Pharmacokinetic Studies of Triazolyl-Oxazolidinone Derivatives with Anticonvulsant Effects in Rats

Background/Objectives: Five triazolyl-oxazolidinone derivatives were reported to suppress seizures in rats with different efficacies and durations of action, which may be due to different pharmacokinetic behaviors. This study sought to investigate the pharmacokinetic characteristics of the five selected triazolyl-oxazolidinone derivatives and to correlate these with their anti-seizure activity in rats. A secondary objective was to identify lead compound(s) in this small series for further modification and subsequent development into drug candidates. Methods: Following intraperitoneal injection, the concentrations of the five selected compounds PH066, PH139, PH162, PH166, and PH192, in plasma and brain tissues were measured using LC/MS/MS methods. The brain tissue concentrations for each derivative were subsequently correlated with its observed anti-seizure activity in male Sprague Dawley rats against electrically induced (6 Hz and MES) and chemically-induced (pentylenetetrazole) seizure models. The area under the concentration–time curves in plasma and brain tissues was determined to estimate the average brain distribution of each compound. Anti-seizure activity was quantified using a standardized behavioral scoring system based on the rat’s response to seizure-inducing stimuli, with scores assigned by two independent observers. Results: Plasma and brain tissue concentrations were determined over the duration of each experiment. The mean maximum plasma concentrations were 14.6, 9.20, 14.8, 18.2, and 9.00 μg/mL, while the mean maximum brain tissue concentrations were 2.68, 0.14, 1.94, 2.80, and 0.86 μg/g for PH066, PH139, PH162, PH166, and PH192, respectively. The brain to plasma distribution ratios were in the range of 0.15–0.20 for PH066, PH162, and PH166, but were much lower for PH139 and PH192. The brain tissue concentration for each compound was correlated with its anti-seizure activity. The decreasing order of anti-seizure efficacy against the 6 Hz model was PH162 > PH166 > PH066 > PH139 > PH192, which correlated well with their plasma and brain concentrations. The decreasing order of protection against the MES model was PH139 > PH192 > PH162 > PH066 > PH166, while the decreasing order of protection against the pentylenetetrazole model was PH162 ≈ PH066 > PH166 ≈ PH192 > PH139. Conclusions: Compounds PH066, PH162 and PH166 achieved relatively high plasma and brain tissue concentrations with good plasma to brain distribution ratios. Therefore, they have favorable pharmacokinetic characteristics when compared with compounds PH139 and PH192. Of all the compounds evaluated, PH162 had the best pharmacokinetic characteristics, with consistent moderate to high protection against all the tested seizure models and with sustained anti-seizure activity. Thus, from these studies the order of anti-seizure efficacy and duration of action is PH162 > PH139 > PH166 ≈ PH066 > PH192. Thus, PH162 emerged as the potential lead compound when both pharmacokinetic and pharmacodynamic characteristics are considered.