Comparative Pharmacokinetic Investigation on Multiple Active Aminoalcohol-Diterpenoid Alkaloids after Single Oral Administrations of Monomers and Aqueous Extract of Fuzi (Aconiti Lateralis Radix Praeparata) by UFLC-MS/MS

Abstract

To further study the aminoalcohol-diterpenoid alkaloids (ADAs) in Fuzi (Aconiti Lateralis Radix Praeparata), a simple and sensitive UFLC-MS/MS method was established and validated for the determination of five ADAs, aconine, mesaconine, hypaconine, deoxyaconine and fuziline, in rat plasma to compare the pharmacokinetic characteristics of pure ADAs and Fuzi decoction. After precipitating protein with methanol, plasma samples were isolated at 0.5 mL/min flow rate on Waters Acquity UPLC BEH C₁₈ column (100 mm × 2.1 mm, 1.7 µm). The mobile phase was composed of 0.1% formic acid-water and methanol with gradient elution. Mass spectrometric inspection was conducted on a 5500 UFLC-MS/MS system with an electrospray ionization source in patterns of positive ion and multiple reaction-monitoring (MRM). All calibration curves were proved to have acceptable linearity (r² > 0.99) in linear ranges. Intra-day and inter-day precision and the accuracy met the requirements. The matrix effects of all analytes were between 85% and 115% of three concentration levels. This method has been under verification for comparative pharmacokinetic research after oral administration between aqueous extract of Fuzi and single pure ADAs. The results demonstrated that there are evident pharmacokinetic discrepancies between them, and administration in the extract form instead of pure form may contribute to higher absorption.

Key words

aminoalcohol-diterpenoid alkaloids - pharmacokinetics - aqueous extract of Fuzi - UFLC-MS/MS - Aconitum carmichaelii - Ranunculaceae

• References

• 1 Ding T. Modern pharmacology theory research and clinical new-application of Aconitum Carmichaeli Debx. Chin J Chin Med 2012; 27: 1630-1631
• 2 Cui H, Qu Y, Huang YF, Cheng CS, Liang ZS, Zhou H. Investigation on Medicinal Plant Resources of Aconitum in Sichuan, Shaanxi and Yunnan. Mod Chin Med 2022; 24: 1264-1271
• 3 Zhou YP. Pharmacological effects and toxicity of Fuzi and its main components. Acta Pharm Sin 1983; 18: 394-400
• 4 Zhou YP, Liu WH. Comparison of pharmacological effects and toxicity of Fuzi on cardiovascular system. J Integr Trad West Med 1984; 4: 48-50
• 5 State Pharmacopeia Committee of China. Aconiti Lateralis Radix Praeparata, Part 1 of Chinese Pharmacopoeia. Beijing, China: Medical Science Press; 2020: 200-201
• 6 Xu S, Liang XL, Li Q, Jin PF. Advances on Chinese herbal medicine Aconiti Lateralis Radix Praeparata. Northwest Pharm J 2017; 32: 248-254
• 7 Liu XX, Jian XX, Cai XF, Chao RB, Chen QH, Chen DL, Wang XL, Wang FP. Cardioactive C₁₉-diterpenoid alkaloids from the lateral roots of Aconitum carmichaeli “Fu Zi”. Chem Pharm Bull 2012; 60: 144-149
• 8 Wang L, Ding JY, Liu XX, Tang MH, Chao RB, Wang FP. Identification of aminoalcohol-diterpenoid alkaloids in Aconiti Lateralis Radix Praeparata and study of their cardiac effects. Acta Pharm Sin 2014; 49: 1699-1704
• 9 Liu X, Wang XL, Wu L, Li H, Qin KM, Cai H, Pei K, Liu T, Cai BC. Investigation on the spectrum-effect relationships of Da-Huang-Fu-Zi-Tang in rats by UHPLC-ESI-Q-TOF-MS method. J Ethnopharmacol 2014; 154: 606-612
• 10 Liu XX, Tang MH, Wang L, Chao RB. Fragmentation study of aminoalcohol-diterpenoid alkaloids by electrospray ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 2016; 30: 161-169
• 11 Ding JY, Liu XX, Xiong DM, Ye LM, Chao RB. Simultaneous determination of thirteen aminoalcohol-diterpenoid alkaloids in the lateral roots of Aconitum carmichaeli by solid-phase extraction-liquid chromatography-tandem mass spectrometry. Planta Med 2014; 80: 723-731
• 12 Huang D, Zhao XQ, Liu XX, Chao RB. Determination of five aminoalcohol-diterpenoid alkaloids in the lateral root of Aconitum carmichaeli by HPLC-ELSD with SPE. J Chromatogr Sci 2017; 55: 940-945
• 13 Liu XX, Tang MH, Liu TH, Wang CY, Tang QX, Xiao YX, Yang RX, Chao RB. The in vivo pharmacokinetics, tissue distribution and excretion investigation of mesaconine in rats and its in vitro intestinal absorption study using UPLC-MS/MS. Xenobiotica 2019; 49: 71-79
• 14 Liu XX, Tang MH, Liu TH, Wang CY, Chao RB. Pharmacokinetics and heart distribution study of hypaconine in rats by UPLC-MS/MS. Lat Am J Pharm 2016; 35: 888-894
• 15 Sun JG, Zhang FY, Peng Y, Liu JH, Zhong YX, Wang GJ. Quantitative determination of diterpenoid alkaloid fuziline by hydrophilic interaction liquid chromatography (HILIC)-electrospray ionization mass spectrometry and its application to pharmacokinetic study in rats. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 913: 55-60
• 16 Gong XH, Zhao MJ, Yuan A, Li Y, Xiong L, Peng C, Li YX. Pharmacokinetics and bioavailability study of neoline in Beagle dogs. Chin J Chin Mater Med 2015; 40: 2656-2660
• 17 Zhang H, Sun S, Zhang W, Xie XQ, Zhu ZY, Chai YF, Zhang GQ. Biological activities and pharmacokinetics of aconitine, benzoylaconine, and aconine after oral administration in rats. Drug Test Anal 2016; 8: 839-846
• 18 Gan JH, Wang C, Song ZQ, Liu YY, Ning ZC, Ma XL, Zhao SY, Liu ZL. Effect of refined honey amount on pharmacokinetics of 9 different alkaloids in Fuzi Lizhongwan. Chin J Exp Tradit Med Form 2018; 24: 90-96
• 19 Li Y, Li YX, Peng C, Zhao MJ, Yuan A, Gong XH, Zhao MJ. Effect of compatibility of Fuzi total alkaloids and rhubarb anthraquinones on pharmacokinetics of Fuzi total alkaloids in rats with insufficiency of spleen-yang and kidney-yang in vivo. Med J Liaoning 2017; 44: 1275-1277
• 20 Li Y, Zhao MJ, Yuan A, Gong XH, Peng C, Li YX. Effect of dosage on pharmacokinetic characteristics of total alkaloids from Aconiti Lateralis Radix Praeparata in rats. Chin J Exp Tradit Med Form 2016; 22: 82-85
• 21 Ye L, Gao S, Feng Q, Liu W, Yang Z, Hu M, Liu ZQ. Development and validation of a highly sensitive UPLC-MS/MS method for simultaneous determination of aconitine, mesaconitine, hypaconitine, and five of their metabolites in rat blood and its application to a pharmacokinetics study of aconitine, mesaconitine, and hypaconitine. Xenobiotica 2012; 42: 518-525
• 22 Lv C. The Toxicokinetics, Absorption and Metabolism of Aconitine as Targeted Marker of Fuzi (Aconitum carmichaeli). [Master Dissertation]. Southern Medical University; 2011: 24-28