The use of esters as prodrugs for oral delivery of beta-lactam antibiotics.

It is apparent that the sequence of events that has been followed in the approach to the discovery and development of a new beta-lactam prodrug has been similar in many of the case histories we have studied and indeed similar to the approach we have followed. Initially, we select a suitable series of prodrug moieties, which either comprises totally novel structures or is deduced from the data bases available (bearing in mind reports of potential toxicity) or both. The successful preparation of these prodrugs and the studies undertaken to ensure they are of known purity and stability is not easy and, as would be expected, is the initial go/no-go decision. Usually, the next stage has involved the assessment of whether or not bioavailability of the parent molecule is increased after administration of the prodrug ester by gavage to laboratory animal species. The selection of which species to use has very often been made according to which has the most information available in those particular laboratories and in the literature. It is this process that can be dishearteningly misleading as was demonstrated in Table IV and Fig. 1. Increasing the range of animal species does not lead to a better ability to predict bioavailability in humans. Hydrolysis studies are important to ensure that any novel prodrug will hydrolyze in human tissues, and also in the clarification of why a particular prodrug is not performing as expected in animals. After selection, it is essential to determine where and how rapidly hydrolysis takes place in the animal species to be used for safety evaluation prior to the first bioavailability studies in humans. The assessment of absolute oral bioavailability has not always been undertaken. This would seem critical for studies in not only the selected animal species but also in humans. In the absence of these data it is difficult to judge whether oral uptake can be increased further by modifying the ester moieties and at the development stage to determine whether or not modifications in formulation could increase bioavailability. When the prodrug is being developed for an injectable beta-lactam already available for humans, there would be no problem, but it would be an important consideration during the development of an entirely novel beta-lactam antibiotic for which no parenteral data are available in humans. Animal data are not totally predictive. The development of prodrugs is not easy, as a consequence of species differences in the properties of the prodrug superimposed on those of the parent compound during the evaluation. However, technical advances have enabled us to assay concentrations more precisely, determine basic physicochemical properties more efficiently, understand absorption processes by the use of in vitro systems, and analyze data far more comprehensively by the use of ever-evolving computer software. The prodrug approach to increasing the oral bioavailability of beta-lactam antibiotics has provided clinically valuable agents and continues. Despite the inherent difficulties, knowledge gained over the years, of the relationships between physicochemical and biological properties of the parent compound and the intact prodrug ester, has contributed to the design of novel prodrugs and a number of novel auxiliaries have been developed.