The buccal absorption of ketobemidone, a strong narcotic analgesic, and various carboxylate and carbonate ester prodrugs was studied in rats. The compounds were administered in the form of aqueous solutions of pH 7.4. The absolute bioavailability of ketobemidone following buccal dosing was 26% whereas the bioavailability of ketobemidone following buccal administration of the prodrugs ranged from 37 to 98%. The highest bioavailability was obtained with the ethyl carbonate ester. An apparent parabolic correlation between bioavailability and lipophilicity of the compounds was seen. All esters were rapidly hydrolyzed to ketobemidone after both buccal and intravenous administration. The acute toxicity of the esters after i.v. administration to mice and rats was similar to that of the parent drug. It is concluded that esterification of the phenolic hydroxyl group in ketobemidone to give a more lipophilic prodrug may be a useful approach to improve the buccal delivery of this analgesic.