Disposition of Dapsone and Monoacetyldapsone in Rats

Abstract

From the time that the noncultivable Mycobacteriurn leprae was grown in mouse foot pads (1, 2), this rodent has been used widely for testing the activity of drugs against M . Zeprae and as the basis for laboratory studies of human leprosy (3). By the mouse foot pad test system, dapsone (4,4'-diaminodiphenyl sulfone, DDS), the most widely used drug for the treatment of human leprosy (4), was found to inhibit multiplication of M . Zeprae in mice exhibiting plasma levels of 1-10 ng DDS/ml ( 5 ) . The lower limit of this range was obtained by extrapolation and must be considered tentative.Previously, the disposition of DDS in mice (6) and human subjects (7) was examined to assess the value of the mouse as a model of man. Those studies showed that mice differed markedly from man in regard to the acetylation of DDS to monoacetyl DDS (MADDS), the deacetylation of MADDS to DDS, and the rate of clearance of DDS from the circulation. The only similarity between the two species was the extent of binding of DDS by plasma proteins. Thus, the mouse proved of little value as a model of man for studies on the disposition of DDS.A further disadvantage of the mouse test system is the limited multiplication of M . Zeprae in the foot pad. Other rodents have been tested (8, 9), but were not found to be superior to the mouse. More recently, Buffalo and Lewis rats that were neonatally thymec-

The Effect of Pregnenolone 16α-Carbonitrile on the Pharmacokinetics and Metabolism of Dapsone in Rats

“…The formed MADDS can then be converted back to dapsone by the deacetylase simultaneously. This interconversion has been found in rats (Gordon et al 1975), rabbits (Pochopin et al 1994) and man (Gelber et al 1971). Classical pharmacokinetic analysis provides limited insight into the individual metabolic pathways involved, because the interconversion process and elimination of metabolite also affect the apparent pharmacokinetic parameters calculated by the traditional methods.…”

Comparative effects of sulfones and rifampin on growth of Mycobacterium lepraemurium in macrophage diffusion chamber cultures

“…The most effective widely used antileprosy drugs today are dapsone (4,4'-diaminodiphenyl sulfone, DDS), the repository form of DDS, acedapsone (4,4'-diacetamidodiphenyl sulfone, DADDS), and rifampin (7,8,11,12,14). Studies in rats and humans have shown that monoacetyl DDS (4-amino-4'-acetamidodiphenyl sulfone, MADDS) is the principal circulatory metabolite of DDS and DADDS (3,4,7), but no direct tests of the possible antileprotic activity of MADDS or DADDS have been performed with M. lepraemurium or M. leprae.…”

“…Studies in rats and humans have shown that monoacetyl DDS (4-amino-4'-acetamidodiphenyl sulfone, MADDS) is the principal circulatory metabolite of DDS and DADDS (3,4,7), but no direct tests of the possible antileprotic activity of MADDS or DADDS have been performed with M. lepraemurium or M. leprae. Levy et al (5) found that MADDS was equal in activity to DDS in mice infected with M. leprae, but the observation that the mice deacetylated MADDS completely to DDS made it impossible to decide whether MADDS exhibited inherent antileprotic activity.…”