Comparative permeability of three saikosaponins and corresponding saikogenins in Caco-2 model by a validated UHPLC-MS/MS method

Siqi Ren; Jingjing Liu; Yunwen Xue; Mei Zhang; Qiwei Liu; Jie Xu; Zunjian Zhang; Rui Song

doi:10.1016/j.jpha.2020.06.006

Volume 11 Issue 4

Aug. 2021

Turn off MathJax

Article Contents

Article Navigation > Journal of Pharmaceutical Analysis > 2021 > 11(4): 435-443

Siqi Ren, Jingjing Liu, Yunwen Xue, Mei Zhang, Qiwei Liu, Jie Xu, Zunjian Zhang, Rui Song. Comparative permeability of three saikosaponins and corresponding saikogenins in Caco-2 model by a validated UHPLC-MS/MS method[J]. Journal of Pharmaceutical Analysis, 2021, 11(4): 435-443. doi: 10.1016/j.jpha.2020.06.006

Citation:

Siqi Ren, Jingjing Liu, Yunwen Xue, Mei Zhang, Qiwei Liu, Jie Xu, Zunjian Zhang, Rui Song. Comparative permeability of three saikosaponins and corresponding saikogenins in Caco-2 model by a validated UHPLC-MS/MS method[J]. Journal of Pharmaceutical Analysis, 2021, 11(4): 435-443. doi: 10.1016/j.jpha.2020.06.006

Citation:

Siqi Ren, Jingjing Liu, Yunwen Xue, Mei Zhang, Qiwei Liu, Jie Xu, Zunjian Zhang, Rui Song. Comparative permeability of three saikosaponins and corresponding saikogenins in Caco-2 model by a validated UHPLC-MS/MS method[J]. Journal of Pharmaceutical Analysis, 2021, 11(4): 435-443. doi: 10.1016/j.jpha.2020.06.006

PDF( 689 KB)

Comparative permeability of three saikosaponins and corresponding saikogenins in Caco-2 model by a validated UHPLC-MS/MS method

doi: 10.1016/j.jpha.2020.06.006

Siqi Ren^a,b,
Jingjing Liu^a,b,
Yunwen Xue^a,b,
Mei Zhang^a,b,
Qiwei Liu^a,b,
Jie Xu^a,b,
Zunjian Zhang^a,b,
Rui Song^{a,b
,
,}

a. Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing, 210009, China;
b. State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing, 210009, China

Funds:

This project was financially supported by the National Natural Science Foundation of China (No.81573626), the Open Project Program of Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, China (No.201503), the Natural Research Foundation of Jiangsu Province, China (No. BK20161456), and the Qing Lan Project of Jiangsu Province, China (2017). We are especially grateful to Feng Xu (Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, China) for his help during this research.

Received Date: Feb. 01, 2020
Accepted Date: Jun. 28, 2020
Rev Recd Date: Jun. 27, 2020
Available Online: Jan. 24, 2022
Publish Date: Aug. 15, 2021

Abstract

Abstract

Saikosaponins (SSs) are the main active components extracted from Bupleuri Radix (BR) which has been used as an important herbal drug in Asian countries for thousands of years. It has been reported that the intestinal bacteria plays an important role in the in vivo disposal of oral SSs. Although the deglycosylated derivatives (saikogenins, SGs) of SSs metabolized by the intestinal bacteria are speculated to be the main components absorbed into the blood after oral administration of SSs, no studies have been reported on the characteristics of SGs for their intestinal absorption, and those for SSs are also limited. Therefore, a rapid UHPLC-MS/MS method was developed to investigate and compare the apparent permeability of three common SSs (SSa, SSd, SSb₂) and their corresponding SGs (SGF, SGG, SGD) through a bidirectional transport experiment on Caco-2 cell monolayer model. The method was validated according to the latest FDA guidelines and applied to quantify the six analytes in transport medium samples extracted via liquid-liquid extraction (LLE). The apparent permeability coefficient (P) determined in this study indicated that the permeability of SGs improved to the moderate class compared to the corresponding parent compounds, predicting a higher in vivo absorption. Moreover, the efflux ratio (ER) value demonstrated an active uptake of SSd and the three SGs, while a passive diffusion of SSa and SSb₂.
- Bupleuri Radix,
- Saikosaponin,
- Saikogenin,
- UHPLC-MS/MS,
- Caco-2 cells,
- Permeability

FullText(HTML)

References(32)

References

F. Yang, X. Dong, X. Yin, et al., Radix Bupleuri: a review of traditional uses, botany, phytochemistry, pharmacology, and toxicology, BioMed Res. Int. 2017 (2017) 7597596. https://doi.org/10.1155/2017/7597596

P. Sun, Y. Li, S. Wei, et al., Pharmacological effects and chemical constituents of bupleurum, Mini Rev. Med. Chem. 19 (2019) 34-55, https://doi.org/10.2174/1871520618666180628155931

M. L. Ashour, M. Wink, Genus Bupleurum: a review of its phytochemistry, pharmacology and modes of action, J. Pharm. Pharmacol. 63 (2011) 305-321, https://doi.org/10.1111/j.2042-7158.2010.01170.x

Z. Li, H. Sun, J. Xing, et al., Chemical and biological comparison of raw and vinegar-baked Radix Bupleuri, J. Ethnopharmacol. 165 (2015) 20-28, https://doi.org/10.1016/j.jep.2015.02.024

X. Li, Y. Song, S. Wang, et al., Saikosaponins: a review of pharmacological effects, J. Asian Nat. Prod. Res. 20 (2018) 399-411, https://doi.org/10.1080/10286020.2018.1465937

X. Li, X. Li, N. Huang, et al., A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins, Phytomedicine. 50 (2018) 73-87, https://doi.org/10.1016/j.phymed.2018.09.174

X. Guan, X. Wang, K. Yan, et al., UFLC-MS/MS determination and pharmacokinetic studies of six Saikosaponins in rat plasma after oral administration of Bupleurum Dropping Pills, J. Pharmaceut. Biomed. Anal. 124 (2016) 288-293, https://doi.org/10.1016/j.jpba.2016.03.009

R. Sun, M. Zeng, T. Du, et al., Simultaneous determinations of 17 marker compounds in Xiao-Chai-Hu-Tang by LC-MS/MS: application to its pharmacokinetic studies in mice, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1003 (2015) 12-21, https://doi.org/10.1016/j.jchromb.2015.09.004

Z. Yan, Y. Chen, T. Li, et al., Identification of metabolites of Si-Ni-San, a traditional Chinese medicine formula, in rat plasma and urine using liquid chromatography/diode array detection/triple-quadrupole spectrometry, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 885-886 (2012) 73-82, https://doi.org/10.1016/j.jchromb.2011.12.017

M.J.C. Santbergen, M. van der Zande, A. Gerssen, et al., Dynamic in vitro intestinal barrier model coupled to chip-based liquid chromatography mass spectrometry for oral bioavailability studies, Anal. Bioanal. Chem. 412 (2020) 1111-1122, https://doi.org/10.1007/s00216-019-02336-6

M. Estudante, J.G. Morais, G. Soveral, et al., Intestinal drug transporters: an overview, Adv. Drug Deliv. Rev. 65 (2013) 1340-1356, https://doi.org/10.1016/j.addr.2012.09.042

T. Du, M. Zeng, L. Chen, et al., Chemical and absorption signatures of Xiao Chai Hu Tang, rapid commun. Mass Spectrom. 32 (2018) 1107-1125, https://doi.org/10.1002/rcm.8114

S. J. Liu, W. Z. Ju, Z. X. Liu, et al., Pharmacokinetic study of saikosaponin a in rat plasma by LC-ESI-MS, Chin. Pharmacol. Bull. 25 (2009) 1380-1383

K. Shimizu, S. Amagaya, Y. Ogihara, Structural transformation of saikosaponins by gastric juice and intestinal flora, J. Pharmacobio-Dyn 8 (1985) 718-725, https://doi.org/10.1248/bpb1978.8.718

H. Kida, T. Akao, M. R. Meselhy, et al., Enzymes responsible for the metabolism of saikosaponins from eubacterium sp. A-44, a human intestinal anaerobe, Biol. Pharm. Bull. 20 (1997) 1274-1278, https://doi.org/10.1248/bpb.20.1274

H. Kida, T. Akao, M.R. Meselhy, et al., Metabolism and pharmacokinetics of orally administered saikosaponin b1 in conventional, Germ-free and eubacterium sp. A-44-infected gnotobiote rats, Biol. Pharm. Bull. 21 (1998) 588-593, https://doi.org/10.1248/bpb.21.588

P.V. Balimane, S. Chong, Cell culture-based models for intestinal permeability: a critique, Drug Discov. Today 10 (2005) 335-343, https://doi.org/10.1016/S1359-6446(04)03354-9

J. Liu, Y. Xue, J. Sun, et al., Pharmacokinetics and oral bioavailability studies of three saikogenins in rats using a validated UFLC-MS/MS method, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1124 (2019) 265-272, https://doi.org/10.1016/j.jchromb.2019.06.020

M. L. Lind, J. Jacobsen, R. Holm, et al., Development of simulated intestinal fluids containing nutrients as transport media in the Caco-2 cell culture model: assessment of cell viability, monolayer integrity and transport of a poorly aqueous soluble drug and a substrate of efflux mechanisms, Eur. J. Pharmaceut. Sci. 32 (2007) 261-270, https://doi.org/10.1016/j.ejps.2007.08.002

S.T. Buckley, S.M. Fischer, G. Fricker, et al., In vitro models to evaluate the permeability of poorly soluble drug entities: challenges and perspectives, Eur. J. Pharmaceut. Sci. 45 (2012) 235-250, https://doi.org/10.1016/j.ejps.2011.12.007

D. A. Volpe, Variability in Caco-2 and MDCK cell-based intestinal permeability assays, J. Pharmacol. Sci. 97 (2008) 712-725, https://doi.org/10.1002/jps.21010

A. Soliev, N. S. Quiming, H. Ohta, et al., Separation of ginsenosides at elevated temperature by ultra high pressure liquid chromatography, J. Liq. Chromatogr. Relat. Technol. 30 (2007) 2835-2849, https://doi.org/10.1080/10826070701588521

N. E. Hoffman, J. H. Y. Chang, Injection solvent enhancement of peak height in reversed-phase liquid chromatography, J. Liq. Chromatogr. 14 (1991) 651-658, https://doi.org/10.1080/01483919108049277

A. Zvonar, K. Berginc, A. Kristl, et al., Microencapsulation of self-microemulsifying system: improving solubility and permeability of furosemide, Int. J. Pharm. 388 (2010) 151-158, https://doi.org/10.1016/j.ijpharm.2009.12.055

J. Bonetti, Y. Zhou, M. Parent, et al., Intestinal absorption of S-nitrosothiols: permeability and transport mechanisms, Biochem. Pharmacol. 155 (2018) 21-31, https://doi.org/10.1016/j.bcp.2018.06.018

B. Press, D. D. Grandi, Permeability for intestinal absorption: Caco-2 assay and related issues, Curr. Drug Metabol. 9 (2008) 893-900, https://doi.org/10.2174/138920008786485119

E. H. Kerns, D. Li, Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization, Academic Press, United States of America, 2008, pp vol. 20, 300-301

F. Ingels, B. Beck, M. Oth, et al., Effect of simulated intestinal fluid on drug permeability estimation across Caco-2 monolayers, Int. J. Pharm. 274 (2004) 221-232, https://doi.org/10.1016/j.ijpharm.2004.01.014

Y. Chen, J. Y. Wang, L. Yuan et al., Interaction of the main components from the traditional Chinese drug pair chaihu-shaoyao based on rat intestinal absorption, Molecules. 16 (2011) 9600-9610, https://doi.org/10.3390/molecules16119600

H. Liu, J. Yang, F. Du, et al., Absorption and disposition of ginsenosides after oral administration of Panax notoginseng extract to rats, Drug Metab. Dispos. 37 (2009) 2290-2298, https://doi.org/10.1124/dmd.109.029819

T. Murakami, Absorption sites of orally administered drugs in the small intestine, Expet Opin. Drug Discov. 12 (2017) 1219-1232, https://doi.org/10.1080/17460441.2017.1378176

A. Dahan, J. M. Miller, G. L. Amidon, Prediction of solubility and permeability class membership: provisional BCS classification of the world's top oral drugs, AAPS J. 11 (2009) 740-746, https://doi.org/10.1208/s12248-009-9144-x

Relative Articles

Supplements(0)

Cited By

Proportional views