Adme properties and tentative identification of metabolites of propoxazepam in mice by radioactive carbon and UPLC-MS/MS methods

Abstract

A novel 3-substituted 1,4-benzodiazepine, 7-bromo-5-(o-chlorophenyl)-3-propoxy-1,2-dihydro-3H-1,4-ben-zodiazepin-2-one (named propoxazepam), has been found to have a potent analgesic anti inflammation and anticonvulsant effect. Both oral and intraperitoneal administrations are similar in activity, although intraperitoneal administration is preferred. It has proven in in vivo studies to be the potent drug in its class against acute and chronic pain. Our data suggest that the mechanism of propoxazepam anticonvulsant properties includes GABAergic and glycinergic systems. Antibradykinin and antileukotriene action, dopaminergic system, NMDA, and alpha-1 adrenergic receptors, except the antiprostaglandin component, are involved in the mechanisms of propoxazepam analgesic effect. Rational drug discovery requires an early appraisal of all factors impacting on the likely success of a drug candidate in the subsequent preclinical, clinical and commercial phases of drug development. The study of absorption, distribution, metabolism and excretion (ADME) of drug has developed into a relatively mature discipline in drug discovery through the application of well-established in vitro and in vivo methodologies.