Comprehensive cytotoxic evaluation of morin, a bioflavonoid against verapamil on rat gastrointestinal epithelium for novel pharmaceutical application involving P-glycoprotein inhibition Gurunath Surampalli a , Basavaraj K. Nanjwade b and Paragouda A. Patil c a Department of Pharmacology, Vaagdevi Institute of Pharmaceutical Sciences, Warangal, Telangana and c Department of Pharmacology, International Medical Programme, USM-KLE University, Belgaum, Karnataka, India and b Department of Pharmaceutics, Omer Al-Mukhtar University, Tobruk, Libya Keywords bioflavonoid; cytotoxic; morin; P-gp inhibition; verapamil Correspondence Gurunath Surampalli, H.No 2–10-910, Bank Colony, Subedari, Wadepalli, Warangal, 506370 Andhra Pradesh, India. E-mail: s.gurunath1979@gmail.com Received October 4, 2014 Accepted January 18, 2015 doi: 10.1111/jphp.12400 Abstract Objective In this study, a comprehensive and comparative cytotoxic evaluation of morin against verapamil on rat intestinal epithelium as P-gp inhibitors through in-vitro gastrointestinal short-term toxicity assays involving permeability studies for safety evaluation was investigated. Methods In this study, the effect of morin (1 mM or 10 mM) or verapamil (1 mM or 10 mM) or sodium deoxycholate (10 mM) was investigated on intestinal epithelium and isolated brush border membrane using biomarker assays. Cytotoxicity was determined using 3-(4,5-dimethylthiazolyl-2)-2,5- diphenyltetrazolium bromide (MTT) assay. The nutrients transport was assessed using everted sacs studies. Paracellular permeability was measured using Lucifer yellow, followed by morphometric analysis of intestinal sacs. Key findings Our results indicated that morin was effective in maintaining cell viability with no significant changes (P > 0.05) in the activity of intestinal brush border markers, membrane integrity and morphometric analysis as compared with control. On the contrary, dramatic (P < 0.01) changes were noticed in the release of membrane markers, cell viability and surface characteristics of intestinal segments when treated with verapamil or sodium deoxycholate as compared with control or morin. Conclusions Our findings confirm that morin is non-toxic to rat intestinal epi- thelium against verapamil demonstrating the potential use of bioflavonoid as safe and novel pharmaceutical adjuvant as P-gp inhibitor. Introduction Membrane transporters can influence the pharmaco- kinetics, safety and efficacy profiles of substrate drugs. [1] P-glycoprotein (P-gp), a membrane transporter pumps a wide range of xenobiotics [2] out of a cell thus limiting drug absorption in gastrointestinal (GI) tract consequently reducing oral bioavailability. [3] Therefore, inhibition of P-gp-mediated efflux is considered as common strategy to develop new chemical entities of P-gp substrates to improve the oral bioavailability [4] that require a small dose for their pharmacological actions or have slow dissolution and diffu- sion rates including sustained release dosage forms. [5] It is well-known that improvement in the bioavailability of P-gp substrate drugs can be achieved through P-glycoprotein inhibitors such as verapamil and cyclosporine A. [6–8] However, these P-pg inhibitors them- selves possess pharmacological or toxicological actions. In addition, P-gp modulators such as polyethylene glycols, non-ionic surfactants, fatty acids and bile salts [9–14] are found promising owing to their low toxicity and high specificity towards P-gp for bioavailability improvement. However, the therapeutic benefits of P-gp modulators are yet to be firmly established. And Pharmacology Journal of Pharmacy Research Paper © 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 1083–1099 1083 Downloaded from https://academic.oup.com/jpp/article/67/8/1083/6128176 by guest on 09 July 2022