Nobuharu Kakeya

Synthesis and relation between physicochemical properties and oral absorption of 7-O-acylmandelamido-3-methyl-3-cephem-4-carboxylic acids☆

O-Acylates (IV) of 7-d-mandelamido-3-methyl-3-cephem-4-carboxylic acid (I) were prepared and their physicochemical properties and oral absorption in mice were measured to search for an orally active cephalosporin having a 7-acyl group other than phenylglycine analogs. The pKa and log P values of IB were 2.8 and 1.02–3.54, respectively, and IV were hydrolyzed to the parent drug (I) in a homogenate of mouse small intestine. The esters, IVb (propionate), IVc (n-butyrate), IVd (i-butyrate), and IVe (n-valerate) produced higher plasma levels of I and improved relative bioavailability (BA) than those observed after oral dosing with I. Among the esters, IVe showed the highest BA, 40.3%. Good correlations between log P and log BA and between log P and peak plasma level (log Cmax) were observed. The esters resulting in good BA have log P values similar to those of orally active penicillins having an acyl group other than phenylglycine analogs, e.g. propicillin (PP-PC) and phenethicillin (PE-PC). The present study indicates that an ester prodrug of the parenteral cephalosporin having a 7-acyl group other than phenylglycine analog can be absorbed effectively through the gastrointestinal tract when log P and the pKa values are in a selected range.