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.

Chemical and physical stability of chimeric L6, a mouse-human monoclonal antibody.

Chimeric L6 is a mouse-human monoclonal antibody specific for tumor cell-associated antigens. The factors affecting the physical and chemical stability of chimeric L6 were assessed at elevated temperatures (30-60 degrees C) and by multiple freezing and thawing. Three routes of degradation were observed: chemical degradation to smaller molecular weight species, irreversible aggregation, and formation of a reversible dimer. The specific pathway depended on the stress condition applied and the pH, with maximal overall stability to both thermal stress and multiple freezing/thawing observed at about pH 5.5. Other factors including antibody concentration, buffer concentration, NaCl concentration, and agitation had minimal influence on the stability. Commonly used sugars, polyhydric alcohols, and amino acids effectively prevented freeze/thaw-induced aggregation.