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N-hydroxylation of 4,4′-diaminodiphenylsulphone (Dapsone) by liver microsomes, and in dogs and humans

Naunyn-Schmiedeberg's Archives of Pharmacology, ISSN: 0028-1298, Vol: 278, Issue: 1, Page: 55-68
1973
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1. During the incubation of Dapsone with rabbit liver microsomes, NADPH and bovine erythrocytes, rapid haemoglobin oxidation was observed. The velocity increased 2-3 times with liver microsomes of rabbits pretreated with phenobarbital. 2. Liver microsomes of rabbits catalyzed the N-hydroxylation of DDS in the presence of O and NADPH. The oxidation was dependent upon microsomal protein, DDS concentration, NADPH concentration and pH. The velocity of N-hydroxylation in incubates with microsomes from rabbits pretreated with phenobarbital was 2-3 times greater than the velocity with microsomes from control animals. Carbon monoxide and metyrapone inhibited the microsomal N-hydroxylation of DDS. The reaction must be included in the cytochrome P-450 dependent N-hydroxylations of primary arylamines. 3. In dogs, very low amounts of free DDS-NOH were found in the urine. 7-10% of an oral dose of 50 mg/kg DDS was excreted in the urine in the form of conjugated DDS-NOH liberated by acid hydrolysis (1 N HCl at 20°C). 4. Human volunteers receiving 200 mg DDS in capsules excreted 0.9-3.4% of the dose as free DDS-NOH and 6-20% as conjugated, acid labile DDS-NOH within 24h. After 72 h 5-7% of the dose was excreted as free DDS-NOH and 25-33% as conjugated, acid labile DDS-NOH. 80-90% of the DDS-NOH conjugates were liberated by treatment with 1 N HCl at 20°C. The total amount of conjugates in the urine was split by glusulase treatment under anaerobic condition. N-Hydroxy metabolites of DDS in the urine can reach 50% of the dose. Dapsone metabolism in humans is the first example in which N-hydroxylation is the principal metabolic pathway. © 1973 Springer-Verlag.

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