A rapid RP-HPLC method for the simultaneous estimation of Ivacaftor and Tezacaftor and in silico study of their metabolitic products

Abstract Background This study was designed to develop a reliable method for estimation of Ivacaftor and Tezacaftor in pure and its pharmaceutical dosage form by RP-HPLC in human plasma. Molecular docking studies were carried out and the results were visualized using PyMol and Discovery studio visua...

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Main Authors: Madhuri Donakonda (Author), Srija Indrakanti (Author), Praveen Kumar Pasala (Author), Malleswari Desari (Author), Shireesha Kammari (Author)
Format: Book
Published: SpringerOpen, 2021-06-01T00:00:00Z.
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100 1 0 |a Madhuri Donakonda  |e author 
700 1 0 |a Srija Indrakanti  |e author 
700 1 0 |a Praveen Kumar Pasala  |e author 
700 1 0 |a Malleswari Desari  |e author 
700 1 0 |a Shireesha Kammari  |e author 
245 0 0 |a A rapid RP-HPLC method for the simultaneous estimation of Ivacaftor and Tezacaftor and in silico study of their metabolitic products 
260 |b SpringerOpen,   |c 2021-06-01T00:00:00Z. 
500 |a 10.1186/s43094-021-00254-y 
500 |a 2314-7253 
520 |a Abstract Background This study was designed to develop a reliable method for estimation of Ivacaftor and Tezacaftor in pure and its pharmaceutical dosage form by RP-HPLC in human plasma. Molecular docking studies were carried out and the results were visualized using PyMol and Discovery studio visualizer (Discovery studio visualizer ver. 2.5). The pharmacokinetic properties such as Swiss ADME and pKCSM of the Ivacaftor and its metabolites Ivacaftor M1, M6 and Tezacaftor and metabolites Tezacaftor M1, M2 were predicted. In admetSAR, web-based query tools incorporating a molecular built-in interface enable the database to be queried by SMILES. Results A simple, linear, precise, and accurate RP-HPLC method was developed and validated for the determination of Ivacaftor (IVA) and Tezacaftor (TEZ) in human plasma. Chromatographic separation was achieved isocratically on Inspire C18, (4.6 × 250 mm, 5 μm) column at 30 °C. Mobile phase consisting of methanol and 0.05% formic acid in ratio of 95:5 with flow rate of 1 mL/min with injection volume 20 μl detector used is PDA at 235 nm. The developed method was validated according to ICH guidelines and found to be linearity range was found to be for TEZ (10-50 μg/mL) and IVA (15-75 μg/mL). IVA and TEZ drugs and its metabolites were retrieved from the PubChem database and the 2D chemical structures were generated from SMILES notation by using the Chemsketch Software. The structure was viewed using Swiss-PDB Viewer to form a better understanding of the molecule for toxicity and biological activity prediction. Conclusion The results obtained by the proposed method from validation parameters and from assay confirmed that the determination of Tezacaftor (TEZ) and Ivacaftor (IVA) in their combined dosage form in human plasma was sensitive and selective method. In silico study has revealed that IVA and its metabolites IVA M1, IVA M6 are according to Lipinski rule. The oral bioactivity of IVA was found to be more when compared to its metabolites (Molinspiration) and TEZ and its metabolites TEZ M1, TEZ M2 even though they have the molecular weight > 500, but all other parameters from Molinspiration revealed better oral bioactivity of TEZ M2. Validation of the developed isocratic RP-HPLC procedure revealed that, regardless of how the sample was purified, the method was characterized by good linearity, sensitivity, reproducibility, specificity, and low values of LOD (0.090 μg/mL) and LOQ (0.275 μg/mL). From the in silico docking results, it is quite evident that metabolites of TEZ and IVA have the great potential against cystic fibrosis. 
546 |a EN 
690 |a Tezacaftor 
690 |a Ivacaftor 
690 |a In silico docking 
690 |a Human plasma 
690 |a RP-HPLC metabolites 
690 |a Therapeutics. Pharmacology 
690 |a RM1-950 
690 |a Pharmacy and materia medica 
690 |a RS1-441 
655 7 |a article  |2 local 
786 0 |n Future Journal of Pharmaceutical Sciences, Vol 7, Iss 1, Pp 1-14 (2021) 
787 0 |n https://doi.org/10.1186/s43094-021-00254-y 
787 0 |n https://doaj.org/toc/2314-7253 
856 4 1 |u https://doaj.org/article/0180835e38e24faca30efe8045a59d6e  |z Connect to this object online.