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.

4-Oxo-β-lactams (Azetidine-2,4-diones) Are Potent and Selective Inhibitors of Human Leukocyte Elastase

“…These were observed to have reasonable stability under physiological conditions, compound 6a being the most stable with a half-life of 37 h (Table ). This value is well within the range of hydrolytic half-lives (pH 7.4 and 37 °C) reported for cephalosporin sulfones, , N -acyl- and N -sulfonylazetidin-4-ones, and other β-lactams but lower than those reported for N -carbamoylazetidin-4-ones . The product of hydrolysis in all cases was the corresponding N -aryl-2,2-diethylpropanedioic acid monoamide 8 (Scheme ), which implies that departure of the benzothiazolylthiol leaving group is not an efficient process under physiological conditions.…”

“…In human plasma, compounds 6a , 6e , and 6i were rapidly hydrolyzed, with half-lives ranging from 0.2 to ∼2 h. 4-Oxo-β-lactams are thus susceptible to plasma enzymes, in line with the pronounced susceptibility of neutral β-lactam derivatives (e.g., penicillin esters) to undergo plasma-catalyzed hydrolysis of the β-lactam ring . Overall, these results indicate that although the oral availability of 4-oxo-β-lactams might be limited by compound stability, these inhibitors might be suitable for aerosolization, a route of administration commonly employed for other agents used for lung diseases .…”

Syntheses and hydrolysis of basic and dibasic ampicillin esters tailored for intracellular accumulation

“…Indeed, the ester was inactive not because its carboxylate function could not be regenerated, but because its b-lactam ring was cleaved ®rst. 6 Ring opening and ester cleavage are competitive reactions. The quickest process wins the race.…”

Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

“…The hydrolysis rates and stability can be tuned by introducing steric bulk at the acyl position (R 2 of I ) or carbonate position (R 2 for II ) or the acetal linkage (R 1 ) of I or II (Figure 1). Simple esters of β-lactams are ineffective since they enhance the hydrolytic lability of the β-lactam carbonyl 22 and/or are incompletely hydrolyzed as found in cephalosporin and carbapenem β-lactams. 20 Several acyloxyalkyl esters of carbapenems have been reported in an effort to improve the bioavailability of the parent carbapenem.…”