Short-Chain Alkyl Esters of L-Dopa as Prodrugs for Rectal Absorption

Abstract

The bioavailability of L-dopa following rectal administration of a series of short-chain alkyl esters of L-dopa was determined in rats and dogs. The esters were stable (>360 min) to hydrolysis in physiological buffer. In vitro enzymatic hydrolysis of the esters in plasma was species dependent, with the hydrolytic rate being faster in rat plasma (t _1/2 < 5 min) than dog plasma (t _1/2 = 68–181 min) or human plasma (t _1/2= 96–238 min). In vivo hydrolysis in dogs, as indicated by the L-dopa plasma profile following intravenous administration of the esters, was very rapid (high extravascular esterase activity). Significant L-dopa bioavailability was observed in rats following rectal administration of the methyl (46%), ethyl (14%), isopropyl (48%), butyl (100%), and 4-hydroxybutyl (13%) esters of L-dopa (rectal L-dopa absorption, <5%). In dogs, significant L-dopa bioavailability was also observed for the methyl (28%), isopropyl (30%), butyl (32%), and 4-hydroxybutyl (34%) esters of L-dopa in the presence of carbidopa. The data indicate that these highly water-soluble (>600 mg/ml) esters of L-dopa are potential candidates for controlled-release rectal delivery systems designed to provide more constant plasma L-dopa levels.