Lorazepam and oxazepam esters. Hydrophobicity, hydrolysis rates and brain appearance

Six prodrug-type esters of oxazepam and lorazepam, which are potent benzodiazepine tranquillizers, were synthesized in 2-14C-labelled form. Pharmacokinetics of the compounds administered i.p. to mice were compared with respect to the effect of the acyl groups on the brain appearance of the esters and the parent drugs. Brain accumulation of the compounds administered was characterized by the areas under the brain-to-blood concentration ratio-time functions (AUQ). The rates of brain penetration were characterized by the slope of the correlation between i.v. dose and 1 -min brain levels. These slopes as well as AUQ values depended upon hydrophobicity (Rm) according to an optimum function. The lag times of the brain appearance of the parent drugs showed a minimum at about the same Rm at which AUQ values were maximal. The rates of brain appearance of the parent compounds correlated with the hepatic microsomal hydrolysis rate of their esters.