Drug-protein conjugates--VIII. The metabolic fate of the dinitrophenyl hapten conjugated to albumin.
Dinitrofluorobenzene has been used as a model chemically reactive metabolite to investigate factors which determine the fate of drug-protein conjugates formed in vivo. The disposition of homologous and heterologous albumin conjugated with 3H-dinitrophenyl groups (3H-DNP) has been investigated in the male Wistar rat. After intravenous administration, conjugates were cleared from plasma, predominantly through the liver, and the hapten was excreted into bile and urine as the novel amino acid derivative N2-acetyl-N6-DNP-lysine. It is assumed that the product arises from lysosomal hydrolysis of the conjugate, followed by N-acetylation, since its biliary excretion was significantly reduced in animals pretreated with suramin, an inhibitor of lysosomal proteolysis. The clearance of DNP-albumin conjugates was dependent upon the degree of conjugation; conjugates with an epitope density of greater than 20 had a short (ca. 1 hr) half-life. In a second study, the disposition of DNP-autologous protein conjugates was monitored in the rabbit over 21 days. The plasma concentration-time profile of the serum conjugates indicated that clearance was dependent upon non-immune mechanisms and that intravenous administration of DNP-serum protein conjugates did not elicit an anti-DNP response.
D000818:Animals; D001646:Bile / Q000378:metabolism; D004136:Dinitrobenzenes / Q000378:metabolism*; D004705:Endocytosis; D006241:Haptens; D006801:Humans; D008297:Male; D009578:Nitrobenzenes / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000378:metabolism*; D014316:Tritium
D004136:Dinitrobenzenes; D006241:Haptens; D009578:Nitrobenzenes; D012709:Serum Albumin; D014316:Tritium