetic parameters for single component were dealt with DAS and the total quantum statistical moment (TQSM) parameters were calculated using formulations.

RESULTAll of the three components followed the two compartmental pharkacokinetic model (P < 0.01) in rats. Compared with the superimposed total concentration, each single component showed difference in parameters up to 10 000 times at most, whereas the RSD of TQSM parameters was 3.510%. The TQSM pharmacokinetic parameters of the three components in Buyanghuanwu injection showed that AUC(t), MRT(t), VRT(t), CL(t), V(t), were (119.8 +/- 27.20) g x min x L(-1), (210.0 +/- 54.49) min, (5.608 +/- 2.723) x 10(4) min2, (0.319 6 +/- 0.068 8) mL x min(-1) x kg(-1) and (64.12 +/- 8.243) mL x kg(-1), respectively, suggesting that the half-life time for the three components were (145.5 +/- 37.76) min and 95% of them were metabolized within 0-674. 2 min.

CONCLUSIONThe TQSM can be used to study pharmacokinetic parameters of multi-component TCM compound, because the method can characterize the pharmacokinetic regularity of quantum-time change in a multi-component system.

Animals ; Benzoates ; pharmacokinetics ; Bridged-Ring Compounds ; pharmacokinetics ; Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal ; pharmacokinetics ; Glucosides ; pharmacokinetics ; Male ; Medicine, Chinese Traditional ; Models, Statistical ; Monoterpenes ; Pyrazines ; pharmacokinetics ; Rats ; Saponins ; pharmacokinetics ; Triterpenes ; pharmacokinetics

OBJECTIVETo study the pharmacokinetics of tetramethylpyrazine (TMP), ferulic acid and their compatibility.

METHODTwenty-four Sprague-Dawley rats were randomly divided into 3 groups: TMP 20 mg x kg(-1), ferulic acid 20 mg x kg(-1) and TMP 20 mg x kg(-1) + ferulic acid 20 mg x kg(-1). All the rats were given intragastric administration then blood samples were obtained from fossa orbitalis at several time points. All the plasmas concentrations were analyzed by HPLC method and the data were treated by DAS 2.0 program.

RESULTThe main pharmacokinetics parameters of TMP 20 mg x kg(-1) group, ferulic acid 20 mg x kg(-1) and TMP 20 mg x kg(-1) + ferulic acid 20 mg x kg(-1) were as follows: t(max) 0.5 h, t1/2 0.856 h,MRT 1.321 h, AUC 5.112 microg x h(-1) x L(-1), C(max) 2.834 microg x L(-1); t(max) 0.083 h, t1/2 1.024 h, MRT 1.324 h, AUC 1.581 microg x h(-1) x L(-1), C(max) 1.492 microg x L(-1); t(max) 0.583 h, t1/2 37.901 h, MRT 3.798 h, AUC 4.097 microg x h(-1) x L(-1), C(max)1.571 microg x L(-1); t(max) 0.6 h, t1/2 7.860 h, MRT 2.894 h, AUC 1.984 microg x h(-1) x L(-1), C(max) 1.03 microg x L(-1), respectively.

CONCLUSIONThe experiments suggested that the compatibility of TMP and ferulic acid had interaction in pharmacokinetics; all the t1/2 and MRT were prolonged and had the effect of lente liberates.

Animals ; Area Under Curve ; Calibration ; Coumaric Acids ; pharmacokinetics ; Female ; Linear Models ; Pyrazines ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results

To explore the mechanism of the absorption enhancement of borneol, the effect of borneol on the intestinal absorption and the pharmacokinetics of tetramethylpyrazine phosphate after oral administration were investigated. In situ intestinal recirculation was performed to study the effect of various concentrations of borneol on the absorption of tetramethylpyrazine phosphate at duodenum, jejunum, ileum and colon. After oral administration of tetramethylpyrazine phosphate, the mixture of tetramethylpyrazine phosphate and borneol and the mixture of tetramethylpyrazine phosphate and verapamil in rats, the concentrations of tetramethylpyrazine phosphate in plasma were determined by RP-HPLC at predesigned time. The pharmacokinetic parameters were compared based on the results of the three animal experiments, and analyzed with software program 3p97. The result showed that tetramethylpyrazine phosphate could be absorbed at all of the four intestinal segments with increasing absorption amount per unit as follows: colon > duodenum > jejunum > ileum, but without saturation, which demonstrated that tetramethylpyrazine phosphate was absorbed via simple diffusion. Borneol could enhance the intestinal absorption of tetramethylpyrazine phosphate, however, not in proportion. There was no obvious difference between the test group and the control group when 10 microg x mL(-1) borneol was added (P > 0.05), while when the concentration comes to 25 microg x mL(-1) and 50 microg x mL(-1), significant differences were observed (P < 0.05). Borneol and verapamil did enhance the bioavailability of tetramethylpyrazine phosphate after oral administration in rats. The enhancing effect of borneol showed only when the concentration came to a certain level but with no specific sites existed in the intestine. One of the mechanisms of borneol on the enhancing effect on absorption of tetramethylpyrazine phosphate might be the inhibition of the metabolism of CYP 3A and exocytosis of P-gp.
Animals ; Biological Availability ; Bornanes ; pharmacokinetics ; Herb-Drug Interactions ; Intestinal Absorption ; drug effects ; Male ; Pyrazines ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the pharmacokinetics of single administration and different compatibility of tetramethylpyrazine (TMP) in rats.

METHODThirty two Sprague-Dawley rats were randomly divided into 4 groups: the TMP (30 mg x kg(-1)) group, the TMP+FA (30 mg x kg(-1) + 50 mg x kg(-1)) group, the TMP+TET (30 mg x kg(-1) mg x kg(-1)) group and the TMP+FA+TET (30 mg x kg(-1) + 50 mg x kg(-1) + 20 mg x kg(-1)) group. After the oral administration, their blood samples were collected to detect plasmas concentrations by HPLC method and to calculate pharmacokinetic parameters DAS 2.0 program.

RESULTIn compatibility with FA, AUC(0-t), Cmax and Tmax showed no significant difference with the single administration of TMP, but t(1/2) and MRT,, were obviously longer than the single administration. In compatibility with TET and FA + TET, AUC (0-t), Cmax and Tmax showed significant increase than the single administration of TMP, whereas t(1/2) and MRT0, did not notably vary from the single administration.

CONCLUSIONFA can prolong TMP's action time in rats, and TET can accelerate TMP's absorption in rats.

Animals ; Chromatography, High Pressure Liquid ; Coumaric Acids ; pharmacokinetics ; Diterpenes ; pharmacokinetics ; Drug Interactions ; Female ; Pyrazines ; pharmacokinetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley

In order to investigate the effect of ligustrazine (Lig) i.p. on peritoneal permeability in peritoneal dialysis and its side effects, creatinine was given intravenously and continuously to maintain the high plasma creatinine level. All the rabbits were divided into three groups: normal control group (group A), group B treated with 0.12% Lig and group C treated with 0.24% Lig. The peritoneal dialysis of all rabbits lasted 2 h. The plasma and dialysate levels of glucose, protein and creatinine were observed immediate, 30 min, 60 min, 90 min, 120 min after dialysis. Creastinine dialysate/plasma ratio (D/P), protein D/P ratio, glucose D/Do at different time points after dialysis and creatinine mass transfer area coefficient (MTAC) at 120 min were calculated. The structures of peritoneum were observed under optical microscope and electron microscope after continuously intraperitoneal injection of Lig for 14 days. The results showed that the 90-min and 120-min creatinine D/P ratios in the group C were higher than in the group A. The 120-min creatinine MATC in the group C was higher than in the group A. The rabbits treated with Lig did not show significant structure changes of peritoneum and signs of peritoneal irritation. It was suggested that Lig could increase mass transfer ability of peritoneum without significant side effects.
Animals ; Biological Transport ; Cell Membrane Permeability ; Creatinine ; blood ; Dialysis Solutions ; chemistry ; Peritoneal Dialysis ; methods ; Peritoneum ; metabolism ; Pyrazines ; pharmacokinetics ; pharmacology ; Rabbits

This study aims to investigate whether a self-made novel pulsatile drug delivery system--razine phosphate pulsincap capsule-will achieve a pulsatile drug release in vivo and to study the drug release sites. A gamma scintigraphic study was conducted to assess the in vivo transit and release behavior of the pulsincap capsule with a drug tablet containing 99mTc-labeled diethylenetriamine pentaacetic acid (DTPA) in the gastrointestinal (GI) tract of dog. The results revealed that after a time interval (lag time), the drug tablet began to disintegrate and then released at the pylorus of stomach or in the small intestine of dogs with a relatively rapid release rate, which was consistent with the expected pulsed release pattern. The in vivo lag time of the pulsincap capsule in dog was shortened with the decrease of erodible plugs(EP) weight. Thus we can achieve a desirable lag time to meet the chronotherapeutic requirements by adjusting the weight of EP.
Animals ; Capsules ; Delayed-Action Preparations ; Dogs ; Gastrointestinal Tract ; metabolism ; Gastrointestinal Transit ; Pyrazines ; administration & dosage ; pharmacokinetics ; Radionuclide Imaging

The purpose of this study was to prepare tetramethylpyrazine hydrochloride transdermal gel and to study its permeation ability in vitro. The skin permeation ability was evaluated by Valian-Chien permeation cells with isolated rat skin. The concentration of tetramethylpyrazine in samples was determined by HPLC. The optimal formulation was composed with 5% azone, 5% peppermint oil, 8% sodium carboxymethylcellulose and 8% tetramethylpyrazine hydrochloride. The accumulative permeation amount of the gel was (6 731.87 +/- 102.31) microg x cm(-2) in 12 h,and the permeation rate was (535.02 +/- 33.89) microg x cm(-2) x h(-1). The release profile in vitro was in line with zero-order formulation. Tetramethylpyrazine hydrochloride gel prepared in the study would be developed as a novel transdermal preparation.
Administration, Cutaneous ; Animals ; Chemistry, Pharmaceutical ; Gels ; In Vitro Techniques ; Male ; Permeability ; Pyrazines ; administration & dosage ; chemistry ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo prepare ligustrazine (TMPZ) ocular sustained-release implant, and investigate its in vitro drug release, pharmacokinetics in rabbit vitreum and in vitro correlation.

METHODLigustrazine ocular sustained-release implants were prepared by micro-twin conical screw mixers with hot-melting extrusion method, with polyactic-co-glycolic acid (PLGA) as the matrix. HPLC was adopted to determine the concentration in vitreum after ligustrazine was implanted in rabbit eyes, in order to examine its in vivo sustained-release behavior, and study the correlation between in vitro and in vivo.

RESULTLigustrazine implants were prepared with a drug-loading rate between 10% and 30%, which was in conformity to the pharmacopoeia in terms of the content uniformity. Its in vitro release was in conformity to the zero-order release model. With PLGA 5050, 2. 5A as a vector, ligustrazine implants with a drug-loading rate of 30% could slowly release drug for more than 3 weeks, indicating a good correlation between in vitro and in vivo release.

CONCLUSIONLigustrazine ocular implants prepared with hot-melting extrusion method is practicable. Ligustrazine ocular implants release drug smoothly in rabbit vitreous vitreums, suggesting good sustained-release effect.

Animals ; Biological Availability ; Drug Implants ; Eye ; Female ; Male ; Polyglycolic Acid ; chemistry ; Pyrazines ; administration & dosage ; chemistry ; pharmacokinetics ; Rabbits ; Vitreous Body

To establish a method for detecting microdialysis recovery of tetramethylpyrazine (TMP) and ferulic acid (FA) and investigating the influencing factors, providing the basis for further in vivo microdialysis experiments. The concentration of FA and TMP in dialysates were determined by high pressure liquid chromatography ( HPLC) and probe recovery were calculated respectively. The influence of the flow rates, medium concentration, temperature and in vivo probe stability on the recovery of FA and TMP were investigated by using concentration difference method (incremental method and decrement method). The recovery obtained by incremental method were similar to by decrement method. The in vitro recovery rate of FA and TMP decreased with the increase of 1-2.5 μL min(-1), and increased obviously with the temperature of 25-42 degrees C under the same conditions. The concentration of FA and TMP had no obvious effect on the probe recovery under the same flow rate. In addition, the recovery of TMP and FA remained stable and showed similar trends under the condition of four concentration cycles, indicating that the intra day reproducibility of the concentration difference method was good. The recovery of brain microdialysis probes in vivo 8 h maintained a relatively stable, but certain differences existed between different brain microdialysis probes, demonstrating that each probe was required for recovery correction in vivo experiment. Microdialysis sampling can be used for the local brain pharmacokinetic study of FA and TMP, and retrodialysis method can be used in probe recovery of FA and TMP in vivo.
Animals ; Brain ; metabolism ; Chromatography, High Pressure Liquid ; Coumaric Acids ; analysis ; isolation & purification ; pharmacokinetics ; Drugs, Chinese Herbal ; Humans ; Microdialysis ; methods ; Pyrazines ; analysis ; isolation & purification ; pharmacokinetics ; Rats