Simultaneous Determination and Drug–Drug Interaction Study of Losartan and Aprepitant Through Pharmacokinetic Approach in Rat Plasma by UHPLC–QqQ-MS/MS

Abstract

Losartan is an anti-hypertensive drug that belongs to the class of angiotensin-II receptor blockers that act by inhibiting the binding of angiotensin II to its receptor. Aprepitant belongs to the class of neurokinin receptor-1 receptor blockers used to treat nausea and vomiting. In the case of severe hypertension, there are the majority of predominant symptoms occurring but one such symptom is nausea and vomiting. This condition may potentially be treated by a combination of losartan and aprepitant, but there is no information about the pharmacokinetic interactions for this combination. When losartan and aprepitant are taken concomitantly there may be a chance that these two drugs may alter the pharmacokinetics of each other. Thus, the effects of both the drugs were assessed on each other. To assess the preclinical pharmacokinetic drug–drug interaction a rapid, simple, and sensitive approach for the simultaneous estimation of losartan and aprepitant in rat plasma by LC–QqQ-MS/MS has been developed and validated. The separation was done on Agilent ZORBAX Eclipse Plus C18 (4.6 mm × 100 mm, 3.5 µm) by gradient elution using 0.1% (v/v) formic acid in water and acetonitrile. Multiple reaction monitoring was performed using a positive ionization mode. The precursor and product ions for losartan, aprepitant, and telmisartan (internal standard) were m/z 423.2 → 207.0, m/z 535.2 → 277.0, and, m/z 515.3 → 276.1, respectively. The proposed method was validated in accordance with USFDA bioanalytical guidelines. The method was found linear, accurate and sensitive to estimate the losartan and aprepitant in rat plasma with the lowest limit of quantification of 1 ng/mL. The pharmacokinetic parameters like half-life, T_max and the area under the curve for aprepitant have been significantly affected when administered with losartan and vice versa. These results provide insights for futuristic investigation at the pharmacodynamic level of drug–drug interactions for this combination.