Determination of Ginkgolides A, B, C, J and Bilobalide in Plasma by LC-ESI (-)/MS/MS (QQQ) and its Application to the Pharmacokinetic Study of Ginkgo Biloba Extract in Rats

Abstract

A simple, rapid, and specific high-performance liquid chromatograph coupled with a tandem mass spectrometry method has been developed and validated for the quantification of ginkgolides in rat plasma, and the main pharmacokinetic parameters of ginkgolides after oral administration of Ginkgo biloba extract (GBE) was acquired.

Methods: Plasma samples were pretreated with ethyl acetate extraction. Sulfamethoxazole was used as the internal standard (IS). Chromatographic separation was achieved on an Eclipse XDB-C18 column (2.1 mm×150 mm, 5 μm) with a mobile phase consisting of methanol/0.1% formic acid water (gradient elution: 0~25 min (77:23)→(60:40), V/V) at a flow rate of 0.3 mL·min⁻¹. The detection was performed on a triple quadruple tandem mass spectrometer using an electrospray ionization (ESI) source for 25 min. The detection was operated by multiple reaction monitoring(MRM) under negative ionization mode of the transitions of m/z 325→163 for BB, 469→423 for GJ, 439→125 for GC, 453→351 for GA, 423→367 for GB and of m/z 252→156 for sulfamethoxazole (IS) respectively.

Results: The pharmacokinetic properties of BB, GJ, GA, GB and GC were in line with the open 2-compartment model after oral administration of GBE in rats; The pharmacokinetic parameters of various lactones were calculated, and drugs-time curve and the curve fitting diagram of 5 ginkgolides were drew; The absorption and distribution rate of BB, GJ, GA, GB and GC were fast in rats in vivo, and half-life of absorption was less than 3 h.

Conclusion: The developed LC-ESI (-)/MS/MS (QQQ) method was successfully applied to assess the pharmacokinetic parameters and oral bioavailability of ginkgolides in rats after administration of GBE, which can provide basis for further clinical efficacy studies.

Key words

ginkgolides - ginkgo biloba extract (GBE) - LC-ESI (-)/MS/MS (QQQ) - pharmacokinetics - rat plasma

• References

• 1 Han L, Fu Y, Cole Adam J et al. Co-encapsulation and sustained-release of four components in ginkgo terpenes from injectable PELGE nanoparticles. Fitoterapia 2012; 83: 721-731
• 2 Guo M, Hu H, Tang S et al. Preparation and quality evaluation of ginkgolide B-loaded self microemulsifying drug delivery system. China Journal of Chinese Materia Medica 2010; 35: 2967-2971
• 3 Tong Y, Chen Y, Pan J et al. Effect of dextran gel on preparation of nano-liposomes loaded with Ginkgolide. Bull Korean Chem 2010; 31: 2542-2546
• 4 Mahadevan S, Park Y. Multifaceted therapeutic benefits of Ginkgo biloba L.: chemistry, efficacy, safety, and uses. Institute of Food Technologists 2007; 73: 1750-3841
• 5 Ude C, Schubert-Zsilavecz M, Wurglics M. Ginkgo biloba extracts: A review of the pharmacokinetics of the active ingredients. Clin Pharmacokinet 2013; 52: 727-749
• 6 Yamamoto S, Nakano K, Ishikawa C et al. Enhanced inhibitory effects of extracts from Ginkgo biloba L. leaves encapsulated in hybrid liposomes on the growth of tumor cells in vitro. Journal of Biochemical Engineering 2002; 12: 125-130
• 7 Tian X, Zhang L, Wang J et al. The protective effect of hyperbaric oxygen and Ginkgo biloba extract on Aβ25-35-induced oxidative stress and neuronal apoptosis in rats. Behavioural Brain Research 2013; 242: 1-8
• 8 Wang N, Chen X, Geng D et al. Ginkgo biloba leaf extract improves the cognitive abilities of rats with D-galactose induced dementia. Journal of Biomedical Research 2013; 27: 29-36
• 9 Seifelnasr M, Abd EI-Fattah AA. Lipid peroxide, phospholipids, glutathione levels and superoxide dismutase activity in rat brain after ischaemia: effect of Ginkgo biloba extract. Pharmacological Research 1995; 32: 273-278
• 10 Hong J, Donghoon S, Lim YA et al. Ticlopidine with Ginko biloba extract: a feasible combination for patients with acute cerebral ischemia. Thrombosis Research 2013; 131: 147-153
• 11 Xie J, Ding C, Ge Q et al. Simultaneous determination of ginkgolides A, B, C and bilobalide in plasma by LC-MS/MS and its application to the pharmacokinetic study of Ginkgo biloba extract in rats. Journal of Chromatography B 2008; 864: 87-94
• 12 Muari P, Minoggio M, Lemoli L et al. Piergiorgio. Liquid Chromatography/atmospheric pressure chemical ionization ion trap mass spectrometry of terpene lactones in plasma of animals. Journal of Pharmaceutical and Biomedical Analysis 2003; 32: 633-639
• 13 Sora DI, Stefanescu V, David V et al. Validation of an LC-MS/MS assay of terpene trilactones in Ginkgo biloba extracts and pharmaceutical formulations through standard addition method. Journal of Pharmaceutical and Biomedical Analysis 2009; 5: 459-468
• 14 Chen F, Li L, Xu F et al. Systemic and cerebral exposure to and pharmacokinetics of flavonols and terpene lactones after dosing standardized Ginkgo biloba leaf extracts to rats via different routes of administration. British Journal of Pharmacology 2013; 170: 440-457
• 15 Zhan Q, Zhang F, Gao S et al. An HPLC-MS/MS method for the quantitative determination of platycodin D in rat plasma and its application to the pharmacokinetics of Platycodi Radix extract. Chinese Journal of Natural Medicines 2014; 12: 154-160