K. Thomsen, H. Bundgaard
Apr 5, 1993
Citations
1
Influential Citations
19
Citations
Quality indicators
Journal
International Journal of Pharmaceutics
Abstract
Abstract A series of phenyl carbamate esters derived from N -substituted 2-aminobenzamides was prepared and evaluated as prodrug forms with the aim of protecting phenolic drugs against first-pass metabolism following peroral administration. The stability of the derivatives was studied in aqueous buffer solutions and in various biological media. The carbamates showed a relatively high stability at pH 1–6 but underwent an apparent specific base-catalyzed cyclization in neutral and alkaline solution to a 2,4(1 H ,3 H )-quinazolinedione with concomitant release of the parent phenol. The rate of this cyclization was not affected by liver, intestinal wall or plasma enzymes but dependent on the p K a of the phenol and the steric and polar properties of the N -substituent within the benzamide moiety. By appropriate selection of this sunstituent it is readily feasible to obtain prodrug derivatives having practically useful rates of cyclization and hence release of the parent phenolic drug at pH 7.4 and 37°C, corresponding to half-lives of 10–60 min. The results suggest that this prodrud principle involving anon-enzymatic but pH-dependent conversion may be a potentially useful approach to reduce the extent of first-pass metabolism of the vulnerable phenol group.