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A new steroidal derivative from the skin of Indian Toad (Bufo melanostictus) as a hypolipidemic and CYP 3A inhibitor
Abstract
Purpose: To investigate the inhibitory effect of a novel steroidal derivative (NSD) on CYP3A in Wistar rats.
Methods: Column chromatography and thin-layer chromatography (TLC) were used for the isolation and identification of NSD, while its structure was elucidated using, Infrared (IR) 13Carbon Nuclear Magnetic Resonance (13C NMR), Proton nuclear magnetic resonance (1H-NMR), and liquid chromatography with tandem mass spectrometry (LC-MS). Toxicity studies were conducted in female Wistar rats according to Organisation for Economic Co-operation and Development (OECD) 423 guidelines. Hyperlipidemia was induced in the rats with high-fat diet (HFD). In vitro cytochrome P-450 (CYP) 3A studies were carried out by erythromycin demethylation assay (EMD), while pharmacokinetic studies were undertaken after treatment for eight days with NSD. Plasma drug concentrations were assessed using high-performance liquid chromatography (HPLC), while pharmacokinetic parameters were computed using WinNonlin 8.2 software. Lipid profile was evaluated by Cholestech LDX analyzer; furthermore, hematoxylin-and eosin-stained histological sections of the arch of the aorta were examined by microscopy.
Results: The lethal dose-50 (LD50) was 200 mg/kg. In vitro studies shown CYP activity in liver microsomes (551.41 ± 107.70 to 136.11 ± 2.978) and in intestine microsomes (496.71 ± 20.23 to 146.20 ± 23.7), compared to control (p ˂ 0.001). Pharmacokinetic studies Cmax, increased from 55.26 ± 5.16 to 387.8 ± 40.95 ng/mL; and area under the curve (AUC) from 547.588 ± 20.150 to 2730.548 ± 27.19. The volume of distribution (Vd), mean residual time (MRT), time to maximum concentration (Tmax) were decreased. NSD significantly reduced serum cholesterol (SC) from 254.5 ± 27.5 to 88.6 ± 8.8 mg/dL, and other lipids as well.
Conclusion: NSD inhibits CYP3A-mediated ATV drug metabolism and is also a potent hypolipidemic agent in vitro and in vivo studies. Co-administration of ATV and NSD may expedite oral bioavailability.
