Arnold J. Repta

Short-chain alkyl esters of L-dopa as prodrugs for rectal absorption.

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 (t1/2 < 5 min) than dog plasma (t1/2 = 68–181 min) or human plasma (t1/2= 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.

A comparison of oral and rectal absorption of L-dopa esters in rats and mice.

Short-chain alkyl esters of L-dopa were administered to rats and mice via oral and rectal routes. Plasma L-dopa esters and L-dopa were determined in the systemic and portal circulation by HPLC. A comparison of isopropyl, butyl, and 4-hydroxybutyl esters of L-dopa demonstrated significantly higher levels of the esters in both systemic and portal blood samples following rectal administration than following oral administration. In most cases, oral administration resulted in nondetectable (<0.01 µg/ml) levels of the esters in plasma. Correspondingly, the plasma levels of L-dopa itself were consistently higher following rectal administration. At very high oral doses (500 mg L-dopa equivalents/kg body weight), systemic plasma levels of the butyl ester could be detected (1.25 µg/ml at 10 min), which might indicate saturation of the esterase activity of the small intestine. These studies indicate that the systemic availability of L-dopa from short-chain alkyl esters of L-dopa may be best optimized by rectal administration, which avoids the relatively high esterase activity characteristic of the small intestine.