Study on the pharmacokinetic profiles of corynoline and its potential interaction in traditional Chinese medicine formula Shuanghua Baihe tablets in rats by LC–MS/MS

https://doi.org/10.1016/j.jpba.2015.09.009Get rights and content

Highlights

  • A novel LC–MS/MS method was established for determining corynoline in rat plasma.

  • The LLOQ of this assay was 0.01 ng/mL.

  • A comparative pharmacokinetics was performed between TCM formula and pure compound.

  • The coexisting components in herbs increased the bioavailability of corynoline.

  • The potential interaction between the components of herbs was explored.

Abstract

Corynoline, the major isoquinoline alkaloid component derived from Corydalis bungeana Herba, has greatly impressed many scientists due to its various pharmacological effects. However, there is little information on its pharmacokinetics. In this study, a sensitive and rapid liquid chromatography with tandem mass spectrometry method has been developed and validated for the determination of corynoline in rat plasma. The calibration curve showed good linearity within the concentration range of 0.01–20 ng/mL. The method was fully validated and successfully applied in a pharmacokinetic study of corynoline in rats, in which the rats were treated with corynoline, corynoline combined with berberine and the traditional Chinese medicine formula Shuanghua Baihe tablets (SBT, containing corynoline, berberine and other ingredients), respectively. Corynoline showed low bioavailability and a high elimination rate. The terminal elimination half-life was prolonged about 3-fold, and the maximum plasma concentration (Cmax), area under the plasma concentration–time curve (AUC0-12) of corynoline were increased by 46.5% and 34.2%, respectively, when the same dosage of corynoline was administered in SBT. Furthermore, compared with the corynoline group, the Cmax and AUC0-12 were increased by 11.1-fold and 5.0-fold respectively, in the rats treated with corynoline combined with berberine. The results suggested that oral administration of the SBT prolonged the elimination half-life of corynoline and increased its bioavailability. Berberine played an important role in the pharmacokinetic drug–drug interaction of corynoline and ingredients in SBT, and the influence of other co-existing compounds in SBT on the pharmacokinetic profiles of corynoline could not be ignored.

Introduction

Corydalis bungeana Turcz., belonging to the Papaveraceae, is a perennial herb scattered over the region of Northeast Asia [1]. The dried whole plant is referred to as C. bungeanae Herba in traditional Chinese medicine (TCM) and is officially recorded in the Chinese Pharmacopoeia [2]. It is a well-known Chinese herbal medicine widely used in many prescriptions, such as Shuanghua Baihe tablets (SBT) and Ganmao Qingre Granules. It is increasingly attracting research attention because of its pharmacological effects [3]. Corynoline, an isoquinoline alkaloid (Fig. 1), is the major component derived from C. bungeana Herba and has been demonstrated to exert multiple pharmacological activity, including anti-inflammation, cell adhesion inhibitory [4], inhibition of acetylcholinesterase [5], antifungal [6] and cytotoxic activity [7]. Moreover, corynoline is the only ingredient assessed for the quality control of this herbal medicine in the Chinese Pharmacopoeia [8].

Shuanghua Baihe tablet is a TCM formula that has been clinically employed for the treatment of oral mucositis (OM) for more than 30 years in china and shown great efficacy [9]. OM is a particularly severe and common acute side effect of chemotherapy or radiotherapy [10]. SBT are composed of ten crude herbs, including Coptidis Rhizoma, C. Bungeanae Herba, Isatidis Radix, Arnebiae Radix, Lonicerae Japonicae Flos, Lophatheri Herba, Rehmanniae Radix, Lilii bulbus, Asari radix et rhizoma and Snake Bile [11]. In this formula, Coptidis Rhizoma is the monarch drug and C. Bungeanae Herba is the minister drug. SBT have the functions of invigorating blood circulation, antibiotic, anti-inflammatory, anti-ulcer and regulation of immune function [12]. Coptidis Rhizoma, another widely used traditional Chinese herbal medicine, exhibits many pharmacological activities including antibacterial [13], anti-inflammatory [14], antifungal [15] activities and so on. Berberine is its main active ingredient [16]. To date, Coptidis Rhizoma and berberine have been widely studied [17], [18], but the information on corynoline in vivo remains little.

TCMs have been used for thousands of years in Asia and attracted increasing research and application in western countries [19]. The therapeutic and pharmacological effects of TCM are usually attributed to synergism among multiple herbs and constituents, termed “TCM formula compatibility” [20]. The TCM formula compatibility might have influence on ADME (absorption, distribution, metabolism and elimination) of some components in the formula in vivo [21]. Increasing attention is currently being paid to scientific evaluation of formula compatibility by means of pharmacokinetic (PK) study [22]. One study showed that repeated administration of berberine decreased CYP2D6, CYP2C9, and CYP3A4 activities, and drug–drug interactions should be considered when berberine is co-administered [23]. Another study showed that corynoline could be metabolized by CYP2C9 and CYP3A4, and corynoline was also demonstrated to inhibit CYP2C9 and CYP3A4 [24]. Berberine is the most important compound in SBT. In this study, in order to investigate the drug–drug interaction of corynoline and ingredients in SBT, berberine was selected for co-administration with corynoline and the PK characteristics of corynoline obtained in the different treatments were compared.

To date, only one study reported the pharmacokinetics of corynoline in rats after oral administration of the extract of C. bungeana Turcz. [8]. However, no comparative PK study of corynoline in rats across different administrations has been reported. The aim of this work is to evaluate the PK properties of corynoline in rats and explore how its PK behavior is altered by the berberine and the other constituents in the SBT. To achieve this, a liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed and validated for determination of corynoline in rat plasma. The results of our study would provide a meaningful basis for evaluating the rationality and compatibility of the combinations of SBT and clinical application.

Section snippets

Chemicals and reagents

The reference standards of corynoline (purity 100%) and donepezil (internal standard, IS, purity 100%) were purchased from the National Institutes for Food and Drug Control (Beijing, China). Corynoline (purity >98%) and berberine (purity >97%) for dosage administration were purchased from Shanghai Tauto Biotech Co., Ltd. (Shanghai, China) and Dalian Meilun Biology technology Co., Ltd. (Dalian, China) respectively. Shuanghua Baihe tablets (Lot No. 1402311, 0.6 g/tablet, containing 0.405 mg

Mass conditions and chromatographic conditions optimization

In order to optimize the mass spectrometric conditions, the standard solution of corynoline and the IS were respectively injected into the mass spectrometer. In Q1 full scan mass spectra, the base peak of coryoline was the protonated molecule ions [M + H]+ at m/z 368.2. The MRM mode was used for its better specificity and sensitivity relative to the single ion monitoring (SIM) mode. More interestingly, the main fragment ions of corynoline were produced at m/z 289.2 with low collision energy (CE,

Conclusion

A sensitive, rapid and specified LC–MS/MS method was developed and successfully applied to the comparative PK study of corynoline in rats across different administrations. The LLOQ of this method was 0.01 ng/mL, which was the lowest reported so far. To date, there is no report about the influence of compatibility on the pharmacokinetics of corynoline in this formula. The t1/2 of corynoline was prolonged about 3-fold after oral administration of SBT, compared with the group of pure corynoline.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant No. 81273482) and the Graduate Innovation Fund of Zhejiang Huahai Pharmaceuticals Co., Ltd. The authors also thank Ernest Simpemba for his kind help in revising the English language of this article.

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