Novel Indole Derivative as the First P-glycoprotein Inhibitor from the Skin of Indian Toad (Bufo melanostictus)

To study the inhibitory effect of novel indole derivative (NID) from Indian toad skin (Bufo melanostictus) on permeability glycoprotein (P-gp).

Dried Indian toad skin was used to isolate NID with column chromatography, and its structure was elucidated by infrared spectra, ¹³C nuclear magnetic resonance (NMR), ¹H NMR spectra, and liquid chromatography-mass spectrometry. Female Wistar rats were used to determine LD₅₀, in vitro permeability studies were done with the intestinal sac method, and in vivo pharmacokinetic studies were carried out to prove the P-gp inhibition using the rat model.

The NID has shown increased clear permeability P_app (x10^-6 cm/sec) significantly (p<0.001) from 1.04±0.11 to 2.90±0.08 in ileum 1.44±0.14 to 3.92±0.13 in jejunum this in vitro results confirmed that P-gp inhibited, this was further confirmed by in vivo studies in in vivo studies observed increased oral bioavailability of digoxin (DIG) significantly in NID treated groups from 3.26±0.25 to 7.47±0.18 ng/mL, the volume of distribution decreased from 232.56±64.59 to 86.57±7.04 L/kg. Area under the curve increased from 37.89±1.13 to 64.62±0.70 ng/mL/hr. This demonstrates NID increased the oral bioavailability of DIG significantly.

Many compounds were isolated from the Indian toad skin. This NID was not reported earlier. Results demonstrate NID increased the oral bioavailability of DIG significantly. The isolated NID from Indian toad skin proved as a potent P-gp inhibitor in both in vitro and in vivo studies, and further studies are needed to develop as a possible new drug candidate.