Metabolism and interactions of antileprosy drugs.

Leprosy is a chronic infectious disease caused my Mycobacterium leprae that primarily affects peripheral nervous system and extremities and is prevalent in tropical countries. Treatment for leprosy with multidrug regimens is very effective compared to monotherapy especially in multibacillary cases. The three major antileprosy drugs currently in use are 4, 4'-diaminodiphenyl sulfone (DDS, dapsone), rifampicin, and clofazimine. During multidrug therapy, the potent antibiotic rifampicin induces the metabolism of dapsone, which results in decreased plasma half-life of dapsone and its metabolites. Furthermore, rifampicin induces its own metabolism and decreases its half-life during monotherapy. Rifampicin upregulates several hepatic microsomal drug-metabolizing enzymes, especially cytochrome P450 (CYP) family that in turn induce the metabolism of dapsone. Clofazimine lacks significant induction of any drug-metabolizing enzyme including CYP family and does not interact with dapsone metabolism. Rifampicin does not induce clofazimine metabolism during combination treatment. Administration of dapsone in the acetylated form (acedapsone) can release the drug slowly into circulation up to 75 days and could be useful for the effective treatment of paucibacillary cases along with rifampicin. This review summarizes the major aspects of antileprosy drug metabolism and drug interactions and the role of cytochrome P450 family of drug metabolizing enzymes, especially CYP3A4 during multidrug regimens for the treatment of leprosy.

The effect of acetylation and deacetylation on the disposition of dapsone and monoacetyl dapsone hydroxylamines in human erythrocytes in-vitro.

The fates of both dapsone and monoacetyl hydroxylamine have been studied in terms of acetylation and deacetylation within the human erythrocyte in-vitro. A comparison between the two metabolites showed equipotency in methaemoglobin generation at 15 min, although the monoacetyl derivative was the more rapid haemoglobin oxidizer. Within the erythrocytes, both dapsone and monoacetyl hydroxylamines were found to undergo acetylation, deacetylation and diacetylation. Of the inhibitors of acetylation studied, folate caused an increase in methaemoglobin formation associated with both metabolites, which led to a rise in both acetylated and non-acetylated amine formation. Amethopterin was associated with a rise in hydroxylamine mediated methaemoglobin formation which coincided with a fall in acetylated products. It is possible that the hydroxylamines undergo erythrocytic processes of acetylation and deacetylation before methaemoglobin-mediated reduction to their respective amines.

Blood dapsone levels in leprosy patients treated with acedapsone.

The metabolism of the repository drug acedapsone (DADDS,4,4'-diacetyldiaminodiphenyl sulfone) was studied in 15 individuals receiving 225 mg of DADDS, intramuscularly for a period of 75 days. Plasma levels of DDS were determined on the 2nd, 7th, 15th, 30th, 60th and 75th day after administration of the drug by spectrophoto-fluorometric technique. The mean peak levels of DDS (85.36 ng/ml) were noticed on 7th day followed by a gradual decrease in DDS concentration. The mean half-life level (44.53 ng/ml) of DDS were observed around the 15th day. The mean DDS level for the entire period of observation after one dose was 41.95 ng/ml. On the 75th day, the DDS level reached the minimum value of 14.76 ng/ml which was still about 5 times more than the minimal inhibitory concentration (MIC) level of DDS against M. leprae (3 ng/ml). The results are discussed.

Activity and effective serum level of repository sulphones (DADDS) in lepromatous leprosy.

35 cases of lepromatous leprosy were studied to evaluate the effective blood level and long depot action of acedapsone (DADDS). It was revealed that serum level of this drug is maintained well above the minimum inhibitory concentration upto 60 days following single intramuscular injection. No significant untoward effects of the drug were encountered except one case of Erythema Nodosum Leprosum and six patients with mild reactional symptoms in the form of fever and arthralgia.

Acedapsone treatment of leprosy patients: response versus drug disposition.

In 22 lepromatous Filipino patients receiving their first injection of 225 mg acedapsone (DADDS), dapsone (DDS), and monoacetyl DDS (MADDS) were present in plasma in approximately equal quantities. Peak levels of parent drug, DDS, and MADDS occurred between 22 and 35 days. The half-times of disappearance (T1/2) from plasma were 43 days for DDS and MADDS and 46 days for DADDS. Acetylator phenotyping with sulfamethazine (SMZ) and DDS showed that 17 patients were rapid and 5 patients were slow acetylators. Correlations between acetylation of SMZ and DDS after DDS and of acetylation of DDS after DDS and DADDS were highly significant. However, acetylation of DDS after DADDS did not differentiate the patients into acetylator phenotypes. The T1/2 of DDS after DDS in the patients was directly related to the minimum levels of DDS at 77 days after DADDS treatment. These minimum levels were 8-fold higher than the minimum inhibitory concentration (MIC) of DDS for Mycobacterium leprae in mice and rats, but not all patients responded satisfactorily. No relationship could be demonstrated between the bacteriologic response and any of the pharmacologic parameters examined in these Filipino patients. In a companion study, minimum levels of DADDS, MADDS, and DDS were determined in 447 leprosy patients of all disease types from the Karimui District of Papua New Guinea who had been receiving 225 mg DADDS every 70 to 80 days for the past 5 years. All patients exhibited DDS levels above the MIC of DDS for M. leprae, no significant differences in plasma sulfone levels were found among disease types, no relationship between rate of healing in paucibacillary patients and sulfone levels were found, and type of response in multibacillary patients and sulfone levels were unrelated. No substantial accumulation of the sulfones in the Karimui patients receiving continuous therapy with DADDS for 5 years was indicated from a comparison with the levels in the Filipino patients following a single injection of DADDS.