Prodrugs of 5-fluorouracil. V. 1-Alkoxycarbonyl derivatives as potential prodrug forms for improved rectal or oral delivery of 5-fluorouracil.
The hydrolysis and physicochemical properties of seven 1-alkoxycarbonyl derivatives of 5-fluorouracil were studied to assess their potential as prodrugs with the aim of enhancing the delivery characteristics of the parent drug. All derivatives were hydrolyzed to quantitatively yield 5-fluorouracil. The pH-rate profiles for the hydrolysis were measured. The rates of hydrolysis were markedly accelerated in the presence of plasma, affording half-lives of hydrolysis less than 4 min in 80% human plasma. The derivatives were more lipophilic than 5-fluorouracil but the aqueous solubility was only slightly reduced or, for one derivative, even greater than that of 5-fluorouracil. A preliminary absorption study in rabbits showed an absolute bioavailability of 5-fluorouracil of 100% following rectal administration of 1-(butoxycarbonyl)-5-fluorouracil as compared with no absorption following administration of 5-fluorouracil itself. The potential utility of the prodrug derivatives to enhance the oral and/or rectal delivery of the parent drug is suggested.
D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002621:Chemistry; D004355:Drug Stability; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011817:Rabbits; D012995:Solubility; D013488:Suppositories
D013488:Suppositories; D005472:Fluorouracil