Effect of food supplement constituents Quercetin, Silibinin and Luteolin on oral uptake of protease inhibitor saquinavir: synthetic meets natural

Effect of food supplement constituents Quercetin, Silibinin and Luteolin on oral uptake of protease inhibitor saquinavir: synthetic meets natural

Karan Mittal, Riddhish Patadia, Chintan Vora, Rajashree Mashru*

Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Kalabhavan, Vadodara – 390001, Gujarat state, India.

Journal of Pharmaceutical Research and Reviews

Saquinavir is the BCS class IV drug, it is a first protease inhibitor for HIV infection treatment, having poor permeability. The main purpose of this study was to study the effect of natural compounds on its bioavailability. In this work, binary systems of SQU with the natural bioenhancers were prepared using physical mixing method. The effect of these compounds were studied using different sophisticated experimental protocols. Firstly the compatability was tested for the three used bioenhancers quercetin (QU), silibinin (Sil), Luteolin (LT). Oral uptake was studied by analyzing the transport of SQU across the human colorectal adenocarcinoma cell line (Caco-2) cell lines. Permeation through the goat intestine tissue was also studied. Pharmacokinetic analysis was also performed in rabbits by administered SQU with different bioenhancers in the form of suspension, and the whole analytical studies for the estimation of SQU in different studies were conducted using LC-MS. In the compatibility studies, bioenhancers found to be showing no or minimal interaction with the SQU. Permeation in the intestinal tissue of goat was significantly increased as compared to the plain drug. The transport of SQU across the Caco-2 cell lines also found to be improved than the plain drug. Pharmacokinetic study showed there was increase in the Cmax by approx. 3 folds using the different bioenhancers. AUC was also found to be increase by more than 2 folds with the each bioenahncer. The maximum oral uptake enhancement was found with the QU following by the Sil and then LT.

Keywords: saquinavir; protease inhibitor; quercetin; silibinin; luteolin; Caco-2 cell monolayer;

Free Full-text PDF

How to cite this article:
Karan Mittal, Riddhish Patadia, Chintan Vora, Rajashree Mashru. Effect of food supplement constituents Quercetin, Silibinin and Luteolin on oral uptake of protease inhibitor saquinavir: synthetic meets natural. Journal of Pharmaceutical Research and Reviews, 2017; 1:2.


1. M. N. Martinez and G. L. Amidon, A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals, The Journal of Clinical Pharmacology, 2002, 42, 620-643.
2. H. Hirayama, J. Morgado, I. Gasinska and K. Pang, Estimations of intestinal and liver extraction in the in vivo rat: studies on gentisamide conjugation, Drug Metab Dispos, 1990, 18, 580-587.
3. B. H. Hellum and O. G. Nilsen, In vitro Inhibition of CYP3A4 Metabolism and P‐Glycoprotein‐Mediated Transport by Trade Herbal Products, Basic & clinical pharmacology & toxicology, 2008, 102, 466-475.
4. B. J. Aungst, Intestinal permeation enhancers, Journal of pharmaceutical sciences, 2000, 89, 429-442.
5. J.-S. Choi and X. Li, Enhanced diltiazem bioavailability after oral administration of diltiazem with quercetin to rabbits, International journal of pharmaceutics, 2005, 297,1-8.
6. S.-C. Shin, J.-S. Choi and X. Li, Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats, International Journal of Pharmaceutics, 2006, 313, 144-149.
7. J.-S. Choi, Y.-J. Piao and K. W. Kang, Effects of quercetin on the bioavailability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition by quercetin, Archives of pharmacal research, 2011, 34, 607-613.
8. R. Saller, R. Meier and R. Brignoli, The use of silymarin in the treatment of liver diseases, Drugs, 2001, 61, 2035-2063.
9. P. Kosina, P. Maurel, J. Ulrichová and Z. Dvořák, Effect of silybin and its glycosides on the expression of cytochromes P450 1A2 and 3A4 in primary cultures of human hepatocytes, Journal of biochemical and molecular toxicology, 2005, 19, 149-153.
10. R. Zuber, M. Modrianský, Z. Dvořák, P. Rohovský, J. Ulrichová, V. Šimánek and P. Anzenbacher, Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities, Phytotherapy Research, 2002, 16, 632-638.
11. P. Džubák, M. Hajdúch, R. Gažák, A. Svobodová, J. Psotová, D. Walterová, P. Sedmera and V. Křen, New derivatives of silybin and 2, 3-dehydrosilybin and their cytotoxic and P-glycoprotein modulatory activity, Bioorganic & medicinal chemistry, 2006, 14, 3793-3810.
12. M. N. Clifford, Chlorogenic acids and other cinnamates–nature, occurrence, dietary burden, absorption and metabolism, Journal of the Science of Food and Agriculture, 2000, 80, 1033-1043.
13. W. Brand, M. E. Schutte, G. Williamson, J. J. van Zanden, N. H. Cnubben, J. P. Groten, P. J. van Bladeren and I. M. Rietjens, Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients, Biomedicine & pharmacotherapy, 2006, 60, 508-519.
14. B. T. Griffin and C. M. O’Driscoll, An examination of the effect of intestinal first pass extraction on intestinal lymphatic transport of saquinavir in the rat, Pharmaceutical research, 2008, 25, 1125-1133.
15. C. M. Perry and S. Noble, Saquinavir soft-gel capsule formulation, Drugs, 1998, 55, 461-486.
16. A. des Rieux, V. Fievez, I. Théate, J. Mast, V. Préat and Y.-J. Schneider, An improved in vitro model of human intestinal follicle-associated epithelium to study nanoparticle transport by M cells, european journal of pharmaceutical sciences, 2007, 30, 380-391.
17. S. M. Pathak, P. Musmade, S. Dengle, A. Karthik, K. Bhat and N. Udupa, Enhanced oral absorption of saquinavir with methyl-beta-cyclodextrin—preparation and in vitro and in vivo evaluation, European Journal of Pharmaceutical Sciences, 2010, 41, 440-451.
18. A. E. Kim, J. M. Dintaman, D. S. Waddell and J. A. Silverman, Saquinavir, an HIV protease inhibitor, is transported by P-glycoprotein, Journal of Pharmacology and Experimental Therapeutics, 1998, 286, 1439-1445.
19. H. H. Usansky, P. Hu and P. J. Sinko, Differential roles of P-glycoprotein, multidrug resistance-associated protein 2, and CYP3A on saquinavir oral absorption in Sprague-Dawley rats, Drug Metabolism and Disposition, 2008, 36, 863-869.
20. M. L. Branham, T. Moyo and T. Govender, Preparation and solid-state characterization of ball milled saquinavir mesylate for solubility enhancement, European Journal of Pharmaceutics and Biopharmaceutics, 2012, 80, 194-202.
21. B. J. Aungst, P-glycoprotein, secretory transport, and other barriers to the oral delivery of anti-HIV drugs, Advanced drug delivery reviews, 1999, 39, 105-116.
22. S. S. Sehnert, Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability, Journal of the National Medical Association, 2004, 96, 1243.