Comparative analysis of the effect of dapsone on liver secretory function in female and male rats

VEGGI, LUIS M.; CROCENZI, FERNANDO A.; ROMA, MARCELO G; PELLEGRINO, JOSÉ M; SÁNCHEZ POZZI, ENRIQUE J; CATANIA, VIVIANA A.; LUQUITA, MARCELO G.; MOTTINO, ALDO D.

Congreso; XXII Reunión Anual de la Sociedad Argentina de Farmacología Experimental.; 2000

Dapsone (D), a drug used in the treatment of leprosy, malaria, etc, produces methemoglobinemia, mediated by the N-hydroxylated metabolite, and hepatotoxicity. In the rat, methemoglobinemia is present in male but not females, because of gender differences in N-hydroxylation. To determine whether the hepatotoxic effect of D is associated to methemoglobinemia, we studied the effect of D on the secretory function in rats from both sexes. D was administered i.p. for 4 days (60 mg/Kg/day). Control rats (C) were treated with the solvent. We measured methemoglobinemia, bile flow and secretory rate, pool size and composition of bile salts in bile. The % of methemoglobinemia in plasma increased in females (D 5.9±1.4 vs C 3.9±0.3, p<0.05) but in lesser degree than in males (D 38.1±5.4 vs C 2.0±0.2, p<0.05). Bile flow (microl/min/g liver) decreased in both females (D 1.96±0.17 vs C 2.38±0.23, p<0.05) and males (D 1.72±0.14 vs C 2.01±0.25, p<0.05). Bile salt secretory rate (nmol/min/g liver) also decreased in females (D 31.8±7.6 vs C 57.0±7.4, p<0.05) and males (D 45.3±5.4 vs C 64.4±9.2, p<0.05). Bile salt pool size (micromole/100 g rat) decreased in females (D 18.6±2.8 vs C 27.2±2.8, p<0.05) and males (D 21.7±3.8 vs C 33.2±6.4, p<0.05) and its hydrophobicity increased in females (D: -0.162±0.028 vs C: -0.370±0.071, p<0.05) and males (D: -0.171±0.001 vs C: -0.410±0.079, p<0.05). We conclude that side effect of D on liver secretory function is not associated to methemoglobinemia and consequently does not depend on the N-hydroylated metabolite.