P.2.c.024 Impact of polymorphism of cytochrome P450 2D6 on clinical effects of mirtazapine

Abstract

Drug hepatotoxicity is partially determined by genetic factors involved in drug metabolism, which may involve the debrisoquine oxidation polymorphism mediated by cytochrome (CYP) 2D6. The purpose of this study was to assess the relationship between drug hepatotoxicity and another genetic polymorphism of drug oxidation, namely that of S-mephenytoin metabolism mediated by CYP2CMP. Mephenytoin hydroxylation capacity was assessed by a hydroxylation index in 24 patients with drug-induced hepatitis and in 23 healthy controls. Hydroxylation index was calculated as the ratio of S-mephenytoin dose to the (0–10 h) urinary excretion of 4-hydroxymephenytoin after oral administration of 100 mg racemic mephenytoin. The test was performed following the patient's recovery. In three patients, hepatitis was related to Atrium®, a drug containing phenobarbital, febarbamate and difebarbamate. The mean hydroxylation index (±SD) value in patients with Atrium® hepatitis (12.4±8.3) was markedly higher than that found in healthy controls (1.8±0.4) or in patients with other drug-induced hepatitis (2.5±3.3). Mean hydroxylation index values were similar in the two latter groups. Considered individually, oxidation capacity was low (hydroxylation index >9) in two of the three patients with Atrium® hepatitis and intermediate (hydroxylation index between 4 and 9) in the third patient. In contrast, all 23 healthy subjects exhibited a high oxidation capacity (hydroxylation index <4). In the 21 patients with other drug-induced hepatitis, oxidation capacity was high in 19 subjects, intermediate in one subject with chlorpromazine hepatitis, and low in one subject with dapsone hepatitis. These data suggest that atrium® hepatotoxicity may be associated with mephenytoin oxidation deficiency, whereas this does not appear to be a factor in the hepatotoxicity of many other drugs.