Multiplex quantitation of 17 drug-derived components in human plasma after administration of a fixed herbal preparation of Sailuotong using combined online SPE-LC-MS/MS methods

Vascular dementia (VaD) is a cognitive dysfunction syndrome caused by ischemic stroke, hemorrhagic stroke, and cerebral vascular disease. VaD accounts for approximately 15%–20% of dementia cases in North America and Europe (Wu et al., 2016). In China, the incidence of VaD is 2.42 per 1000 person-years in individuals aged 60 years or above (Jia et al., 2020). At present, although the underlying etiology of VaD has not been completely elucidated, there is not much controversy regarding the fact that VaD is a combined outcome of various pathophysiological alternations induced by chronic cerebral hypoperfusion, such as oxidative stress, central cholinergic system dysfunction, neuroinflammation, neuronal apoptosis, and synaptic plasticity dysfunction (Kuang et al., 2021). Limited by a single or few therapeutic targets, current drugs used in VaD are only suitable for symptomatic treatment, and there are still no licensed medications that meet the criteria of the US Food and Drug Administration or the European Medicine Agency for this disease (O'Brien and Thomas, 2015). Therefore, drugs aimed at multiple pathophysiological factors may be the future direction of VaD treatment. Taking advantage of the outstanding features of multicomponent and multitarget, herbal therapy can be a potential candidate for the treatment of VaD.

Sailuotong (SLT) capsule is a standard herbal preparation composed of ginseng (the dried root and rhizome of Panax ginseng C. A. Meyer), ginkgo (the leaves of Ginkgo biloba L.), and saffron (the stigma of Crocus sativus L.). SLT is prescribed compatibly for the treatment of vascular dementia (VaD) based on the function of its herbal ingredients. Ginseng is widely used as a tonic for the restoration of strength in China. Its function of cognition-enhancing, anti-anxiety and anti-depression have been recorded in the ancient medical literature of Bencaogangmu in the 16th century. Ginkgo and saffron have been traditionally used for a long time as medicines with the main effect of promoting blood circulation and removing blood stasis according to their function described in Chinese Pharmacopoeia. Pharmacological studies on SLT have demonstrated its effectiveness in treating focal cerebral ischemia, focal cerebral ischemia/reperfusion and multi-infarct dementia in rats (Xu et al., 2008, 2012; Zhang et al., 2015; Zheng et al., 2010). The therapeutic mechanism of SLT was revealed as anti-inflammation, antioxidative stress, antiapoptotic and platelet aggregation, as well as improving blood flow and brain tissue acetylcholine content (Fan et al., 2021; Seto et al., 2017; Steiner et al., 2017; Xu et al., 2008; Zhang et al., 2019). International clinical trials on the efficiency of SLT have been carried out in China and Australia cooperatively (Liang et al., 2014; Steiner et al., 2016). The outcome of two preliminary pilot trials in Australia showed that SLT has the potential to improve working memory performance in healthy adults and has greater effects than placebo on the VaD assessment scale-cognitive subscale in VD patients (Liu J et al., 2007; Steiner et al., 2016). A randomized controlled double-blind phase II study was performed at 16 academic centers throughout China and demonstrated that SLT is safe and effective for treating mild to moderate VaD at doses of 120 and 180 mg twice a day (Jia et al., 2018).

Although pharmacological and clinical studies have demonstrated the validity of SLT in the treatment of VaD, a clear biological picture behind their broad diversity is not yet elucidated. To answer how the formula herbs and their active ingredients cooperate to produce comprehensive effects, it is necessary to clarify the exposure profile of drug-derived components inner body first. Ginsenosides, ginkgo flavonoids, and terpenoids along with crocins are major active ingredients in the formulation. Our previous pharmacokinetic investigation of formula herbs in rats has found that ginsenosides and ginkgolides could be absorbed into the blood as their prototypes (Zhang et al., 2014a, 2014b), while ginkgo flavonoids and crocin-1, a primary component in saffron extract, enter into the systemic circulation in the form of metabolites (Zhang et al., 2011, 2012). Despite these available preclinical pharmacokinetic data, clinical pharmacokinetic studies are still indispensable due to the existence of species differences in drug metabolism and disposition(Dalgaard, 2015). Pharmacokinetic information based on the clinical therapeutic dose of SLT, including exposure components of SLT, their concentration levels and dynamic changes can provide the most convincing material basis for elucidating its curative effect.

Both our previous studies and existing literatures have shown that the absorption of ginsenosides is quite limited, and published human pharmacokinetic studies adopted a much higher oral dosage than that of SLT. For example, the plasma concentration of ginsenosides was detected following a single 10 g dose of American ginseng powder(Wang et al., 2011) or 3 g Korean Red Ginseng extract(Kim, 2013). In the paper that reported the most sensitive method so far to detect human plasma, they used a dose of repeated 3 pouches of Red Ginseng extract (Jin et al., 2019). Meanwhile, there is a dearth of human pharmacokinetic information regarding ginkgo flavonoids. Nieder published the first data of plasma analysis on flavonoids after dosage of 50,100, and 300 mg ginkgo extract, in which only total concentration was displayed. Wójcicki et al. compared three different GBE formulations concerning the oral bioavailability of Ginkgo flavonoid glycosides, while no information about dosage was provided in the paper. Nonetheless, it can be inferred from these only two clinical literatures that the ginkgo flavonoids presented in the systemic circulation at a very low concentration after taking ginkgo extracts. Therefore, the development of bioanalytical methods for the clinical study of SLT faces big challenges of achieving sufficient sensitivity and accuracy in the scenario of numerous analytes and extremely low exposure levels of the majority of them.

In addition to explaining the mechanism, obtaining a quantitative profile of drug-derived components at therapeutic doses is essential to improve the effectiveness and safety of the clinical application of TCMs, such as the designation of a reasonable dosing regime or determination of potential metabolic interaction with concomitant drugs. However, due to the complexity of the ingredients of TCMs, the limited clinic PK research can hardly cover these fields. As an important fundamental step to carry out in-depth pharmacokinetic research in the future, aiming at the promising herbal combination for the treatment of VaD, this paper devotes to establishing a highly sensitive quantitative method that can reveal the exposure profiles of drug-derived components of SLT in humans comprehensively. Moreover, the significance of this paper is to provide referable practices and solutions in terms of complex bio-analysis of TCMs toward clinical needs.

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