In Vitro Evaluation of Pharmacokinetic Properties of Selected Dual COX-2 and 5-LOX Inhibitors

Evaluation of pharmacokinetic properties is a significant step at the early stages of drug development. In this study, an in vitro evaluation of the pharmacokinetic properties of five newly synthesized compounds was performed. These compounds belong to N-hydroxyurea and hydroxamic acid derivatives and analogs of NSAIDs indomethacin, flurbiprofen, diclofenac, ibuprofen, and naproxen (compounds <b>1</b>, <b>2</b>, <b>3</b>, <b>11,</b> and <b>12</b>, respectively) with dual COX-2 and 5-LOX inhibitory activity. Two in vitro methods (biopartitioning micellar chromatography (BMC) and PAMPA) were used to evaluate passive gastrointestinal absorption, while high-performance affinity chromatography (HPAC) and differential pulse voltammetry (DPV) were used to evaluate binding to human serum albumin (HSA). The introduction of N-hydroxyurea and hydroxamic acid groups into the structure of NSAIDs decreases both expected passive gastrointestinal absorption (BMC <b>k</b> values were from 3.02 to 9.50, while for NSAIDs were from 5.29 to 13.36; PAMPA <b>-logPe</b> values were between 3.81 and 4.76, while for NSAIDs were ≤3.46) and HSA binding (HPAC <b>logk</b> values were from 2.03 to 9.54, while for NSAIDs were ≥11.03; DPV peak potential shifts were between 7 and 34, while for NSAIDs were ≥54). Structural modifications of all tested compounds that increase lipophilicity could be considered to enhance their passive gastrointestinal absorption. Considering lower expected HSA binding and higher lipophilicity of tested compounds compared to corresponding NSAIDs, it can be expected that the volume of distribution of compounds <b>1</b>, <b>2</b>, <b>3</b>, <b>11,</b> and <b>12</b> will be higher. Reduced HSA binding may also decrease interactions with other drugs in comparison to corresponding NSAIDs. All tested compounds showed significant microsomal instability (25.07-58.44% decrease in concentration) in comparison to indomethacin (14.47%) and diclofenac (20.99%).