Acetylation and N-hydroxylation of dapsone were evaluated in drug-free, non-smoking, normal subjects and subjects with cirrhosis (n = 7 for each group) after oral administration of 100 mg dapsone. Acetylation was not correlated with oral dapsone clearance or reduced in cirrhosis (0.37 +/- 0.43 versus 0.52 +/- 0.32). Fractional metabolic clearance of dapsone to its hydroxylamine was associated with dapsone oral clearance (r = 0.96, p less than 0.001, n = 14). In patients with cirrhosis, liver disease was associated with a trend to reduction in oral clearance (22%) and metabolic clearance of dapsone (48%). Protein binding was minimally reduced by cirrhosis (73% +/- 1% versus 69% +/- 3% in patients with cirrhosis (p less than 0.02). The dapsone recovery ratio was validated as a phenotypic index of the metabolic clearance of dapsone (r = 0.74, p less than 0.05). In an extended comparison of 14 patients with cirrhosis to 70 control subjects, cirrhosis was associated with reductions of 28% in dapsone recovery ratio (p less than 0.001), and 37% in acetylation ratio (p less than 0.01). Neither dapsone recovery ratio nor acetylation ratio correlated with Pugh Score, conventional liver function tests, indocyanine green clearance, or phenotypic measures of S-mephenytoin hydroxylase or debrisoquin hydroxylase activity. We conclude that cirrhosis is associated with minor changes in dapsone disposition and that dosage modification is not required. In addition, there is evidence that cirrhosis has a selective influence on activity of individual isozymes of cytochrome P450.

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Debrisoquine hydroxylase activity has been attributed to CYP2D6 and poor metabolizers of debrisoquine have a reduced relative risk of developing aggressive bladder cancer. Production of a proximate carcinogen could occur in liver or bladder mucosa. However, it is not known if CYP2D6 is expressed in human bladder mucosa. In vivo whole body debrisoquine hydroxylase activity was measured as the debrisoquine recovery ratio (DBRR) following single dose oral administration of debrisoquine (10 mg) in 10 normal subjects and 20 patients with bladder cancer prior to diagnostic cystoscopy. Semi-quantitative PCR was used to measure mRNA for CYP2D6 in bladder tissue obtained at cystoscopy. Of the 30 subjects, three were phenotypically and genotypically poor metabolizers. Among the extensive metabolizers, there were extensive intersubject variations in DBRR. A 10-fold variation in CYP2D6 mRNA levels was observed in bladder tissue. There was a highly significant association between DBRR and CYP2D6 mRNA expression (r2 = 0.702, P < 0.001). These results demonstrate the presence of CYP2D6 mRNA in bladder mucosa. Furthermore, they are consistent with debrisoquine hydroxylation being mediated by CYP2D6 and suggest that differences in mRNA concentration are rate limiting for enzyme activity and that bladder mucosal regulation reflects total body regulation for this enzyme. The expression of CYP2D6 in bladder mucosa suggests that this enzyme could be involved in the local production of a proximate carcinogen in this tissue and contribute to the pathogenesis of bladder cancer in man.