Huanyu Guan,Xiaoming Wang,Shiping Wang,Yang He,Jiajing Yue,Shanggao Liao,Yuanda Huang,Yue Shi
Shengjiang Xiexin decoction (SXD) exerts protective effects against gastrointestinal injury induced by irinotecan hydrochloride (CPT-11). The intestinal bacteria-associated in vitro pharmacokinetics of 16 components of SXD in normal rats and those with CPT-11-induced gastrointestinal toxicity were compared in this study. A sensitive and reproducible ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) method was developed for the quantification of 16 components of SXD in a rat intestinal bacteria incubation system, using naringin, naringenin and tetrahydropalmatine as internal standards (ISs). The samples were prepared via salting-out assisted liquid–liquid extraction (SALLE) with NaCl to reduce matrix effects. Chromatographic separation was performed on a sub-2 μm analytical column with acetonitrile and 0.1% aqueous formic acid as mobile phase. All of the analyzed components and ISs were detected via multiple reaction monitoring (MRM) scanning with electrospray ionization. The proposed method was successfully applied for the in vitro pharmacokinetic analysis of the multiple components of a complex mixture consisting of a traditional Chinese medicine (TCM) and an intestinal bacterial incubation system. The pharmacokinetic parameters of some flavonoid glycosides and aglycones in the rats with CPT-11-induced gastrointestinal toxicity were significantly different (p < 0.05, p < 0.01) from those in the normal rats, which suggested that consumption of CPT-11 could qualitatively and/or quantitatively alter the intestinal bacteria as well as the metabolic activities of enzymes. The in vitro pharmacokinetic analysis of these components in the intestinal bacterial incubation system provided valuable information for achieving a deeper understanding of the mechanisms involved in the alteration of intestinal bacteria induced by CPT-11 and further in vivo pharmacokinetic research on SXD. The intestinal bacteria-based pharmacokinetic method could benefit the study of interactions between TCMs and chemical drugs in clinical use.
Yu Du,Chang Li,Shouchao Xu,Jiehong Yang,Haitong Wan,Yu He
Background Astragali Radix-Safflower combination (ARSC) is widely utilized in clinic to treat cerebral ischemia/reperfusion injury (CI/RI). Whereas, there is no in-depth research of the pharmacokinetics (PK) and pharmacodynamics (PD) analysis of ARSC after intragastric administration in rats with CI/RI. Purpose The purpose of this research is to investigate the PK characteristics of eight active ingredients (astragaloside IV, calycosin , calycosin-7-O-β-glucoside, formononetin , ononin , hydroxysafflor yellow A, syringin and vernine) of ARSC, and the regulation of neurotransmitters disorders, revealing the pharmacodynamic substance basis and the mechanism of ARSC in treating CI/RI from the molecular level. Methods We established a new method which based on blood-brain dual channel microdialysis (MD) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to continuously gather, and determine the components of ARSC and neurotransmitters related to CI/RI in vivo . The collected data were analyzed by sigmoid-E max function. The neurotransmitters primarily regulated in CI/RI rat were discussed by principal component analysis and the compound most associated with total pharmacodynamics was chosen by partial least squares regression . Results The validated LC-MS/MS method had specificity and selectivity to simultaneously analyze the concentration of eight active components of ARSC extract and five neurotransmitters of CI/RI rats. The recovery rates of brain MD probe and blood MD probe were stable within six hours. The MD probes recovery rates decreased with the increase of flow rates, but the solution concentration had little effect on the probes recovery rates. It was feasible to correct the recovery rates of probes in vivo by using reverse dialysis method. All eight active ingredients of ARSC could pass across the blood brain barrier after CI/RI. ARSC regulated the release of glutamate (Glu), γ-aminobutyric acid (GABA), dopamine (DA), 5-hydroxytryptamine (5-HT) and aspartic acid (Asp). Notably, astragaloside IV and hydroxysafflor yellow A might have better regulatory effect on neurotransmitters in comparison with other six measured components of ARSC, and Glu was the neurotransmitter mainly regulated in CI/RI rats. Conclusion The ARSC was able to treat CI/RI through ameliorating neurotransmitters disorders. There was a hysteresis between the peaked drug concentration and maximum therapeutic effect of ARSC. The drug effective concentrations range of ASIV, calycosin, calycosin-7-O-β-glucoside, syringin and vernine in blood microdialysate and calycosin, syringin, vernine in brain microdialysate were narrow, which need be paid attention in clinical use.
The use of conventional opioids that act on μ-receptors is a recognized care agent for moderate-to-severe acute treatment. However, recent attention has shifted to a new class of μ-receptor agonists which can selectively activate the G-protein pathway and thus have better efficacy and fewer side effects. Recently, YZJ-4729 was developed as a new G protein selective μ-opioid receptor agonist. And for its clinical trial investigation usage, a rapid LC-MS/MS method was established for the concurrent measurement of YZJ-4729 and its major metabolite M10 in human plasma. A step involving the precipitation of proteins was used for plasma sample preparation. The chromatography separation was done on a Poroshell 120 EC-C18 analytical column (2.1 × 50 mm, 2.7-μm, Agilent). Gradient elution was performed with 5.0 mM ammonium acetate (NH 4 Ac) and 0.1 % formic acid (FA) water solution as the mobile phase A and pure acetonitrile (ACN) as the mobile phase B. Detection occurred in the mode of positive ion electrospray ionization through multiple reaction monitoring using deuterium YZJ-4729 (d6-YZJ-4729) as the internal standard. The ionic transitions used were YZJ-4729: m/z 409.3 → 244.2; d6-YZJ-4729: m/z 415.3 → 244.2; M10: m/z 425.3 → 260.2;). The method showed excellent linearity across the ranges of 0.500 to 500 ng/mL for YZJ-4729 and 0.0500 to 50.0 ng/mL for M10. The method was utilized to assess the plasma concentrations of YZJ-4729 and M10 in healthy volunteers after a 30-min intravenous infusion in the phase I clinical study, and the clinical pharmacokinetic profiles of YZJ-4729 and M10 were described.
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