Simultaneous determination of four PDE5 inhibitors and metabolites in rat plasma by UPLC-MS/MS.
Abstract
Herein, we developed a sensitive UPLC-MS/MS method for the simultaneous determination of four PDE5 inhibitor and twelve metabolites in rat plasma. A total of 16 chemicals were separated on gradient elution with mobile phase A (0.1 % formate acetonitrile) and mobile phase B (0.1 % formate and 2 mmol/L ammonium formate aqueous solution) on an ACQUITY UPLC HSS T3 column (100 mm×2.1 mm, 1.8 μm) after protein precipitation, followed by the detection on the positive ion mode of electrospray ion source (ESI) via dynamic multi-reaction monitoring mode (MRM). The method provided good linearity over the range of 0.25-20 ng/mL for all compounds with correlation coefficients R greater than 0.99. The recoveries were higher than 75.5 %, the matrix factors were 2.1 %-20.4 %. The precision, accuracy and stability were also within acceptable criteria. A rat model was established to investigate the metabolic profile of Sildenafil, Vardenafil, Acetildenafil and Tadalafil. Blood samples from the experimental group were analyzed using ultra-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS). Notably, desmethyltadalafil and methyl-desmethyltadalafil were not detected in the plasma. However, their glucuronide conjugates, desmethyltadalafil glucuronide and methyl-desmethyltadalafil glucuronide, were identified and characterized via tandem mass spectrometry (MS/MS). At present, cases of poisoning or even death due to overdose of phosphodiesterase type 5 (PDE5) inhibitors…
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