The use of cimetidine to reduce dapsone‐dependent methaemoglobinaemia in dermatitis herpetiformis patients.

Abstract

1. We have attempted to reduce dapsone‐dependent methaemoglobinaemia formation in six dermatitis herpetiformis patients stabilised on dapsone by the co‐administration of cimetidine. 2. In comparison with control, i.e. dapsone alone, methaemoglobinaemia due to dapsone fell by 27.3 +/‐ 6.7% and 26.6 +/‐ 5.6% the first and second weeks after commencement of cimetidine administration. The normally cyanotic appearance of the patient on the highest dose of dapsone (350 mg day‐ 1), underwent marked improvement. 3. There was a significant increase in the trough plasma concentration of dapsone (2.8 +/‐ 0.8 x 10(‐5)% dose ml‐1) at day 21 in the presence of cimetidine compared with control (day 7, 1.9 +/‐ 0.6 x 10(‐5)% dose ml‐1, P less than 0.01). During the period of the study, dapsone‐mediated control of the dermatitis herpetiformis in all six patients was unchanged. 4. Trough plasma concentrations of monoacetyl dapsone were significantly increased (P less than 0.05) at day 21 (1.9 +/‐ 1.0 x 10(‐5)% dose ml‐ 1) compared with day 7 (1.6 +/‐ 0.9 x 10(‐5)% dose ml‐1:control). 5. Over a 12 h period, 20.6 +/‐ 8.9% (day 0) of a dose of dapsone was detectable in urine as dapsone hydroxylamine. Significantly less dapsone hydroxylamine was recovered from urine at day 14 (15.0 +/‐ 8.4) in the presence of cimetidine, compared with day 0 (control: P less than 0.05). 6. The co‐administration of cimetidine may be of value in increasing patient tolerance to dapsone, a widely used, effective, but comparatively toxic drug.

Efficacy of Dapsone in the Treatment of Pemphigus Vulgaris: A Single-Center Case Study

“…Cimetidine, a histamine H 2 receptor antagonist, can reduce the N-hydroxylation of dapsone [31] . This reduction was demonstrated to result in more than a 25% decrease in methemoglobinemia in patients who received dapsone for the treatment of dermatitis herpetiformis [32] . The coadministration of cimetidine can be considered in selected patients, especially when high doses of dapsone are needed.…”

Enzyme-Mediated Protein Haptenation of Dapsone and Sulfamethoxazole in Human Keratinocytes: II. Expression and Role of Flavin-Containing Monooxygenases and Peroxidases

“…Various hepatic enzymes, such as the cytochrome P450-dependent monooxygenases, cyclooxygenases, and PRXs, have been shown to be active in SMX and DDS metabolism (Cribb et al, 1990;Mitra et al, 1995;Goebel et al, 1999;Winter et al, 2000). Although survival of reactive metabolites during transit from liver to skin has not been demonstrated, evidence suggests the presence of the hydroxylamine metabolites of these drugs in plasma and urine after therapeutic doses (Coleman et al, 1992;Mitra et al, 1995;Winter et al, 2000). It is noteworthy that the concentration of SMX in skin blisters of subjects receiving this drug achieves 82% of those observed in plasma (Krolicki, 2002).…”

Dapsone Therapy for Pustular Psoriasis: Case Series and Review of the Literature

“…Studies on vitamin C doses that are >1 m M (attainable by intravenous administration) have found methemoglobinemia reduction; however, oral administration cannot exceed 200 µ M because of the gastrointestinal absorption [28,29,30]. Studies on the cytochrome P450 inhibitor cimetidine in rats and small studies on humans have found that concurrent administration reduces levels of methemoglobinemia [31,32]. In humans, this reduction was demonstrated with a dose of cimetidine 8-hourly, with 800 mg/h prior to the dapsone dose and 2 subsequent doses of 400 mg each, administered for 3 weeks (but not longer than 12 weeks) [33].…”