Quantification of tadalafil in HLMs using an ultrafast UPLC-MS/MS method to assess metabolic stability, including in silico analysis of metabolic lability, DEREK alerts, and ADME characteristics
Abstract
Tadalafil (Cialis) is an FDA-approved oral drug used for benign prostatic hyperplasia, pulmonary arterial hypertension, and erectile dysfunction. A fast, environmentally friendly, and reliable UPLC-MS/MS method was established to quantify tadalafil (TDF) in human liver microsomes (HLMs) and assess its in vitro metabolic stability. Unlike previously reported TDF assays, which target plasma or other biological fluids, the present method uniquely couples HLM-based metabolic-stability assessment with in silico metabolic soft-spot, toxicity, and ADME prediction and dual greenness evaluation in a single workflow. The method is linear over 1 to 4000 ng mL-1, provides detection within 1 min, and maintains high precision and repeatability regardless of the presence of HLMs. TDF and baricitinib (internal standard) were separated using an Eclipse Plus 1.8 µm C18 column (reversed-phase; 50 mm × 2.1 mm), with a mobile phase of 0.1% HCOOH in water (45%) and in acetonitrile (55%). The approach's accuracy and precision ranged from -4.35% to 7.33% (intra-day) and -5.02% to 12.0% (inter-day). TDF's in vitro half-life was 59.65 min, with a slow intrinsic clearance (Clint) of 13.59 mL min-1 kg-1. In silico results reveal that minor modifications at C28 of the 1,3-benzodioxole ring (95%) could enhance the safety and stability of the new derivatives relative to TDF.
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