Renal and Biliary Disposition of Dapsone in the Dog

Abstract

Dapsone (4,4'-diaminodiphenylsulfone [DDS]) was administered intravenously to anesthetized dogs; urine was collected, heparinized venous blood was obtained, and bile was collected from some of the dogs. A constant infusion of inulin was maintained, and isosmotic or hypoosmotic fluids were administered. Dogs were studied under conditions of standardized, increased or decreased urine flow, and before and after plasmapheresis. Plasma, urine, and bile samples were analyzed for DDS and DDS conjugates; the degree of binding of DDS by plasma proteins was also determined. The renal clearances of inulin and DDS were calculated. No monoacetyldapsone (MADDS) was detected in the plasma, and only negligible quantities were found in the urine. Small quantities of DDS and DDS conjugates were detected in the bile in 4 h following the dose. Between 10 and 30% of the administered drug could be identified as DDS plus DDS conjugates in the urine in 8 h after the dose. Renal clearance of unbound DDS was proportional to the urine flow rate, and the clearance ratio of DDS to inulin approached the same maximal value as that for urea. Although the rate of urinary excretion of DDS conjugates was the same in the dog as in man, the rates of excretion of DDS and of DDS plus DDS conjugates were greater in the dog than in man, suggesting that the acetylation of DDS to MADDS by man but not by the dog and the greater degree of plasma protein binding of DDS and MADDS by man account for the longer half-time of disappearance of DDS in man compared to that in the dog.In recent years, the disposition in man of dapsone (4,4'-diaminodiphenylsulfone, DDS), the drug most widely used in the treatment of leprosy patients (19), has been the subject of intensive investigation. The drug is acetylated polymorphically, its half-time of disappearance (t½) from the plasma is quite long, it is extensively metabolized, and both DDS and its acetylated metabolite (4-amino-4'-acetamidodiphenylsulfone, MADDS) are strongly bound by plasma proteins. MADDS represented 52% of the total of plasma DDS plus MADDS among nine rapid acetylators of isoniazid and sulfamethazine, whereas the corresponding value for 10 slow acetylators of these drugs was 17% (4). (4). DDS was found to be 70 to 81% and MADDS 97 to 100% bound by the plasma proteins of four rapid and six slow acetylators of DDS, and the degree of binding did not appear to be related to the acetylator phenotype (2). Finally, a study of the binding of DDS and MADDS to human serum albumin (18) showed the binding constant of MADDS to be quite large (2.35 x 105 liters/ mol), about 10 times larger than that of DDS. Another study reported MADDS to be 20 to 25 times more tightly bound than was DDS (5).A survey of other mammalian species demonstrated that, whereas DDS is extensively bound by the plasma proteins of all species studied (1),