SETTING: Japanese in-patients with pulmonary tuberculosis and normal liver function receiving treatment with isoniazid and rifampicin (INH + RMP). OBJECTIVE: To elucidate the relationship between N-acetyltransferase 2 (NAT2) genotype and the incidence of isoniazid + rifampicin-induced hepatotoxicity. DESIGN: Prospective study. After NAT2* genotyping, 77 patients were classified into three groups according to their NAT2* genotypes: rapid-type (a homozygote of NAT2*4), intermediate-type (a heterozygote of NAT2*4 and mutant alleles) and slow-type (a combination of mutant alleles). Their biochemical profiles of liver function test were investigated for 3 months to assess the development of serum aminotransferase elevation. RESULT: Of the 77 patients, 18.2% developed adverse hepatic reaction within the first month of INH + RMP treatment. A significant association was observed between hepatotoxicity and NAT2* genotype: compared with rapid-type, the relative risk was 4.0 (95% CI 1.94-6.06) for intermediate-type and 28.0 (95%CI 26.0-30.0) for slow-type. Especially in slow-type, the incidence of hepatotoxicity and serum aminotransferase elevation was significantly higher than in the other two types. CONCLUSION: Slow NAT2* genotype significantly affected the development of INH + RMP-induced hepatotoxicity. This suggests the possibility that NAT2* genotyping prior to medication may be useful in evaluating patients with high risk for INH + RMP-induced hepatotoxicity.
SETTING: Japanese in-patients with pulmonary tuberculosis and normal liver function receiving treatment with isoniazid and rifampicin (INH + RMP). OBJECTIVE: To elucidate the relationship between N-acetyltransferase 2 (NAT2) genotype and the incidence of isoniazid + rifampicin-induced hepatotoxicity. DESIGN: Prospective study. After NAT2* genotyping, 77 patients were classified into three groups according to their NAT2* genotypes: rapid-type (a homozygote of NAT2*4), intermediate-type (a heterozygote of NAT2*4 and mutant alleles) and slow-type (a combination of mutant alleles). Their biochemical profiles of liver function test were investigated for 3 months to assess the development of serum aminotransferase elevation. RESULT: Of the 77 patients, 18.2% developed adverse hepatic reaction within the first month of INH + RMP treatment. A significant association was observed between hepatotoxicity and NAT2* genotype: compared with rapid-type, the relative risk was 4.0 (95% CI 1.94-6.06) for intermediate-type and 28.0 (95%CI 26.0-30.0) for slow-type. Especially in slow-type, the incidence of hepatotoxicity and serum aminotransferase elevation was significantly higher than in the other two types. CONCLUSION: Slow NAT2* genotype significantly affected the development of INH + RMP-induced hepatotoxicity. This suggests the possibility that NAT2* genotyping prior to medication may be useful in evaluating patients with high risk for INH + RMP-induced hepatotoxicity.
Authors: L G Possuelo; J A Castelan; T C de Brito; A W Ribeiro; P I Cafrune; P D Picon; A R Santos; R L F Teixeira; T S Gregianini; M H Hutz; M L R Rossetti; A Zaha Journal: Eur J Clin Pharmacol Date: 2008-04-18 Impact factor: 2.953