Possible association between poor metabolism of mephenytoin and hepatotoxicity caused by Atrium, a fixed combination preparation containing phenobarbital, febarbamate and difebarbamate.
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.(ABSTRACT TRUNCATED AT 250 WORDS)[1]References
- Possible association between poor metabolism of mephenytoin and hepatotoxicity caused by Atrium, a fixed combination preparation containing phenobarbital, febarbamate and difebarbamate. Horsmans, Y., Lannes, D., Pessayre, D., Larrey, D. J. Hepatol. (1994) [Pubmed]
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