RESUMO
OBJECTIVES: Cytochrome P4502E1 (CYP2E1) is involved in the metabolism of isoniazid and the mediation of its hepatotoxicity. It exhibits genetic polymorphism in humans. This study evaluated the polymorphism of CYP2E1 in adult healthy Western Indians and patients on antituberculous drugs by phenotyping and genotyping. METHODS: A 500 mg single dose of chlorzoxazone (CZX) was administered to 136 healthy adult Western Indian participants. Venous blood samples 2 h postdose were analyzed for the levels of CZX and 6-hydroxy CZX, and the metabolic ratio (MR) was calculated to determine the extent of rapid and poor metabolizers using probit plot analysis. Patients on antituberculous drugs who had raised the liver enzymes or clinical symptoms of hepatotoxicity were also recruited. Genotyping for CYP2E1 * 5B allele was performed by polymerase chain reaction - rapid fragment length polymorphism technique. RESULTS: A total of 139 healthy participants were enrolled, of which the final analysis consisted of data from 136 participants for genotyping and 137 for phenotyping. Only 1 participant had reported mild drowsiness 2 h postdose, and no other adverse events were observed. The median (range) MR of population was 0.2 (0.1-4.0), and no polymorphisms were detected using phenotype data. A total of 134/136 (98.5%) had c1/c1 genotype and 1/136 each (0.75%) had c1/c2 and c2/c2 genotypes, respectively. Of the 2/136 participants harboring c2 allele, one had MR of 0.1 (c1/c2) and another had 0.5 (c2/c2). A total of 25 cases of antituberculous drug-induced hepatotoxicity and 50 control patients were recruited, of which finally 22 cases and 49 controls were available for evaluation. All the cases had c1/c1 genotype while 42/49 (85.7%) controls had c1/c1, 6/49 (12.2%) had c1/c2, and 1/49 (2.1%) had c2/c2 genotype and the crude odds ratio was 7.9 (0.4, 145.6). CONCLUSIONS: A background prevalence of CYP2E1*B polymorphism and their activity in Western Indian population was observed. The study suggests no association between the CYP2E1 genotyping with antituberculous drug-induced hepatotoxicity.
Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Clorzoxazona/efeitos adversos , Sistema Enzimático do Citocromo P-450/genética , Indígenas Norte-Americanos/genética , Polimorfismo Genético , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/genética , HumanosAssuntos
Clorzoxazona/efeitos adversos , Falência Hepática Aguda/induzido quimicamente , Transplante de Fígado/métodos , Relaxantes Musculares Centrais/efeitos adversos , Adulto , Biópsia , Clorzoxazona/uso terapêutico , Feminino , Seguimentos , Humanos , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/cirurgia , Dor Lombar/tratamento farmacológico , Relaxantes Musculares Centrais/uso terapêutico , Tomografia Computadorizada por Raios XAssuntos
Clorzoxazona/efeitos adversos , Dermatoses da Perna/induzido quimicamente , Relaxantes Musculares Centrais/efeitos adversos , Vasculite Leucocitoclástica Cutânea/induzido quimicamente , Idoso , Humanos , Dermatoses da Perna/patologia , Masculino , Vasculite Leucocitoclástica Cutânea/patologiaRESUMO
Acute rhabdomyolysis under treatment with HMG-CoA reductase inhibitors ("statins") is a group-specific if rare side effect. Muscle toxicity of statins can be potentiated by medication influencing their metabolism. Here drug interactions on the level of the microsomal cytochrome P450 enzymes play an important role. We report the first case of marked rhabdomyolysis with cholestatic hepatitis in a 73-year-old woman treated with simvastatin and chlorzoxazone. Withdrawal of the causal medication and conservative therapy with volume substitution and forced diuresis was followed by almost complete resolution of the symptoms with normalisation of the blood tests. Possible mechanisms involved in the drug interactions are discussed. Thorough knowledge of the enzyme systems involved in drug metabolism helps to predict possible adverse drug interactions and prevent toxic effects.
Assuntos
Clorzoxazona/efeitos adversos , Colestase Intra-Hepática/induzido quimicamente , Rabdomiólise/induzido quimicamente , Sinvastatina/efeitos adversos , Idoso , Clorzoxazona/uso terapêutico , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipertonia Muscular/tratamento farmacológico , Sinvastatina/uso terapêuticoRESUMO
A 64 year old patient developed severe hepatocellular damage with jaundice and coagulopathy during ingestion of a combination of paracetamol and chlorzoxazone in therapeutic dosage. The risk factors for the development of liver cell necrosis following ingestion of paracetamol in therapeutic dosage are discussed. In particular in patients with risk factors (e.g. alcoholics and patients with heart failure) paracetamol-induced liver failure has to be considered in the presence of high transaminases, even when paracetamol was ingested in therapeutic dosage. Chlorzoxazone itself rarely can induce an idiosyncratic hepatocellular damage.
Assuntos
Acetaminofen/efeitos adversos , Analgésicos não Narcóticos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Clorzoxazona/efeitos adversos , Dor Lombar/tratamento farmacológico , Relaxantes Musculares Centrais/efeitos adversos , Acetaminofen/administração & dosagem , Analgésicos não Narcóticos/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/patologia , Clorzoxazona/administração & dosagem , Quimioterapia Combinada , Humanos , Fígado/patologia , Pessoa de Meia-Idade , Relaxantes Musculares Centrais/administração & dosagemAssuntos
Doença Hepática Induzida por Substâncias e Drogas , Clorzoxazona/efeitos adversos , Redes de Comunicação de Computadores , Rotulagem de Medicamentos , Relaxantes Musculares Centrais/efeitos adversos , Comitê de Profissionais/organização & administração , Humanos , Educação de Pacientes como Assunto , Estados Unidos , United States Food and Drug AdministrationRESUMO
A drug rechallenge proved chlorzoxazone to be hepatotoxic in a patient who had been treated with a combination of it and acetaminophen (Parafon Forte) for several months. Failure to demonstrate a toxic response to acetaminophen coupled with a dramatic response to a single dose of chlorzoxazone implicated chlorzoxazone as the hepatotoxic agent. A review of US Food and Drug Administration records and cases reported in the medical literature disclosed 23 cases of chlorzoxazone-associated hepatotoxic reactions occurring since 1970. These cases were examined in terms of age, duration of therapy, other confounding etiologic factors, and ultimate outcome. There were two deaths involving hepatic failure. Reports of adverse reactions among six commonly used analgesic-muscle relaxants in Sweden have indicated a low, but comparatively greater, incidence of hepatotoxic reactions associated with a chlorzoxazone-containing compound.