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Simultaneous Determination of Losartan and Rosuvastatin in Rat Plasma Using Liquid Chromatography–Tandem Mass Spectrometric Technique for Application into Pharmacokinetic and Drug–Drug Interaction Studies

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Abstract

The combined therapy benefits of losartan and rosuvastatin, within the vascular injury, have been well characterized. Nonetheless, the pharmacokinetic interactions between such therapeutic agents have not been yet figured out, making the need for a sensitive analytical technique to be of great significance. In view of this, a highly selective, sensitive, and well-validated liquid chromatography–tandem mass spectrometric technique has been developed for the simultaneous estimation of losartan (LOS) and rosuvastatin (ROS) within the rat plasma using simvastatin as an internal standard. The proposed technique adopted a simple plasma protein preparation by acetonitrile for the extraction and purification of the drug-plasma samples obtained from the rat animal models. A separation process on the Agilent™ Eclipse-Plus® (C18, 0.46 × 15 cm, 3.5 μm) columns was conducted using gradient mobile phase system comprising of water/0.1%w/v formic acid and acetonitrile at 0.9 mL min−1 flow rate. Precursor quantification into production was performed using the multiple reaction monitoring within the positive-ionization mode. Method linearity was obeyed within 1–5000 ng mL−1 for both LOS and ROS, while the validation process was performed according to the guidelines adopted by the US-FDA bioanalytical framework. The pharmacokinetic interactions after oral co-administration of both drugs furnished significant changes within their respective pharmacokinetic parameters including peak-plasma concentration, elimination t1/2, AUC, volume of distribution, and plasma clearance. Additionally, a mutual competitive displacement for each drug from their plasma albumin bindings showed a significant impact on drug's pharmacokinetic profile and was demonstrated through molecular modeling investigations. Finally, the presented study laid an evidence for a two-way pharmacological synergism with the combined therapy of LOS and ROS via increased hepatic influx of ROS and peak-plasma concentration of EXP3174, the LOS more potent metabolite. Therefore, the proposed method provides a useful tool for the drug–drug interaction investigations being valuable for prospective bioequivalence studies and therapeutic drug monitoring.

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Acknowledgments

The authors are grateful to staff member of Department of Pharmacology, Faculty of Pharmacy, Suez Canal University for support and help.

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Authors and Affiliations

  1. Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt

    Magdy Atef Wadie, Safaa M. Kishk, Khaled M. Darwish, Samia M. Mostafa & Mohamed Saleh Elgawish

  2. Center for Molecular Spectroscopy and Dynamic, Institute of Basic Science, Korea University, Seoul, 02841, Republic of South Korea

    Mohamed Saleh Elgawish

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  1. Magdy Atef Wadie
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Wadie, M.A., Kishk, S.M., Darwish, K.M. et al. Simultaneous Determination of Losartan and Rosuvastatin in Rat Plasma Using Liquid Chromatography–Tandem Mass Spectrometric Technique for Application into Pharmacokinetic and Drug–Drug Interaction Studies. Chromatographia 83, 1477–1494 (2020). https://doi.org/10.1007/s10337-020-03967-z

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