Attenuation of intestinal efflux pump thru polymers and preservatives

Ramin Mohammadzadeh; Behzad Baradaran; Bahman Yousefi; Hadi Valizadeh; Parvin Zakeri-milani

Attenuation of intestinal efflux pump thru polymers and preservatives

Abstract

P-glycoprotein (P-gp), the efflux membrane protein found in the upper exterior of epithelial cells in human intestine, is capable of exhibiting variations in the intestinal transport. This study was set with the purpose of testing the capability often pharmaceutical excipients namely Carbopol, Xanthan, Tragacanth, Sodium Benzoate, Hydroxypropyl methylcellulose, Methylparaben, Methylcellulose, Cetyltrimethylammonium bromide and Vitamin E in regulating P-gp protein expression and the multidrug resistance (MDR1) gene, by means of a monolayer of human colon cancer cell line (Caco-2). Using MTT test, the least sub-toxic concentrations of mentioned excipients were assessed in Caco-2 cells. Subsequently the impact of the excipients on P-gp activity was evaluated by quantifying the amount of Rhodamine-123 uptake into cells. Besides, P-glycoprotein expression was scrutinized via Western-blotting. Among the tested excipients, Tragacanth and Xanthan showed a similar western blotting and Rhodamine-123 assay results as the control group. Carbopol 934, Vitamin E, and Methylcellulose showed 27.2%, 43% and 50.9% increase in Rhodamine accumulation, respectively. According to the obtained results it is concluded that using appropriate concentrations of the Carbopol 934, Vitamin E and Methylcellulose can attenuate the P-gp activity and expression where such reduction ought to be taken into consideration due to its role in the changes of permeability and absorption of the pharmaceutical compounds.

Keywords

References

[1] Fuhrmann K, Fuhrmann G. Recent advances in oral delivery of macromolecular drugs and benefits of polymer conjugation. Curr Opin Colloid Interface Sci. 2017; 31: 67-74. [CrossRef]
[2] Ma Y, Fan X, Li L. pH-sensitive polymeric micelles formed by doxorubicin conjugated prodrugs for co-delivery of doxorubicin and paclitaxel. Carbohydr Polym. 2016; 137: 19-29. [CrossRef]
[3] Mahmood A, Bernkop-Schnürch A. SEDDS: A game changing approach for the oral administration of hydrophilic macromolecular drugs. Adv Drug Deliv Rev. 2018; pii: S0169-409X(18)30165-0. [CrossRef]
[4] Budha NR, Frymoyer A, Smelick GS, et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: Is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther. 2012; 92(2): 203-213. [CrossRef]
[5] Darwich AS, Neuhoff S, Jamei M, Rostami-Hodjegan A. Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: a simulation assessment using the "Advanced Dissolution, Absorption, Metabolism (ADAM)" model. Curr Drug Metab. 2010; 11(9): 716-729. [CrossRef]
[6] Jaferian S, Soleymaninejad M, Daraee H. Verapamil (VER) enhances the cytotoxic effects of docetaxel and vinblastine combined therapy against non-small cell lung cancer cell lines. Drug Res. 2018; 68(3): 146-152. [CrossRef]
[7] Sita G, Hrelia P, Tarozzi A, Morroni F. P-glycoprotein (ABCB1) and oxidative stress: Focus on Alzheimer's disease. Oxid Med Cell Longev. 2017; 2017(7905486): 1-13. [CrossRef]
[8] Sugano K, Kansy M, Artursson P, et al. Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov. 2010; 9(8): 597-614. [CrossRef]

[9] Zahir-Jouzdani F, Lupo N, Hermann M, et al. Glyceryl ester surfactants: Promising excipients to enhance the cell permeating properties of SEDDS. Eur J Pharm Biopharm. 2018; 129: 154-161. [CrossRef]
[10] Chow EC, Talattof A, Tsakalozou E, et al. Using physiologically based pharmacokinetic (PBPK) modeling to evaluate the impact of pharmaceutical excipients on oral drug absorption: Sensitivity analyses. AAPS J. 2016; 18(6): 1500-1511. [CrossRef]
[11] Vaithianathan S, Haidar SH, Zhang X, et al. Effect of common excipients on the oral drug absorption of biopharmaceutics classification system class 3 drugs cimetidine and acyclovir. J Pharm Sci. 2016; 105(2): 996-1005. [CrossRef]
[12] Zhang W, Li Y, Zou P, et al. The effects of pharmaceutical excipients on gastrointestinal tract metabolic enzymes and transporters-an update. AAPS J. 2016; 18(4): 830-843. [CrossRef]
[13] Jain M, Dave D, Jain P, et al. Efficacy of xanthan based chlorhexidine gel as an adjunct to scaling and root planing in treatment of the chronic periodontitis. J Indian Soc Periodontol. 2013; 17(4): 439-443. [CrossRef]
[14] Pahuja P, Arora S, Pawar P. Ocular drug delivery system: a reference to natural polymers. Expert Opin Drug Deliv. 2012; 9(7): 837-861. [CrossRef]
[15] Llamas-Moreno JF, Baiza-Duran LM, Saucedo-Rodriguez LR, et al. Efficacy and safety of chondroitin sulfate/xanthan gum versus polyethylene glycol/propylene glycol/hydroxypropyl guar in patients with dry eye. Clin Ophthalmol. 2013; 7: 995-999. [CrossRef]
[16] Barta CA, Sachs-Barrable K, Feng F, Wasan KM. Effects of monoglycerides on P-Glycoprotein: Modulation of the activity and expression in Caco-2 cell monolayers. Mol Pharm. 2008; 5(5): 863-875. [CrossRef]
[17] Groves E, Chaw CS. Incorporation of calcium salts into xanthan gum matrices: Hydration, erosion and drug release characteristics. Drug Dev Ind Pharm. 2015; 41(10): 1608-1616. [CrossRef]
[18] Ghayempour S, Montazer M, Mahmoudi Rad M. Tragacanth gum as a natural polymeric wall for producing antimicrobial nanocapsules loaded with plant extract. Int J Biol Macromol. 2015; 81: 514-520. [CrossRef]
[19] Florence AT, Jani PU. Novel oral drug formulations. Their potential in modulating adverse effects. Drug Saf. 1994; 10(3): 233-266. [CrossRef]
[20] Pahan K. Immunomodulation of experimental allergic encephalomyelitis by cinnamon metabolite sodium benzoate. Immunopharmacol Immunotoxicol. 2011; 33(4): 586-593. [CrossRef]
[21] Afshar M, Moallem SA, Khayatzadeh J, et al. Teratogenic effects of long term consumption of potassium benzoate on eye development in BALB/c fetal mice. Iran J Basic Med Sci. 2013; 16(4): 593-598. [CrossRef]
[22] Mamani PL, Ruiz-Caro R, Veiga MD. Matrix tablets: The effect of hydroxypropyl methylcellulose/anhydrous dibasic calcium phosphate ratio on the release rate of a water-soluble drug through the gastrointestinal tract I. In vitro tests. AAPS Pharm Sci Tech. 2012; 13(4): 1073-1083. [CrossRef]
[23] Li CL, Martini LG, Ford JL, Roberts M. The use of hypromellose in oral drug delivery. J Pharm Pharmacol. 2015; 57(5): 533-546. [CrossRef]
[24] Stabenfeldt SE, Garcia AJ, LaPlaca MC. Thermoreversible laminin-functionalized hydrogel for neural tissue engineering. J Biomed Mater Res A. 2016; 77(4): 718-725. [CrossRef]
[25] Stabenfeldt SE, LaPlaca MC. Variations in rigidity and ligand density influence neuronal response in methylcellulose laminin hydrogels. Acta Biomater. 2011; 7(12): 4102-4108. [CrossRef]
[26] Goswami N, Gupta VR, Jogia HA. Development and validation of a novel stability-indicating RP-HPLC method for the simultaneous determination of halometasone, fusidic acid, methylparaben, and propylparaben in topical pharmaceutical formulation. Sci Pharm. 2013; 81(2): 505-518. [CrossRef]
[27] Roy C, Chakrabarty J, Modi PB. Validated stability-indicating reverse-phase ultra-performance liquid chromatography method for simultaneous determination of sodium methylparaben, sodium propylparaben and ketorolac tromethamine in topical dosage forms. Indian J Pharm Sci. 2013; 75(2): 197-204. [CrossRef]
[28] Kumar PA, Raju TV, Thirupathi D, et al. Development and validation of a stability-indicating LC-method for the simultaneous estimation of levodropropizine, chloropheniramine, methylparaben, propylparaben, and levodropropizine impurities. Sci Pharm. 2013; 81(1): 139-150. [CrossRef]
[29] Ito E, Yip KW, Katz D, et al. Potential use of cetrimonium bromide as an apoptosis-promoting anticancer agent for head and neck cancer. Mol Pharmacol. 2019; 76(5): 969-983. [CrossRef]
[30] Brigelius-Flohe R, Traber MG. Vitamin E: Function and metabolism. FASEB J. 1999; 13(10): 1145-1155. [CrossRef]
[31] Gradauer K, Dunnhaupt S, Vonach C, et al. Thiomer-coated liposomes harbor permeation enhancing and efflux pump inhibitory properties. J Control Release. 2013; 165(3): 207-215. [CrossRef]
[32] Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview. Adv Drug Deliv Rev. 2013; 55(1): 3-29. [CrossRef]
[33] Sharma M, Prasad R. The quorum-sensing molecule farnesol is a modulator of drug efflux mediated by ABC multidrug transporters and synergizes with drugs in Candida albicans. Antimicrob Agents Chemother. 2011; 55(10): 4834-4843. [CrossRef]
[34] Shaikh SA, Li J, Enkavi G, et al. Visualizing functional motions of membrane transporters with molecular dynamics simulations. Biochemistry. 2013; 52(4): 569-587. [CrossRef]
[35] Kumar YS, Adukondalu D, Sathish D, et al. P-Glycoprotein and cytochrome P450 mediated herbal drug interactions. Drug Metabol Drug Interact. 2010; 25(1-4): 3-16. [CrossRef]
[36] Sane R, Agarwal S, Mittapalli RK, Elmquist WF. Saturable active efflux by P-glycoprotein and breast cancer resistance protein at the blood-brain barrier leads to nonlinear distribution of elacridar to the central nervous system. J Pharmacol Exp Ther. 2013; 345(1): 111-124. [CrossRef]
[37] Nanayakkara AK, Follit CA, Chen G, et al. Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells. Sci Rep. 2018; 8(1): 967. [CrossRef]
[38] To KKW, Wu X, Yin C, et al. Reversal of multidrug resistance by Marsdenia tenacissima and its main active ingredients polyoxypregnanes. J Ethnopharmacol. 2017; 203: 110-119. [CrossRef]
[39] Shen S, He Y, Zeng S. Stereoselective regulation of MDR1 expression in Caco-2 cells by cetirizine enantiomers. Chirality. 2017; 19(6): 485-490. [CrossRef]
[40] Huynh-Delerme C, Huet H, Noël L, et al. Increased functional expression of P-glycoprotein in Caco-2 TC7 cells exposed long-term to cadmium. Toxicol In Vitro. 2015; 19(4): 439-447. [CrossRef]
[41] Sugihara N, Toyama K, Michihara A, et al. Effect of benzo[a]pyrene on P-glycoprotein mediated transport in Caco-2 cell monolayer. Toxicology. 2006; 223(1-2): 156-165. [CrossRef]
[42] Fromm MF. P-Glycoprotein: A defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther. 2010; 38: 69-74. [CrossRef]
[43] Takano M, Yumoto R, Murakami T. Expression and function of efflux drug transporters in the intestine. Pharmacol Ther. 2016; 109(1): 137-161. [CrossRef]
[44] Krogstad V, Vethe NT, Robertsen I, et al. Determination of tacrolimus concentration and protein expression of P-glycoprotein in single human renal core biopsies. Ther Drug Monit. 2018; 40(3): 292-300. [CrossRef]
[45] Wang J, Gan C, Sparidans RW, et al. P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) affect brain accumulation and intestinal disposition of encorafenib in mice. Pharmacol Res. 2018; 129: 414-423. [CrossRef]
[46] Rege BD, Kao JP, Polli JE. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci. 2012; 16(4-5): 237-246. [CrossRef]
[47] Zhang H, Yao M, Morrison RA, Chong S. Commonly used surfactant, Tween 80, improves absorption of P-glycoprotein substrate, digoxin, in rats. Arch Pharmacal Res. 2013; 26(9): 768-772. [CrossRef]
[48] Gurjar R, Chan CYS, Curley P, et al. Inhibitory effects of commonly used excipients on P-glycoprotein in vitro. Mol Pharm. 2018; 15(11): 4835-4842. [CrossRef]
[49] Mohammadzadeh R, Baradaran B, Valizadeh H, et al. Reduced ABCB1 expression and activity in the presence of acrylic copolymers. Adv Pharm Bull. 2014; 4(3): 219-224. [CrossRef]
[50] Mesgari Abbasi M, Valizadeh H, Hamishekar H, et al. The effects of cetirizine on P-glycoprotein expression and function in vitro and in situ. Adv Pharm Bull. 2016; 6(1): 111-118. [CrossRef]

Details

Primary Language

English

Subjects

Clinical Pharmacy and Pharmacy Practice

Journal Section

Research Article

Authors

Ramin Mohammadzadeh This is me
Iran

Behzad Baradaran
Iran

Bahman Yousefi This is me
Iran

Hadi Valizadeh This is me
Iran

Parvin Zakeri-milani This is me
Iran

Publication Date

June 27, 2025

Submission Date

January 14, 2019

Acceptance Date

March 14, 2019

Published in Issue

Year 2019 Volume: 23 Number: 4

IZ

https://izlik.org/JA45GD36EA

Cite

RIS / Bibtex

APA

Mohammadzadeh, R., Baradaran, B., Yousefi, B., Valizadeh, H., & Zakeri-milani, P. (2025). Attenuation of intestinal efflux pump thru polymers and preservatives. Journal of Research in Pharmacy, 23(4), 632-641. https://izlik.org/JA45GD36EA

AMA

1.Mohammadzadeh R, Baradaran B, Yousefi B, Valizadeh H, Zakeri-milani P. Attenuation of intestinal efflux pump thru polymers and preservatives. J. Res. Pharm. 2025;23(4):632-641. https://izlik.org/JA45GD36EA

Chicago

Mohammadzadeh, Ramin, Behzad Baradaran, Bahman Yousefi, Hadi Valizadeh, and Parvin Zakeri-milani. 2025. “Attenuation of Intestinal Efflux Pump Thru Polymers and Preservatives”. Journal of Research in Pharmacy 23 (4): 632-41. https://izlik.org/JA45GD36EA.

EndNote

Mohammadzadeh R, Baradaran B, Yousefi B, Valizadeh H, Zakeri-milani P (June 1, 2025) Attenuation of intestinal efflux pump thru polymers and preservatives. Journal of Research in Pharmacy 23 4 632–641.

IEEE

[1]R. Mohammadzadeh, B. Baradaran, B. Yousefi, H. Valizadeh, and P. Zakeri-milani, “Attenuation of intestinal efflux pump thru polymers and preservatives”, J. Res. Pharm., vol. 23, no. 4, pp. 632–641, June 2025, [Online]. Available: https://izlik.org/JA45GD36EA

ISNAD

Mohammadzadeh, Ramin - Baradaran, Behzad - Yousefi, Bahman - Valizadeh, Hadi - Zakeri-milani, Parvin. “Attenuation of Intestinal Efflux Pump Thru Polymers and Preservatives”. Journal of Research in Pharmacy 23/4 (June 1, 2025): 632-641. https://izlik.org/JA45GD36EA.

JAMA

1.Mohammadzadeh R, Baradaran B, Yousefi B, Valizadeh H, Zakeri-milani P. Attenuation of intestinal efflux pump thru polymers and preservatives. J. Res. Pharm. 2025;23:632–641.

MLA

Mohammadzadeh, Ramin, et al. “Attenuation of Intestinal Efflux Pump Thru Polymers and Preservatives”. Journal of Research in Pharmacy, vol. 23, no. 4, June 2025, pp. 632-41, https://izlik.org/JA45GD36EA.

Vancouver

1.Ramin Mohammadzadeh, Behzad Baradaran, Bahman Yousefi, Hadi Valizadeh, Parvin Zakeri-milani. Attenuation of intestinal efflux pump thru polymers and preservatives. J. Res. Pharm. [Internet]. 2025 Jun. 1;23(4):632-41. Available from: https://izlik.org/JA45GD36EA