@article {Zhangdmd.117.079673, author = {Nating Zhang and Chen Cheng and Olajide E Olaleye and Yan Sun and Li Li and Yuhong Huang and Feifei Du and Junling Yang and Fengqing Wang and Yanhong Shi and Fang Xu and Yanfen Li and Qi Wen and Naixia Zhang and Chuan Li}, title = {Pharmacokinetics-Based Identification of Potential Therapeutic Phthalides from XueBiJing, a Chinese Herbal Injection Used in Sepsis Management}, elocation-id = {dmd.117.079673}, year = {2018}, doi = {10.1124/dmd.117.079673}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {XueBiJing, an injectable five-herb preparation, has been incorporated into routine sepsis care in China. Phthalides, originating from XueBiJing{\textquoteright}s component herbs Ligusticum chuanxiong rhizomes and Angelica sinensis roots, are believed to contribute to its therapeutic effects due to their presence in the preparation and antisepsis-related properties. This study aimed to identify potential therapeutic phthalides that are bioavailable to act on XueBiJing{\textquoteright}s therapeutic targets and that could serve as pharmacokinetic markers to supplement classical biomarkers for sepsis care. Among 10 phthalides detected in XueBiJing, senkyunolides I and G were the major circulating phthalides in human subjects, but their different pharmacokinetics might influence their contribution to XueBiJing{\textquoteright}s therapeutic action. Senkyunolide I exhibited a large distribution volume (1.32 l/kg) and was moderately bound in plasma (54\% unbound), whereas senkyunolide G exhibited a small distribution volume (0.10 l/kg) and was extensively bound in plasma (3\% unbound). Clearance of senkyunolide I from the systemic circulation was governed by UGT2B15-mediated hepatic glucuronidation; the resulting electrophilic glucuronides were conjugated with GSH in the liver. Senkyunolide G was selectively bound to albumin (99\%) in human plasma. To our knowledge, the human pharmacokinetic data of XueBiJing{\textquoteright}s phthalides are reported here for the first time. Based on this study and such studies for the other component herbs, follow-up pharmacodynamic assessments of bioavailable herbal compounds are planned to understand XueBiJing{\textquoteright}s chemical basis responsible for its therapeutic action. Senkyunolides I and G, having the preceding disposition characteristics that could be detectably altered by septic pathophysiology, could serve as pharmacokinetic markers for sepsis care.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2018/03/09/dmd.117.079673}, eprint = {https://dmd.aspetjournals.org/content/early/2018/03/09/dmd.117.079673.full.pdf}, journal = {Drug Metabolism and Disposition} }