Pharmacokinetics-Based Identification of Potential Therapeutic Phthalides from XueBiJing, a Chinese Herbal Injection Used in Sepsis Management

Abstract

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.

Metabolomic Insights Into the Synergistic Effect of Biapenem in Combination With Xuebijing Injection Against Sepsis

“…It has been clinically prescribed for septic patients with good effectiveness on toxic heat flourishing and blood stasis syndrome, as it is considered to possess the efficacies of activating circulation, removing blood stasis, and eliminating toxins (Yin and Li, 2014). In China, approximately 0.8 million patients received treatment with XBJ yearly, about 80% of which were sepsis or septic shock cases (Zhang et al, 2018). In fact, XBJ was most commonly used in combination with antibiotics (e.g., BIPM) for sepsis treatment in clinical practice, instead of being used alone.…”

Xuebijing Injection Maintains GRP78 Expression to Prevent Candida albicans–Induced Epithelial Death in the Kidney

“…Methods of extraction, preparation, and quality control of XBJ were the same as previously reported (Huang et al, 2011;Chen et al, 2016;Li et al, 2016;Zhang et al, 2018). Briefly, ingredients from Carthamus tinctorius flowers ("Honghua" in Chinese) were first extracted with ethanol then with water.…”

“…Xuebijing (XBJ) injection was prepared with extracts from five different Chinese herbs [Carthamus tinctorius flowers (Honghua), Paeonia lactiflora roots (Chishao), Ligusticum chuanxiong rhizomes (Chuanxiong), Angelica sinensis roots (Danggui), and Salvia miltiorrhiza roots (Danshen)] (Cheng et al, 2016;Li et al, 2016;Li et al, 2019;Zhang et al, 2018). Approved by the Food and Drug Administration of China in 2004, XBJ has been frequently used as an add-on therapy for multiple organ dysfunction syndromes, sepsis, and septic shock in China for over a decade (Chen et al, 2018a;Gao et al, 2015;Shi et al, 2017).…”

Molecular Mechanism of Action of Repurposed Drugs and Traditional Chinese Medicine Used for the Treatment of Patients Infected With COVID-19: A Systematic Scoping Review

“…Xue Bi Jing Injection, an established TCM in China, has been recommended for severe symptoms of COVID-19 patients [123,138]. Unlike other drugs that undergo a conventional clinical trial phase, it proceeded from bedside to bench and finally back to bedside before approval was obtained from China Food and Drug Administration in 2004 (Chinese Society of Critical Care Medicine, 2015) [160]. Consequently, the annual consumption of this TCM in China for the treatment of pneumonia and other diseases has reached 800000 [160].…”

“…Unlike other drugs that undergo a conventional clinical trial phase, it proceeded from bedside to bench and finally back to bedside before approval was obtained from China Food and Drug Administration in 2004 (Chinese Society of Critical Care Medicine, 2015) [160]. Consequently, the annual consumption of this TCM in China for the treatment of pneumonia and other diseases has reached 800000 [160]. Xue Bi Jing Injection consist of numerous compounds, as illustrated in Figure 10, which are extracted from five medicinal plants; Radix Salviae Miltiorrhiae, Rhizoma Chuanxiong, Flos Carthami, Angelica Sinensis and Radix Paeoniae Rubra [161].…”