Influence of Toad Parotid Gland Secretion from Indian Toad (Bufo melanostictus) in Diabetic Rats: An Experimental Evidence of P-Glycoprotein Inhibition

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.

Toad venom-derived bufadienolides and their therapeutic application in prostate cancers: Current status and future directions

“…Firstly, both cinobufagin and bufalin could inhibit P-glycoprotein (P-gp, also named as ABCB1 or multidrug resistance mutation 1, MDR1) ( Yuan et al, 2017 ; Madugula and Neerati, 2020 ; Zhan et al, 2020 ; Neerati and Munigadapa, 2022 ). Since P-gp plays an essential role, and sometime the leading role in inducing anticancer drug of both conventional and targeted therapies resistance via transporting them out of cancer cells ( Robey et al, 2018 ; Wang et al, 2020b ; Feng et al, 2020 ; Thomas and Tampe, 2020 ; Wang et al, 2021 ), cinobufagin and bufalin may likely have potentials in sensitizing certain conventional chemotherapeutics that are substrates of P-gp.…”

“…Firstly, both cinobufagin and bufalin could inhibit P-glycoprotein (P-gp, also named as ABCB1 or multidrug resistance mutation 1, MDR1) (Yuan et al, 2017;Madugula and Neerati, 2020;Zhan et al, 2020;Neerati and Munigadapa, 2022).…”