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Current Analytical Chemistry

Author(s): Tanya Ralli, Zoya Saifi, Zakiya Usmani, Vidhu Aeri, Mohd. Aqil and Kanchan Kohli*

DOI: 10.2174/0115734110264011231020094913

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Enhancing the Bioavailability of Silymarin Phytopharmaceutical by using Piperine and Fulvic Acid and Simultaneously Quantifying Three Biomarkers in Plasma

Page: [669 - 676] Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Background: Silymarin (SM) is a mixture of seven flavonolignans (FL) and one flavonoid extracted from the seeds of the milk thistle plant. The major FLs include silibinin, silychristin, silydianin, and isosilibinin. Silibinin, a mixture of two diastereomers, i.e., silybin A and silybin B, has been found to be the most active biomarker molecule in the extract of SM. Some studies have also demonstrated the usefulness of other biomarkers. However, most studies have characterized SM extract with respect to silibinin only. In our previous study, we isolated five different biomarkers (silychristin, silibinin, and isosilibinin (mixture of isosilybin A and B)) and denoted them as SM phytopharmaceuticals (PP). In other research, we have combined the SM PP with two bioavailability enhancers, i.e., Piperine (PIP) and fulvic acid (FA). The formulation containing 140 mg SM PP, 10% PIP and 20% FA was optimized using dissolution testing, and its enhanced permeability was demonstrated by ex-vivo gut sac study and Confocal laser scanning microscopy (CLSM).

Methods: In this research, we have compared the bioavailability of SM suspension with SM PP and the optimized formulation in C57BL/6J mice. Furthermore, the bioavailability estimation was done for three biomarkers simultaneously, i.e., silychristin, silibinin, and isosilibinin.

Results: Comparing the results for three different groups, it was found that the order of Cmax was F1> SM PP> SM suspension for all three biomarkers. For all the three biomarkers, the value of Cmax was at least two times more for F1 as compared to SM suspension. However, the Tmax remained constant i.e., 2 h for all the three groups and for all the three biomarkers. Furthermore, the clearance values were found to be in the order SM suspension > SM PP > F1.

Conclusion: The PIP and FA present in this combination increased the clearance value and Cmax, respectively, of the formulation. Hence, this combination of SM PP with PIP and FA has shown a better pharmacokinetic profile than SM suspension, thus, it can serve as a better alternative for the treatment of liver disease.

Graphical Abstract

[1]
Ralli, T.; Kalaiselvan, V.; Tiwari, R.; Shukla, S.; Kholi, K. Clinical and Regulatory Status of Silymarin. Appl. Clin. Res. Clin. Trials Regul. Aff., 2021, 8(2), 104-111.
[2]
Neha, A.S. Silymarin and its role in chronic diseases. Adv. Exp. Med. Biol., 2016, 929, 25-44.
[3]
Lee, J.I. Separation and characterization of silybin, isosilybin, silydianin and silychristin in milk thistle extract by liquid chromatography–electrospray tandem mass spectrometry. J. Chromatogr. A, 2006, 1116(1–2), 57-68.
[http://dx.doi.org/10.1016/j.chroma.2006.03.053]
[4]
AbouZid, S.; Ahmed, O.M. Silymarin flavonolignans: Structure–activity relationship and biosynthesis. Stud. Nat. Prod. Chem., 2013, 40, 469-484.
[5]
Biedermann, D. Silychristin: Skeletal alterations and biological activities. J. Nat. Prod., 2016, 79(12), 3086-3092.
[http://dx.doi.org/10.1021/acs.jnatprod.6b00750]
[6]
Pferschy-Wenzig, E-M. Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma. J. Nat. Prod., 2014, 77(4), 842-847.
[http://dx.doi.org/10.1021/np400943b]
[7]
Polyak, S.J. Identification of hepatoprotective flavonolignans from silymarin. Proc. Natl. Acad. Sci., 2010, 107(13), 5995-5999.
[http://dx.doi.org/10.1073/pnas.0914009107]
[8]
Davis-Searles, P.R.; Yuka, N.; Nam-Cheol, K. Milk thistle and prostate cancer: Differential effects of pure flavonolignans from Silybum marianum on antiproliferative end points in human prostate carcinoma cells. Cancer Res., 2005, 65(10), 4448-4457.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-4662]
[9]
Christodoulou, E. Serum and tissue pharmacokinetics of silibinin after per os and iv administration to mice as a HP-β-CD lyophilized product. Int. J. Pharm., 2015, 493(1-2), 366-373.
[10]
Javed, S.; Kohli, K.; Ahsan, W.J.B.J.o.P.S. Bioavailability augmentation of silymarin using natural bioenhancers: An in vivo pharmacokinetic study. Braz. J. Pharm. Sci., 2022, 58, e20160.
[http://dx.doi.org/10.1590/s2175-97902022e20160]
[11]
Sornsuvit, C.; Hongwiset, D.; Yotsawimonwat, S.; Toonkum, M.; Thongsawat, S.; Taesotikul, W. The bioavailability and pharmacokinetics of silymarin SMEDDS formulation study in healthy thai volunteers. Evid. Based Complement. Alternat. Med., 2018, 2018, 1-7.
[http://dx.doi.org/10.1155/2018/1507834] [PMID: 30108644]
[12]
Brinda, B.J.; Zhu, H.J.; Markowitz, J.S. A sensitive LC–MS/MS assay for the simultaneous analysis of the major active components of silymarin in human plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2012, 902, 1-9.
[http://dx.doi.org/10.1016/j.jchromb.2012.06.003] [PMID: 22766231]
[13]
Ralli, T.; Tripathi, T.; Kalaiselvan, V.; Tiwari, R.; Aeri, V.; Kohli, K. Silymarin as a phyto-pharmaceutical: Isolation, simultaneous quantification of four biomarkers and in-silico anti-inflammatory activity. Chin. J. Anal. Chem., 2023, 51(3), 100174.
[http://dx.doi.org/10.1016/j.cjac.2022.100174]
[14]
Ralli, T.; Saifi, Z.; Kumari, A.; Aeri, V.; Kohli, K. In-silico, in-vitro and ex-vivo evidence of combining silymarin phytopharmaceutical with piperine, and fulvic acid for enhancing its solubility and permeability. Pharm. Dev. Technol., 2023, 28(7), 595-610.
[http://dx.doi.org/10.1080/10837450.2023.2227966] [PMID: 37342048]
[15]
Zhu, H-J. An assessment of pharmacokinetics and antioxidant activity of free silymarin flavonolignans in healthy volunteers: A dose escalation study. Drug Metab. Dispos., 2013, 41(9), 1679-1685.
[http://dx.doi.org/10.1124/dmd.113.052423]
[16]
Cheng, T. Computation of octanol−water partition coefficients by guiding an additive model with knowledge. J. Chem. Inf. Model., 2007, 47(6), 2140-2148.
[17]
Silicristin.. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/silicristin(Accessed on: 21st May 2023)
[18]
Silybin. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Silybin(Accessed on: 23rd May 2023)
[19]
Isosilybin. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Isosilybin(Accessed on: 15th May 2023)