ABSTRACT
A rapid, sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous determination and pharmacokinetic investigation of Tetramethylpyrazine (TMP) and Ferulic acid (FA) in rat striatum. The method was validated over the concentration range of 1.15-505ng/mL for TMP and 3.23-101ng/mL for FA, with a lower limit of quantitation (LLOQ) of 1.15ng/mL and 3.23ng/mL, respectively. This method can be successfully applied in pharmacokinetic studies of TMP and FA in striatum of awake and anesthetic rats. The cerebral blood flow velocity (CBF) during middle cerebral artery occlusion (MCAO) was monitored by Laser speckle contrast imaging, to observe whether the compatibility of TMP and FA could improve CBF against cerebral ischemia/reperfusion (I/R) injury. Infarct volume was examined to evaluate severity of ischemic brain injury. The pharmacokinetic study indicated that T1/2, Cmax, MRT and AUC0-inf were changed after combined administration of TMP and FA, when compared with either drug alone both in awake and anesthetic groups. The pharmacodynamics results showed that co-administration of drugs could enhance the CBF during middle cerebral artery occlusion and reduced the infarct volume. Taken together, the compatibility treatment of TMP and FA might be a promising therapeutic strategy for ischemic stroke. Further study is required to optimize the compatibility proportion.
Subject(s)
Chromatography, High Pressure Liquid/methods , Corpus Striatum/metabolism , Coumaric Acids/pharmacokinetics , Microdialysis/methods , Pyrazines/pharmacokinetics , Reperfusion Injury/metabolism , Tandem Mass Spectrometry/methods , Animals , Cerebrovascular Circulation/physiology , Coumaric Acids/pharmacology , Drug Synergism , Limit of Detection , Male , Pyrazines/pharmacology , Rats , Reperfusion Injury/physiopathology , Reperfusion Injury/prevention & control , Sensitivity and SpecificityABSTRACT
The purpose of the present study was to prepare and optimize sinomenine (SIN) pluronic lecithin organogels system (PLO), and to evaluate the permeability of the optimized PLO in vitro and in vivo. Box-Behnken design was used to optimize the PLO and the optimized formulation was pluronic F127 of 19.61%, lecithin of 3.60% and SIN of 1.27%. The formulation was evaluated its skin permeation and drug deposition both in vitro and in vivo compared with gel. Permeation and deposition studies of PLO were carried out with Franz diffusion cells in vitro and with microdialysis in vivo. In vitro studies, permeation rate (Jss) of SIN from PLO was 146.55 ± 2.93 µg/cm(2)/h, significantly higher than that of gel (120.39 µg/cm(2)/h) and the amount of SIN deposited in skin from the PLO was 10.08 ± 0.86 µg/cm(2), significantly larger than that from gel (6.01 ± 0.04 µg/cm(2)). In vivo skin microdialysis studies showed that the maximum concentration (Cmax) of SIN from PLO in "permeation study" and "drug-deposition study" were 150.27 ± 20.85 µg/ml and 67.95 µg/ml, respectively, both significantly higher than that of SIN from gel (29.66 and 6.73 µg/ml). The results recommend that PLO can be used as an advantageous transdermal delivery vehicle to enhance the permeation and skin deposition of SIN.
Subject(s)
Antirheumatic Agents/metabolism , Drug Delivery Systems/methods , Lecithins/metabolism , Morphinans/metabolism , Poloxamer/metabolism , Skin Absorption/physiology , Administration, Cutaneous , Animals , Antirheumatic Agents/administration & dosage , Drug Evaluation, Preclinical/methods , Gels , Lecithins/administration & dosage , Male , Morphinans/administration & dosage , Organ Culture Techniques , Poloxamer/administration & dosage , Rats , Rats, Sprague-Dawley , Skin Absorption/drug effectsABSTRACT
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.
