State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (Nat.Z., C.C., O.E.O., Y.Su., L.L., F.D., J.Y., F.W., Y.Sh., F.X., Q.W., Nai.Z., C.L.); University of Chinese Academy of Sciences, Beijing (Nat.Z., C.L.); and Second Affiliated Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin (Y.H., Y.L.), China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (Nat.Z., C.C., O.E.O., Y.Su., L.L., F.D., J.Y., F.W., Y.Sh., F.X., Q.W., Nai.Z., C.L.); University of Chinese Academy of Sciences, Beijing (Nat.Z., C.L.); and Second Affiliated Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin (Y.H., Y.L.), China
Drug Metab Dispos. 2018 Jun;46(6):823-834. doi: 10.1124/dmd.117.079673. Epub 2018 Mar 9.
XueBiJing, an injectable five-herb preparation, has been incorporated into routine sepsis care in China. Phthalides, originating from XueBiJing's component herbs rhizomes and roots, are believed to contribute to its therapeutic effects due to their presence in the preparation and antisepsis-related properties. This investigation aimed to identify potential therapeutic phthalides that are bioavailable to act on XueBiJing's therapeutic targets and that could serve as pharmacokinetic markers to supplement classic 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'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 glutathione in the liver. Senkyunolide G was selectively bound to albumin (99%) in human plasma. To our knowledge, the human pharmacokinetic data of XueBiJing's phthalides are reported here for the first time. Based on this investigation and such investigations of the other component herbs, follow-up pharmacodynamic assessments of bioavailable herbal compounds are planned to elucidate XueBiJing'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.
血必净是一种注射用的五味中药制剂，已在中国纳入常规脓毒症治疗。认为来源于血必净组方药材苍术和川芎根茎和根的苯酞类化合物，由于其存在于制剂中以及具有抗感染相关特性，有助于发挥其治疗作用。本研究旨在鉴定可用于作用于血必净治疗靶点的潜在治疗性苯酞类化合物，并作为药代动力学标志物来补充脓毒症治疗的经典生物标志物。在血必净中检测到的 10 种苯酞类化合物中，氧化前胡素 I 和 G 是人体中主要的循环苯酞类化合物，但它们不同的药代动力学可能影响它们对血必净治疗作用的贡献。氧化前胡素 I 表现出较大的分布容积（1.32 l/kg）和中等程度的血浆结合（54%未结合），而氧化前胡素 G 表现出较小的分布容积（0.10 l/kg）和广泛的血浆结合（3%未结合）。氧化前胡素 I 从体循环中的清除受 UGT2B15 介导的肝葡萄糖醛酸化控制；由此产生的亲电葡萄糖醛酸化物在肝脏中与谷胱甘肽结合。氧化前胡素 G 选择性地与人血浆白蛋白（99%）结合。据我们所知，这里首次报道了血必净苯酞类化合物的人体药代动力学数据。基于此项研究以及对其他组方药材的此类研究，计划进行后续的生物利用度草药化合物药效学评估，以阐明血必净的治疗作用的化学基础。氧化前胡素 I 和 G 具有先前的处置特征，可能会被脓毒症病理生理学改变，可作为脓毒症治疗的药代动力学标志物。
