Pharmacokinetics of dapsone and amino acid prodrugs of dapsone.
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 approximately 25% of the clearance of DDS. The L-amino acid derivatives of DDS were rapidly (t1/2 < 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.
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
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Pochopin
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Charman
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D000596:Amino Acids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003622:Dapsone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D006207:Half-Life; D007275:Injections, Intravenous; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits; D013056:Spectrophotometry, Ultraviolet
D000596:Amino Acids; D000890:Anti-Infective Agents; D011355:Prodrugs; D003622:Dapsone; C018965:monoacetyldapsone