title: Facile plasma-catalysed degradation of penicillin alkyl esters but with no liberation of the parent penicillin.
abstract: The methyl ester and some glycolamide esters of benzylpenicillin and ampicillin were shown to be rapidly degraded by human plasma at 37 degrees 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 beta-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.
authors.affiliation: Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry AD, Copenhagen.
authors.forename: N M
authors.initials: NM
authors.lastname: Nielsen
authors.forename: H
authors.initials: H
authors.lastname: Bundgaard
mesh_terms: D001711:Biotransformation; D004952:Esters; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D010406:Penicillins / Q000097:blood*; D013329:Structure-Activity Relationship
chemical_list: D004952:Esters; D010406:Penicillins