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Phenyl carbamates of amino acids as prodrug forms for protecting phenols against first-pass metabolism

1992; Elsevier BV; Volume: 81; Issue: 2-3 Linguagem: Inglês

10.1016/0378-5173(92)90017-v

1873-3476

J. G. Hansen, Niels Mørk, Henning Bundgaard,

Organophosphorus compounds synthesis

Various phenyl carbamate esters derived from amino acids, a dipeptide and amino acid esters and amides were prepared and assessed as potential prodrugs 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 were rather stable in weakly acidic solutions but were hydrolyzed more facilely at physiological pH, the rates increasing greatly with decreasing pKa value of the phenol. The hydrolysis of the amino acid carbamates was not catalyzed significantly by liver or intestinal wall enzymes but human plasma showed a marked catalytic effect. This latter effect could predominantly be ascribed to a catalysis exhibited by serum albumin. These results suggest that derivatization of phenolic drugs to form α-amino acid or dipeptide carbamate esters may be a potentially useful prodrug approach to reduce the extent of first-pass metabolism of the vulnerable phenol group.