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

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Summary

  1. 1.

    During the incubation of Dapsone1 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. 2.

    Liver microsomes of rabbits catalyzed the N-hydroxylation of DDS in the presence of O2 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. 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. 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.

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  1. Pharmakologisches Institut der Universität Tübingen, Tübingen, Germany

    H. Uehleke & S. Tabarelli

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  1. H. Uehleke
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Uehleke, H., Tabarelli, S. N-hydroxylation of 4,4′-diaminodiphenylsulphone (Dapsone) by liver microsomes, and in dogs and humans. Naunyn-Schmiedeberg's Arch. Pharmacol. 278, 55–68 (1973). https://doi.org/10.1007/BF00501863

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