Quantitation of Thioether-Prodrug NS1040 and Its Metabolites in Rat Plasma Using Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

摘要

Human immunodeficiency virus type-1 (HIV-1) plagues millions. Hence, there is still a need for new inexpensive therapies which act on novel targets. The thioether prodrug NS1040 is under preclinical investigation for HIV-1. Thioethers are a popular prodrug motif, but their inherent instability poses a challenge for bioanalytical assay development. Previous, methods relied on converting all metabolites to one form, usually the active metabolite for quantitation. This approach does not provide an accurate depiction of in vivo metabolite levels, often leading to an overestimation of the active form's concentration. Therefore, highly sensitive and selective UPLC-MS/MS assays for the determination of NS1040 and its three major metabolites (MDH1-38, NS1060 and M5) are necessary for ADME and PK/PD studies.