Biopharmaceutical Study on the Oral and Rectal Administrations of Enamine Prodrugs of Amino Acid-like β-Lactam Antibiotics in Rabbits

概要

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Enamine derivatives of ampicillin, amoxicillin and cephalexin were prepared by reacting the drugs with ethyl acetoacetate under mild conditions. The enamine structures of these compounds were determined by measurements of the nuclear magnetic resonance (NMR) spectra. The compounds were easily hydrolyzed in vitro in aqueous solution and the rate accelerated as the pH was lowered. The determination of Rf and rate of migration of the enamine derivatives showed that the enamine derivatives were more lipophilic than the corresponding parent drugs. The bioavailabilities of these prodrugs were studied following oral and rectal administrations in rabbits. The bioavailabilities of the parent antibiotics were not improved by the oral administration of the corresponding enamine prodrugs. However, the bioavailabilities of ampicillin and amoxicillin were markedly improved by rectal administration of the corresponding enamine prodrugs. The improved bioavailabilities exceeded those of the parent drugs following oral administration in rabbits. The enamine prodrug of ampicillin was found to promote the rectal absorption of ampicillin upon coadministration of these two drugs. Thus, enamine derivatives of amino acid-like β-lactam antibiotics appear to be interesting candidates for possible clinical use as prodrugs for rectal administration.
公益社団法人日本薬学会の論文
1981-07-25