PMID- 37343654 OWN - NLM STAT- MEDLINE DCOM- 20230824 LR - 20230824 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 317 DP - 2023 Dec 5 TI - Pharmacokinetic evaluation of Sinisan containing vinegar-processed products in depressive rats, a comprehensive perspective of 'individual herb, herb-pair, and herbal formula'. PG - 116817 LID - S0378-8741(23)00685-2 [pii] LID - 10.1016/j.jep.2023.116817 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: As a classical formula for the treatment of depression, the clinical application of vinegar-processed products of Bupleuri Radix (Bupleurum chinense DC., BR) and Paeoniae Radix Alba (Paeonia lactiflora Pall., PRA) contained in Sinisan (SNS) is still controversial. AIM OF THE STUDY: Three levels of 'individual herb, herb-pair, and herbal formula' were employed to investigate whether and how the processing of main drugs affected the active constituents of pharmacokinetics in SNS, as well as their impacts on the hepatic CYP450 enzyme. MATERIALS AND METHODS: Rats were subjected to construct a chronic unpredictable mild stimulation (CUMS) model. A rapid and sensitive ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) analytical method was developed and validated for simultaneously quantitative evaluation of thirteen potential active compounds of SNS in depressive rat plasma, and successfully applied to a holistic comparison of pharmacokinetics. The differences in pharmacokinetic parameters based on three different forms of drug composition from BR and PRA before and after vinegar-processing were compared. Meanwhile, qRT-PCR and Western Blot were utilized to explore the metabolic activity of three isoforms of CYP450 enzyme scattered in the livers of depressive rats. RESULTS: The characteristic pharmacokinetics profiles of thirteen representative constituents in CUMS rats were influenced by vinegar-processing of BR and PRA and/or the compatibility. In detail, there were significant differences in the C(max), AUC(0-24), AUC(0-infinity), t(1/2), and MRT(0-24) of most constituents among the three different forms of drug composition from BR and PRA before and after vinegar-processing, with the most obvious changes in six constituents from the adjuvant and mediating guide drugs. And also, the pharmacokinetic parameters of seven constituents from BR and PRA in SNS containing vinegar-processed products obviously changed after compatibility. Additionally, the mRNA and protein levels of CYP1A2, CYP2E1, and CYP3A1 were observed to increase significantly with the processing of BR and PRA and the combination/formulation. CONCLUSIONS: In conclusion, SNS containing vinegar-processed products was more conducive to the absorption of most activated constituents compared to the original formula in vivo. The vinegar-processing of BR and PRA and the compatibility co-contribute to the pharmacokinetic variability of active compounds of SNS in CUMS rats, and the extent of contribution varies among drugs, which might be related to the regulation of the hepatic drug metabolizing enzymes. The finding of the investigation could help to better understand how active compounds metabolized in vivo, which might be helpful for guiding the clinical application of SNS containing vinegar-processed products. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Zhu, Hui AU - Zhu H AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: zhui_0826@njucm.edu.cn. FAU - Zhang, Yating AU - Zhang Y AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: zhangyatingzyt@126.com. FAU - Duan, Yu AU - Duan Y AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: duanyu1681@sina.com. FAU - Pei, Ke AU - Pei K AD - School of Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, 030619, PR China. Electronic address: peike_pk@126.com. FAU - Tu, Sicong AU - Tu S AD - Brain & Mind Centre, Faculty of Medicine & Health, The University of Sydney, NSW, 2050, Australia. Electronic address: Sicong.tu@sydney.edu.au. FAU - Chen, Yijing AU - Chen Y AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: cyjing1999@163.com. FAU - Cai, Hao AU - Cai H AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: haocai@njucm.edu.cn. LA - eng PT - Journal Article DEP - 20230619 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 3Z3866YW6P (peony root extract) RN - 0 (shigyaku-san) RN - Q40Q9N063P (Acetic Acid) RN - 0 (Drugs, Chinese Herbal) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - Bupleurum falcatum SB - IM MH - Rats MH - Animals MH - *Acetic Acid MH - Tandem Mass Spectrometry/methods MH - *Drugs, Chinese Herbal/pharmacology MH - Cytochrome P-450 Enzyme System/metabolism MH - Chromatography, High Pressure Liquid/methods OTO - NOTNLM OT - Formula compatibility OT - Pharmacokinetics OT - Sinisan OT - UHPLC-MS/MS OT - Vinegar-processing COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/06/22 01:07 MHDA- 2023/08/24 06:42 CRDT- 2023/06/21 19:13 PHST- 2023/04/23 00:00 [received] PHST- 2023/06/09 00:00 [revised] PHST- 2023/06/17 00:00 [accepted] PHST- 2023/08/24 06:42 [medline] PHST- 2023/06/22 01:07 [pubmed] PHST- 2023/06/21 19:13 [entrez] AID - S0378-8741(23)00685-2 [pii] AID - 10.1016/j.jep.2023.116817 [doi] PST - ppublish SO - J Ethnopharmacol. 2023 Dec 5;317:116817. doi: 10.1016/j.jep.2023.116817. Epub 2023 Jun 19.