A Simple UPLC/MS-MS Method for Simultaneous Determination of Lenvatinib and Telmisartan in Rat Plasma, and Its Application to Pharmacokinetic Drug-Drug Interaction Study.

Yanjun Cui,Yuhao Fu,Liju Fan,Xiao Li,Zhanjun Dong,Ying Li,Xueru He

doi:10.3390/molecules27041291

Abstract

Lenvatinib is a multi-targeted tyrosine kinase inhibitor that inhibits tumor angiogenesis, but hypertension is the most common adverse reaction. Telmisartan is an angiotensin receptor blocker used to treat hypertension. In this study, a simple ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of lenvatinib and telmisartan, and it was applied to the pharmacokinetic drug interaction study. Plasma samples were treated with acetonitrile to precipitate protein. Water (containing 5 mM of ammonium acetate and 0.1% formic acid) and acetonitrile (0.1% formic acid) were used as the mobile phases to separate the analytes with gradient elution using a column XSelect HSS T3 (2.1 mm × 100 mm, 2.5 μm). Multiple reaction monitoring in the positive ion mode was used for quantification. The method was validated and the precision, accuracy, matrix effect, recovery, and stability of this method were reasonable. The determination of analytes was not interfered with by other substances in the blank plasma, and the calibration curves of lenvatinib and telmisartan were linear within the range of 0.2–1000 ng/mL and 0.1–500 ng/mL, respectively. The results indicate that lenvatinib decreased the systemic exposure of telmisartan. Potential drug interactions were observed between lenvatinib and telmisartan.

Highlights

Protein kinases are a group of enzymes concerned with the phosphorylation process that involves the migration of the phosphate group of ATP to proteins and plays an important role in regulating cellular signaling pathways
Hypertension is associated with VEGFRTKIs antitumor efficacy; studies have shown that patients who developed hypertension had a better response than those who did not [7]
LEN belongs to the biopharmaceutics classification system (BCS) II or IV drugs with poor water solubility [37]; TEL is a poorly water-soluble drug that belongs to BCS II, and solubility is related to PH [38]

Summary

Introduction

Protein kinases are a group of enzymes concerned with the phosphorylation process that involves the migration of the phosphate group of ATP to proteins and plays an important role in regulating cellular signaling pathways. Tyrosine kinase inhibitors (TKIs) play a vital role in tumor treatment in the clinical setting. Most patients have varying degrees of elevated blood pressure and may be accompanied by proteinuria when TKIs that target vascular endothelial growth factor receptors (VEGFR) to inhibit angiogenesis are applied [4,5,6]. The mechanism of VEGFR-TKIs induced hypertension is not clearly elucidated, but it is related to its antiangiogenic effect. The main reasons might be decreased nitric oxide production, decreased prostacyclin production, and increased endothelin 1 production, leading to vasoconstriction and thinning of the vascular bed, causing increased vascular resistance and increased blood pressure. Increased endothelin 1 production, leading to vasoconstrictio thinning of the vascular bed, causing increased vascular resistance and increased pressure.

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Conclusion