A Phase I study evaluating the pharmacokinetic profile of a novel oral analgesic propoxazepam

Abstract

Introduction and Objective. Propoxazepam, 7-bromo-5 - (o-chlorophenyl)-3-propoxy – 1,2-dihydro – 3H-1,4- benzodiazepin-2-one, in the models of nociceptive and neuropathic pain showed significant analgesic activity. The aim of the study was to investigate the pharmacokinetics of propoxazepam and its metabolites after a single oral dose in healthy volunteers. Materials and method. 12 volunteers were orally dosed with 5 mg propoxazepam under fasting conditions. Blood samples were collected up to 72 hours after administration and propxazepam extracted with liquid-phase extraction and analyzed with high-performance liquid chromatography–tandem mass spectrometry. Results. Maximum propoxazepam concentration (22.276 ng/mL) was reached in blood by 4 hours after administration. It had a large volume of distribution (~6.3 L/kg), the elimination half-life 30.11 hours, MRT 37.77 hours, common clearance – 9062.929 mL/hour. Both propoxazepam and its metabolites (3-hydroxy derivative and glucuronide) were detected in the urine of volunteers. The urinary excretion rate of propoxazepam is proportional to its concentration in plasma. Only a small amount of unchanged propoxazepam was excreted with urine – 0.062 % of the administered dose. Renal clearance – 6.46 mL/hour. Conclusions. A single dose (5 mg) of Propoxazepam administered orally showed good tolerability, pharmacokinetically characterized by rapid absorption, slow elimination and low quantities of unchanged parent urinary excreted. The oxidized metabolite (3-hydroxypropoxazepam) and its glucuronide were excreted with urin, a total of up to 10.5% of the administered dose, which indicates a high degree of metabolism and possible hepatointestinal circulation.