Abstract
Background
Although apigenin possesses diverse pharmacological activities, its utilization as a bioactive substance is limited by poor oral bioavailability. The aim of this study was to improve the bioavailability of apigenin by co-administration of friedelin.
Methods
To achieve this, the intestinal permeability of apigenin in the absence or presence of friedelin was investigated in both Caco-2 cells and single-pass rat intestinal perfusion models.
Results
The apparent permeability coefficients (Papp) of apigenin in the presence of friedelin were substantially increased by 1.63- and 1.60-fold in Caco-2 cells and single-pass rat intestinal perfusion models, respectively. Such increases in the Papp indicated that friedelin could significantly enhance the absorption of apigenin into the body. The increased bioavailability of apigenin in rats following the oral administration of apigenin 50 mg/kg body weight with friedelin 50 mg/kg body weight was further confirmed by increases in the peak concentration of apigenin (Cmax), elimination half-life (T1/2) and area under the plasma concentration-time curve (AUC).
Conclusions
Friedelin suppressed ATPase activity of P-glycoprotein (P-gp) indicated that the improved bioavailability of apigenin may be ascribed to P-gp inhibition by the co-administered friedelin.
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References
Peterson J, Dwyer J. Flavonoids: dietary occurrence and biochemical activity. Nutr Res 1998;18(12):1995–2018.
Czeczot H, Bilbin M. Effect of flavones and their metabolites on induction of SOS repair in the strain PQ37-E.coli K-12. Acta Biochim Pol 1991;38(1):71–4.
Gupta S, Afaq F, Mukhtar H. Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem Biophys Res Commun 2001;287(4):914–20.
Sam SK, Ji YL, Yoo KC, Gap SK, Byung hH. Neuroprotective effects of flavones on hydrogen peroxide-induced apoptosis in SH-SY5Y neuroblastoma cells. Bioorg Med Chem Lett 2004;14:2261–4.
Lee JH, Zhou HY, Cho SY, Kim YS, Lee YS, Jeong CS. Anti-inflammatory mechanisms of apigenin: inhibition of cyclooxygenase-2 expression, adhesion of monocytes to human umbilical vein endothelial cells, and expression of cellular adhesion molecules. Arch Pharm Res 2007;30(10):1318–27.
Coldham NG, Zhang AQ, Key P, Sauer MJ. Absolute bioavailability of [14C] genistein in the rat; plasma pharmacokinetics of parent compound, genistein glucuronide and total radioactivity. Eur J Drug Metab Pharmacokinet 2002;27(4):249–58.
Dudhatra GB, Mody SK, Awale MM, Patel HB, Modi CM, Kumar A, et al. A comprehensive review on pharmacotherapeutics of herbal bioenhancers. Sci World J 2012;2012:637953.
Kesarwani K, Gupta R, Mukeriee A. Bioavailability enhancers of herbal origin: an overview. Asian Pac J Trop Biomed 2013;3(4):253–66.
Bajad S, Bedi KL, Singla AK, Johri RK. Piperine inhibits gastric emptying and gastrointestinal transit in rats and mice. Planta Med 2001;67(2):176–9.
Reen RK, Jamwal DS, Taneja SC, Koul JL, Dubey RK, Wiebel FJ, et al. Impairment of UDP-glucose dehydrogenase and glucuronidation activities in liver and small intestine of rat and guinea pig in vitro by piperine. Biochem Pharmacol 1993;46(2):229–38.
Han Y, Tan TMC, Lim LY. In vitro and in vivo evaluation of the effects of piperine on P-gp function and expression. Toxicol Appl Pharmacol 2008;230(3):283–9.
Kesarwani K, Gupta R, Mukerjee A. Bioavailability enhancers of herbal origin: an overview. Asian Pac J Trop Biomed 2013;3(4):253–66.
Sunil C, Duraipandiyan V, Ignacimuthu S, A.I-Dhabi NA. Antioxidant, free radical scavenging and liver protective effects of friedelin isolated from Azima tetracantha Lam, Leaves. Food Chem 2013;139(1–4):860–5.
Antonisamy P, Duraipandiyan V, Aravinthan A, A.I-Dhabi NA, Ignacimuthu S, Choi KC, et al. Protective effects of friedelin isolated from Azima tetracantha Lam: against ethanol-induced gastric ulcer in rats and possible underlying mechanisms. Eur J Pharmacol 2015;750:167–75.
Tian XJ, Yang XW, Yang X, Wang K. Studies of intestinal permeability of 36 flavonoids using Caco-2 cell monolayer model. Int J Pharm 2009;367(1–2):58–64.
Li M, Si L, Pan H, Rabba AK, Yan F, Qiu J, et al. Excipients enhance intestinal absorption of ganciclovir by P-gp inhibition: assessed in vitro by everted gut sac and in situ by improbed intestinal perfusion. Int J Pharm 2011;403(1–2):37–45.
Varma MV, Ashokraj Y, Dey CS, Panchagnula R. P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol Res 2003;48(4):347–59.
Garrigos M, Mir LM, Orlowski S. Competitive and non-competitive inhibition of the multidrug-resistance-associated P-glycoprotein ATPase—further experimental evidence fora multisite model. Eur JBiochem 1997;244(2):664–73.
Hu M. Commentary: bioavailability of flavonoids and polyphenols: call to arms. Mol Pharm 2007;4(6):803–6.
Khajuria A, Thusu N, Zutshi U. Piperine modulates permeability characteristics of intestine by inducing alterations in membrane dynamics: influence on brush border membrane fluidity, ultrastructure and enzyme kinetics. Phytomed 2002;9:224–31.
Atal CK, Dubey RK, Singh J. Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism. J Pharmacol Exp Therap 1985;232:258–62.
Song NN, Li QS, Liu CX. Intestinal permeability of metformin using single-pass intestinal perfusion in rats. World J Gastroenterol 2006;12(25):4064–70.
Garberg P, Eriksson P, Schipper N, Sjöström B. Automated absorption assessment using Caco-2 cells cultured on both of polycarbonate membranes. Pharm Res 1999;16(3):441–5.
Artursson P. Epithelial transport of drugs in cell culture: a model for studying the passive diffusion of drugs over intestinal absorptive (caco-2) cells. JPharm Sci 1990;79(6):476–82.
Audus KL, Bartel RL, Hidalgo IJ, Borchardt RT. The use of cultured epithelial and endothelial cells for drug transport and metabolism studies. Pharm Res 1990;7(5):435–51.
Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun 1991;175(3):880–5.
Briodie BB, Hogben CA, Schanker LS, Tocco DJ. Absorption of drugs from the rat small intestine. J Pharmacol Exp Ther 1958;123(1):81–8.
Nielsen SE, Dragsted LO. Column-switching high-performance liquid chromatographic assay for determination of apigenin and acacetin in human urine with ultraviolet absorbance detection. J Chromatogr B Biomed Sci Appl 1998;713(2):379–86.
Havsteen BH. The biochemistry and medical significance of the flavonoids. Pharmacol Ther 2002;96(2–3):67–202.
Chen J, Lin H, Hu M. Metabolism of flavonoids via enteric recycling: role of intestinal disposition. J Pharmacol Exp Ther 2003;304(3):1228–35.
Griffiths LA, Smith GE. Metabolism of apigenin and related compounds in the rat. Biochem J 1972;128(4):901–11.
Ueda K, Yoshida A, Amachi T. Recent progress in P-glycoprotein research. Anticancer Drug Des 1999;14(2):115–21.
Hunter J, Hirst BH, Simmons NL. Drug absorption limited by P-glycoprotein-mediated secretory drug transport in human intestinal epithelial Caco-2 cell layers. Pharm Res 1993;10(5):743–9.
al-Shawi MK, Senior AE. Characterization of the adenosine triphosphatase activity of chinese hamster P-glycoprotein. J Biol Chem 1993;268:4197–206.
Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999;39(1):361–98.
Shapiro AB, Ling V. ATPase activity of purified and reconstituted P-glycoprotein from Chinese hamster ovary cells. J Biol Chem 1994;269:3745–54.
Shaprio AB, Ling V. Effect of quercetin on Hoechst 33342 transport by purified and reconstituted P-glycoprotein. Biochem Pharmacol 1997;53:587–96.
Hu T, To KK, Wang L, Zhang L, Lu L, Shen J, et al. Reversal of P-glycoprotein (P-gp) mediated multidrug resistance in colon cancer cells by cryptotanshinone and dihydrotanshinone of salvia miltiorrhiza. Phytomedeicine 2014;21(11):1264–72.
Yoshida N, Koizumi M, Adachi I, Kawakami J. Inhibition of P-glycoprotein-mediated transport by terpenoids contained in herbal medicines and natural products. Food Chem Toxicol 2006;44(12):2033–9.
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Lee, JA., Ha, S.K., Kim, YC. et al. Effects of friedelin on the intestinal permeability and bioavailability of apigenin. Pharmacol. Rep 69, 1044–1048 (2017). https://doi.org/10.1016/j.pharep.2017.04.012
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DOI: https://doi.org/10.1016/j.pharep.2017.04.012