Pharmacokinetics And Pharmacodynamic Tudy Of Antidepressant Effective Fraction From Xiaoyaosan

RATIONALES:Depression is a common mental disorder, it is predicted that it will become the second disabling disease in 2020, many medical workers have paid attention to it. Since the side effects of anti-depressant could not be ignored, researchers are paying more and more attention on developing anti-depressants from Traditional Chinese Medicine (TCM). As one of the most famous anti-depression formula, Xiaoyaosan became the top selection, but the material basis of its anti-depression component, metabolism characteristics and the mechanism of action are not clarified. Our research group has demonstrated that the petroleum ether fraction of Xiaoyaosan (XYP-A) is the anti-depression effective component, but the chemical component and the relationship between them is not clear, so the research on the pharmacokinetics of XYP-A is important.OBJECTIVE:In order to offer scientific basis for the clinical application of Xiaoyaosan and the development of anti-depressants from traditional Chinese medicine, the screening of the anti-depressive component of XYP-A, the investigation on the PK behavior, law of concerted application, comparative PK behavior, PK-PD correlation are conducted.METHOD:Screen the index component of XYP-A active component through developing the serum pharmacochemistry method and monoamine reuptake experiments in vitro. Investigate the pharmacokinetics, tissue distribution and excretion after XYP-A administration to normal rats. Develop the index component assay method of serum petroleum ether fraction of Bupleurum scorzonerifolium, Angelica Sinensis, and the pharmacokinetics of control rats after administration of single drugs to investigate the influence of compatibility of TCM. The relevant research of PK-PD correlation and the PK behavior are studied after administration of XYP-A on CUMS rats.RESULTS:1. The results of serum pharmacochemistry method and monoamine reuptake experiments in vitro showed that the index components of antidepression is as follows: ligustilide, (2Z,8Z,10E)-Pentadecatriene-4,6-diyn-l-ol (RB-1), (2Z,8E,10E)-Pentadecatriene-4,6-diyn-l-ol (RB-2), (2Z,8Z,10E)-heptadecatriene-4,6-diyn-l-ol (RB-3), Bupleurynol (RB-4).2. Developed a sensitive, stable, accurate, dependent method for measurement of serum ligustilide, RB-1-4. After XYP-A administration, ligustilide, RB-2 and RB-4 could be discovered in the serum. Blood concentration-time curve showed double peaks. The absorption and elimination of ligustilide were fast, the absorption of RB-2 and RB-4 were fast and the elimination were slow; compared with the petroleum ether fraction of single drug, the absorption rate were all lower.3. The result of the tissue distribution and excretion of ligustilide, RB-2 and RB-4 showed that ligustilide was widespread in rat and only existed for shorter time in tissues, while RB-2 and RB-4 were widespread and existed for longer time. The excretion research demonstrated that ligustilide RB-2 and RB-4 found in urine and fence is less than 5% of administration dosage, suggesting the excretion of the three component is mainly metabolites.4. The PK study of CUMS rats showed that under pathological state, the absorption of rats were slower than that of control rats. Serum ligustilide measurement showed that the concentration was lower than the limit of quantization, the AUC values of RB-2 and RB-4 were higher compared with control rats. The results of PD suggested that Xiaoyaosan showed anti-depression effect on CUMS rats, but no influence on control rats, PK-PD model was matched successfully, blood concentration and effect accorded with Emax model, effect-blood concentration curve was clockwise "hysteresis loop". Conclusions:1. Ligustilide、RB-1、RB-2、RB-3、RB-4 might be the effective component of XYP-A, served the material basis of the anti-depression effect.2. The results of pharmacokinetics and tissue distribution and excretion demonstrated that the PK parameters were suitable for the study on the potential anti-depressants.3. Compared with the PK study of single drug, law of concerted application of drugs could result in less absorption of active component, which was in accordance with the astringency of TCM theories, offered scientific basis for compatibility regularity of formula.4. PK-PD research found the hysteresis of effect, the active component served therapeutical effect on CUMS rats, while no influence on control rats, which was in accordance with the view that medicine only play a role when the organism is in pathological state. This study served PK basis for the safety and effectiveness assessment of Xiaoyaosan preclinical research.