Prodrugs of cimetidine with increased lipophilicity: N-acyloxymethyl and N-alkoxycarbonyl derivatives.

Bioreversible derivatization of cimetidine to afford more lipophilic prodrugs was performed by N-acyloxymethylation of its imidazole group as well as by N-acylation with various chloroformates. Both the N-acyloxymethyl and N-alkoxycarbonyl derivatives were readily hydrolyzed to cimetidine in human plasma and in rat liver homogenate. The pH-rate profiles for the hydrolysis of the derivatives were derived at 60 degrees C. The derivatives were all more lipophilic than the parent drug as determined by partition experiments in octanol-aqueous buffer systems. In vitro studies using the modified Ussing-chamber technique showed that some derivatives possessed increased permeability coefficients for the transport across the rat jejunum relative to cimetidine. The results obtained suggest that these derivatives may be useful to improve the biomembrane transport characteristics of the hydrophilic cimetidine.