Pharmacokinetics of dapsone and amino acid prodrugs of dapsone

N. L. Pochopin, W. N. Charman, V. J. Stella

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Amino acid amides of dapsone (DDS), a primary aromatic amine, have been synthesized as water-soluble, chemically stable prodrugs that target peptidase enzymes for cleavage to the parent drug in vivo. The pharmacokinetics of DDS, monoacetyldapsone (MADDS; a known metabolite), and various L- and D-amino acid derivatives of DDS were investigated in New Zealand white rabbits after intravenous administration. DDS and MADDS exhibit reversible kinetics and establish a pseudoequilibrium in vivo. In this study, the analytical procedure assayed for both DDS and MADDS, with formation of MADDS accounting for ~25% of the clearance of DDS. The L-amino acid derivatives of DDS were rapidly (t( 1/2 ) < 2 min) and quantitatively converted to DDS after intravenous administration to rabbits. Data are consistent with conversion of the L-amino acid amides to DDS by the action of stereospecific aminopeptidase enzymes and suggest that they would be good prodrug candidates. The corresponding D-amino acid derivatives were also quantitatively converted to DDS, but the half-lives ranged from 30 to 60 min. The specific mechanism for conversion of the D-amino acid amides to DDS is unknown.

Original languageEnglish
Pages (from-to)770-775
Number of pages6
JournalDrug Metabolism and Disposition
Issue number5
Publication statusPublished - 1 Jan 1994
Externally publishedYes

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