RT Journal Article
SR Electronic
T1 Pharmacokinetics of dapsone and amino acid prodrugs of dapsone.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 770
OP 775
VO 22
IS 5
A1 Pochopin, N L
A1 Charman, W N
A1 Stella, V J
YR 1994
UL http://dmd.aspetjournals.org/content/22/5/770.abstract
AB 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.