Influence of Toad Parotid Gland Secretion from Indian Toad (Bufo melanostictus) in Diabetic Rats: An Experimental Evidence of P-Glycoprotein Inhibition
Journal of Pharmaceutical Research International,
Page 125-135
DOI:
10.9734/jpri/2020/v32i2030736
Abstract
The study was conducted to improve the oral bioavailability of glyburide (GLY) with Indian Toad Parotid Gland Secretions (TPGS). P-glycoprotein is an efflux transporter cellular protein and effluxes xenobiotics and drugs to the outside of cells lead to decreased concentration of drugs at the target site. P-gp inhibitors essentially increase the levels and there is a need for new P-gp inhibitors to develop for the improvement of the oral bioavailability of P-gp substrate drugs because the existing inhibitors have serious side effects. This study was aimed to describe the P-gp inhibitory action from TPGS, Bufo melanostictus, in diabetic rats by using glyburide as p-gp substrate. Acute toxicity studies showed 300 mg/kg as toxic dose and 50 mg/kg was selected as study dose according to OECD 423. LC-HRMS study conducted to identify the new compounds. Apparent permeability (Papp) was estimated by non-everted sac method (In Vitro) with rat jejunum and ileum to confirm the P-gp inhibitory activity of TPGS by using fexofenadine (FEX) as P-gp substrate. In in-vivo protocol rats grouped into 4 groups (n=6), the first one is normal, second diabetic, third GLY 30 mg/kg, and fourth group GLY+ TPGS, 50 mg/kg for the single and multiple-dose treatment study. The spectrometric analysis revealed the new compounds, and TPGS Papp (X10-6 cm/s) in rat jejunum and ileum was significantly increased from 2.0±0.1 to 6.4±0.3 and 1.2±0.3 to 3.0±0.3 respectively. Blood glucose concentration in rats more than 250 mg/dl were considered as diabetic and in single, multiple-dose interaction studies (SDI, MDI) the concentrations decreased from 140.0±2.0 and 122.0±2.2 µg/dl respectively. The pharmacokinetic parameters like Cmax, Cl and in SDI, MDI and significant increase of C max and AUC t and decrease of Cl was observed. The above results conclude that TPGS had the potential P-gp inhibitory activity and improved the oral bioavailability of GLY significantly. Subsequent experimentation is warranted to chemically characterize the compounds from TPGS as potential new P-gp inhibitors.
Keywords:
- Toxinous TPGS
- LC-HRMS
- Bufo melanostictus
- P-gp
- Glyburide
How to Cite
References
Blaylock LA, Ruibal R, Platt-Aloia K. Skin structure and wiping behavior of phyllomedusine frogs. Copeia. 1976;1976: 283-295.
Bowie JH, Separovic F, Tyler MJ. Host-defense peptides of Australian anurans. part 2. Structure, activity, mechanism of action, and evolutionary significance. Peptides. 2012;37:174-188.
Langowski JKA, Singla S, Nyarko A, Schipper H, van den Berg FT, Kaur S, Astley HC, Gussekloo SWS, Dhinojwala A, van Leeuwen JL. Comparative and functional analysis of the digital mucus glands and secretions of tree frogs. Frontiers in Zoology. 2019;16:19.
Mills JW, Prum BE. Morphology of the exocrine glands of the frog skin. Am J Anat. 1984;171:91-106.
Nalbantsoy A, Karis M, Yalcin HT, Gocmen B. Biological activities of skin and parotoid gland secretions of bufonid toads (Bufo bufo, Bufo verrucosissimus and Bufotes variabilis) from Turkey. Biomed Pharmacother. 2016;80:298-303.
Obert HJ, Schneider H. [Glands in the skin of the fire-bellied toad (Bombina bombina(L.); Discoglossidae, Anura): Type, number, size and distribution under natural and experimental conditions]. Z Mikrosk Anat Forsch. 1978;92:241-72.
Qi J, Tan CK, Hashimi SM, Zulfiker AH, Good D, Wei MQ. Toad glandular secretions and skin extractions as anti-inflammatory and anticancer agents. Evid Based Complement Alternat Med. 2014; 2014:312684.
Tatsunori S, Sakaé K, Noboru Y. Morphology of the skin glands of the crab-eating frog (Rana cancrivora). Zoological Science. 1995;12:623-626.
Toledo RC, Jared C. Cutaneous adaptations to water balance in amphibians. Comparative Biochemistry and Physiology Part A: Physiology. 1993; 105:593-608.
Wang H, Ran R, Yu H, Yu Z, Hu Y, Zheng H, Wang D, Yang F, Liu R, Liu J. Identification and characterization of antimicrobial peptides from skin of Amolops ricketti (Anura: Ranidae). Peptides. 2012;33:27-34.
Welsch U, Storch V, Fuchs W. The fine structure of the digital pads of rhacophorid tree frogs. Cell Tissue Res. 1974;148:407-16.
Green DM. Adhesion and the toe-pads of treefrogs. copeia. 1981;1981:790-796.
Dominguez E, Navas P, Hidalgo J, Aijon J, Lopez-Campos JL. Mucous glands of the skin of Rana ridibunda. A histochemical and ultrastructural study. Basic Appl Histochem. 1981;25:15-22.
Schumacher U, Adam E, Hauser F, Probst JC, Hoffmann W. Molecular anatomy of a skin gland: Histochemical and biochemical investigations on the mucous glands of Xenopus laevis. J Histochem Cytochem. 1994;42:57-65.
Sian Rutland C, Cigler P, Kubale V. Reptilian skin and its special histological structures. Intech Open; 2019.
G. H. Venomous Animals and Their Toxins. Springer-Verlag Berlin Heidelberg; 1981.
Daly JW, Myers CW, Whittaker N. Further classification of skin alkaloids from neotropical poison frogs (Dendrobatidae), with a general survey of toxic/noxious substances in the amphibia. Toxicon. 1987;25:1023-95.
Cei JM, Erspamer V, Roseghini M. Taxonomic and evolutionary significance of biogenic amines and polypeptides occurring in amphibian skin. I. Neotropical leptodactylid frogs. Syst Zool. 1967;16: 328-42.
Huret JL, Minor SL, Dorkeld F, Dessen P, Bernheim A. Atlas of genetics and cytogenetics in oncology and haematology, an interactive database. Nucleic Acids Res. 2000;28:349-51.
Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 2009;323:1718-22.
Neerati P. Detection of antidiabetic activity by crude paratoid gland secretions from common Indian toad (Bufo melanostictus). J Nat Sci Biol Med. 2015; 6:429-433.
Rostelato-Ferreira S, Dal Belo CA, da Cruz-Höfling MA, Hyslop S, Rodrigues-Simioni L. Presynaptic effect of a methanolic extract of toad (Rhinella schneideri) poison in avian neuromuscular preparation. J Venom Res. 2011;2:32-36.
Córdova PWH, Leitão SG, Cunha-Filho G, Bosch RA, Alonso IP, Pereda-Miranda R, Gervou R, Touza NA, Quintas LE, Noël F. Bufadienolides from parotoid gland secretions of Cuban toad Peltophryne fustiger (Bufonidae): Inhibition of human kidney Na(+)/K(+)-ATPase activity. Toxicon. 2016;110:27-34.
Allen DR, McWhinney BC. Quadrupole time-of-flight mass spectrometry: A paradigm shift in toxicology screening applications. Clin Biochem Rev. 2019;40: 135-146.
Naveen KM, Prasad N. Toxinous secretions from indian toad (Bufo meanostictus) with potential antioxidant and anti-inflammatory activities. International Journal of Biology, Pharmacy and Allied Sciences. 2020;9:(In Press).
Padgaonkar AV, Suryavanshi SV, Londhe VY, Kulkarni YA. Acute toxicity study and anti-nociceptive activity of Bauhinia acuminata Linn. leaf extracts in experimental animal models. Biomedicine & Pharmacotherapy. 2018;97:60-66.
OECD. Acute Oral Toxicity-Acute Toxic Class Method, OECD Publishing [Web Page]. Test No. 423.
Wada S, Kano T, Mita S, Idota Y, Morimoto K, Yamashita F, Ogihara T. The role of inter-segmental differences in P-glycoprotein expression and activity along the rat small intestine in causing the double-peak phenomenon of substrate plasma concentration. Drug Metab Pharmacokinet. 2013;28:98-103.
Akbarzadeh A, Norouzian D, Mehrabi MR, Jamshidi S, Farhangi A, Verdi AA, Mofidian SMA, Rad BL. Induction of diabetes by Streptozotocin in rats. Indian J Clin Biochem. 2007;22:60-64.
Trinder P. Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol. 1969;22:158-61.
Kumar A, Srirangam P, Pradeep Kumar Y, Madhu B. Development and validation of HPLC method for the determination of glibenclamide in rat serum. International Journal of Pharma and Bio Sciences. 2011;2:478-485.
Demori I, Rashed ZE, Corradino V, Catalano A, Rovegno L, Queirolo L, Salvidio S, Biggi E, Zanotti-Russo M, Canesi L, Catenazzi A, Grasselli E. Peptides for skin protection and healing in Amphibians. Molecules (Basel, Switzerland). 2019;24:347.
Rodríguez C, Rollins-Smith L, Ibáñez R, Durant-Archibold AA, Gutiérrez M. Toxins and pharmacologically active compounds from species of the family Bufonidae (Amphibia, Anura). J Ethnopharmacol. 2017;198:235-254.
Sakugawa T, Miura M, Hokama N, Suzuki T, Tateishi T, Uno T. Enantioselective disposition of fexofenadine with the P-glycoprotein inhibitor verapamil. Br J Clin Pharmacol. 2009;67:535-540.
Amin ML. P-glycoprotein Inhibition for optimal drug delivery. Drug Target Insights. 2013;7:27-34.
Nagare N, Damre A, Singh KS, Mallurwar SR, Iyer S, Naik A, Chintamaneni M. Determination of site of absorption of propranolol in rat gut using in situ single-pass intestinal perfusion. Indian Journal of Pharmaceutical Sciences. 2010;72:625-629.
Varma MVS, Ashokraj Y, Dey CS, Panchagnula R. P-glycoprotein inhibitors and their screening: A perspective from bioavailability enhancement. Pharmacological Research. 2003;48:347-359.
Bansal T, Mishra G, Jaggi M, Khar RK, Talegaonkar S. Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats. European Journal of Pharmaceutical Sciences. 2009;36:580-590.
Choi J-S, Piao Y-J, Kang KW. 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.
Weinheimer M, Fricker G, Burhenne J, Mylius P, Schubert R. The application of P-gp inhibiting phospholipids as novel oral bioavailability enhancers — An in vitro and in vivo comparison. European Journal of Pharmaceutical Sciences. 2017;108:13-22.
Golstein PE, Boom A, van Geffel J, Jacobs P, Masereel B, Beauwens R. P-glycoprotein inhibition by glibenclamide and related compounds. Pflugers Arch. 1999;437:652-60.
Kalsi H, Grewal RK. Interaction of mouse intestinal P-glycoprotein with oral antidiabetic drugs and its inhibitors. Indian J Exp Biol. 2015;53:611-6.
-
Abstract View: 305 times
PDF Download: 263 times
