FACILE PLASMA-CATALYSED DEGRADATION OF PENICILLIN ALKYL ESTERS BUT WITH NO LIBERATION OF THE PARENT PENICILLIN

The methyl ester and some glycolamide esters of benzylpenicillin and ampicillin were shown to be rapidly degraded by human plasma at 37.degree. C with no parent penicillin being produced. The plasma-catalysed degradation which was also observed in rat plasma proceeds most likely through hydrolytic cleavage of the .beta.-lactam bonds of the penicillin esters and is suggested to be due to the presence of an ester-specific .beta.-lactamase in plasma. The results show that the failure of simple alkyl esters of penicillins to function as prodrugs is not due to a high enzymatic stability of the esters, as widely believed, but rather to a pronounced susceptibility to undergo hydrolytic cleavage of their .sbd.lactam ring in-vivo. Since double ester prodrugs of penicillins, such as the pivaloyloxymethyl ester of ampicillin, are readily hydrolysed in plasma to yield the parent penicillin although at a rate lower than e.g. that of inactivation of a simple methyl ester, the plasma enzyme apparently attacking the .beta.-lactam bond of penicillin esters appears to have a high degree of specificity for the ester structure.