Oxazepam Esters. 1. Correlation between Hydrolysis Rates and Brain Appearance of Oxazepam

Gabor Maksay, Zsuzsanna Tegyey, Vera Kemeny, Istvan Lukovits, László Ötvös, Éva Palosi

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Abstract

Esters of the centrally acting oxazepam were investigated to find quantitative correlations between the pharmacokinetics of the parent drug and in vitro biotransformation rates and physicochemical properties of its prodrugs. The 14C-labeled aliphatic and ω-phenyl-substituted esters were administered intravenously to mice. Brain levels of the esters and oxazepam were determined and the latter was fitted to a simplified exponential equation. In vitro hydrolysis rate of the esters catalyzed by the hepatic microsomal fraction was measured with a pH stat. Pharmacokinetic constants characterizing the rising part of oxazepam brain levels correlate well with the chromatographic RMvalues and with in vitro maximal hydrolysis rates of the esters. The hydrolysis is capacity limited in the liver. In a closely related set of aliphatic esters, oxazepam brain penetration also correlates with the steric constant (Es) of its esters.

Original languageEnglish
Pages (from-to)1436-1443
Number of pages8
JournalJournal of Medicinal Chemistry
Volume22
Issue number12
DOIs
Publication statusPublished - febr. 1 1979

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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