| The use of L-amino acid amides as soluble derivatives of poorly water-soluble primary aromatic amine drugs was investigated. It was envisaged that these prodrugs would have sufficient chemical stability for development of aqueous formulations with adequate shelf-lives, and once administered intravenously would rapidly and quantitatively revert to the parent drug through the action of peptidase enzymes. Prodrugs of two model drugs, prazosin and dapsone, were assessed in order to determine the effect of the amino acid promoiety on physicochemical and enzymatic behavior.;Prodrugs of dapsone containing Gly, L-Ala, L-Leu, L-Lys and L-Phe promoieties exhibited significantly better water solubility as HCl salts than the parent drug, and rates of chemical degradation at elevated temperature suggested that stability at room temperature should be adequate. In vitro in the presence of peptidase enzymes and in plasma and blood the L-aminoacyl and glycyl prodrugs of dapsone were hydrolyzed to the parent drug although absolute rates varied among the different derivatives and depended on the enzyme used. Compounds containing D-amino acid residues were stable to the enzymes in vitro. However, in vivo all derivatives were quantitatively converted to dapsone although the rates of hydrolysis of the L-amino acid derivatives were much faster than the D-isomers. No distinctions were noted in the pharmacokinetics of the various L-amino acid amides and therefore choice of a specific derivative as a prodrug would depend on other factors such as solubility or ease of synthesis.;Amino acid amides of prazosin showed less promise as prodrugs due to facile chemical degradation via an intramolecular rearrangement. Investigation of the degradation process revealed the involvement of the amino group of the amino acid. Derivatization of this functional group to a carbamate resulted in a derivative that did not undergo this rearrangement, and after i.v. administration to dogs rapidly delivered 70% of the parent drug. However, a limiting characteristic of this prodrug was hydrolytic lability of the amide bond in aqueous solution, which could limit the application of this approach to similar heteroaromatic amine drugs. |
