RESUMEN
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.
Asunto(s)
Antituberculosos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Clorzoxazona/efectos adversos , Sistema Enzimático del Citocromo P-450/genética , Indígenas Norteamericanos/genética , Polimorfismo Genético , Estudios de Casos y Controles , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , HumanosAsunto(s)
Clorzoxazona/efectos adversos , Fallo Hepático Agudo/inducido químicamente , Trasplante de Hígado/métodos , Relajantes Musculares Centrales/efectos adversos , Adulto , Biopsia , Clorzoxazona/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Fallo Hepático Agudo/diagnóstico , Fallo Hepático Agudo/cirugía , Dolor de la Región Lumbar/tratamiento farmacológico , Relajantes Musculares Centrales/uso terapéutico , Tomografía Computarizada por Rayos XAsunto(s)
Clorzoxazona/efectos adversos , Dermatosis de la Pierna/inducido químicamente , Relajantes Musculares Centrales/efectos adversos , Vasculitis Leucocitoclástica Cutánea/inducido químicamente , Anciano , Humanos , Dermatosis de la Pierna/patología , Masculino , Vasculitis Leucocitoclástica Cutánea/patologíaRESUMEN
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.
Asunto(s)
Clorzoxazona/efectos adversos , Colestasis Intrahepática/inducido químicamente , Rabdomiólisis/inducido químicamente , Simvastatina/efectos adversos , Anciano , Clorzoxazona/uso terapéutico , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipertonía Muscular/tratamiento farmacológico , Simvastatina/uso terapéuticoRESUMEN
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.
Asunto(s)
Acetaminofén/efectos adversos , Analgésicos no Narcóticos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Clorzoxazona/efectos adversos , Dolor de la Región Lumbar/tratamiento farmacológico , Relajantes Musculares Centrales/efectos adversos , Acetaminofén/administración & dosificación , Analgésicos no Narcóticos/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Clorzoxazona/administración & dosificación , Quimioterapia Combinada , Humanos , Hígado/patología , Persona de Mediana Edad , Relajantes Musculares Centrales/administración & dosificaciónAsunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Clorzoxazona/efectos adversos , Redes de Comunicación de Computadores , Etiquetado de Medicamentos , Relajantes Musculares Centrales/efectos adversos , Comité de Profesionales/organización & administración , Humanos , Educación del Paciente como Asunto , Estados Unidos , United States Food and Drug AdministrationRESUMEN
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.