RESUMEN
The pyrazolone drug metamizole is a widely used analgesic. Analysis of liver microsomes from patients treated with metamizole revealed selectively higher expression of cytochromes P450, CYP2B6 and CYP3A4 (3.8- and 2.8-fold, respectively), and 2.9-fold higher bupropion hydroxylase activity compared with untreated subjects. Further investigation of metamizole and various derivatives on different potential target genes in human primary hepatocytes demonstrated time- and concentration-dependent induction by metamizole of CYP2B6 (7.8- and 3.1-fold for mRNA and protein, respectively, at 100 muM) and CYP3A4 (2.4- and 2.9-fold, respectively), whereas other genes (CYP2C9, CYP2C19, CYP2D6, NADPH:cytochrome P450 reductase, ABCB1, constitutive androstane receptor (CAR), pregnane X receptor (PXR)) were not substantially altered. Using reporter gene assays, we show that metamizole is not acting as a direct ligand to either PXR or CAR, suggesting a phenobarbital-like mechanism of induction. These data warrant further studies to elucidate the drug-interaction potential of metamizole, especially in patients with long-term treatment.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Hidrocarburo de Aril Hidroxilasas/biosíntesis , Sistema Enzimático del Citocromo P-450/biosíntesis , Dipirona/farmacología , Oxidorreductasas N-Desmetilantes/biosíntesis , Anciano , Hidrocarburo de Aril Hidroxilasas/genética , Western Blotting , Catálisis , Células Cultivadas , Receptor de Androstano Constitutivo , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/genética , ADN/biosíntesis , ADN/genética , Dipirona/análogos & derivados , Relación Dosis-Respuesta a Droga , Inducción Enzimática/efectos de los fármacos , Femenino , Genotipo , Hepatocitos/efectos de los fármacos , Humanos , Técnicas In Vitro , Isoenzimas/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Persona de Mediana Edad , Oxidorreductasas N-Desmetilantes/genética , Plásmidos , Receptor X de Pregnano , ARN/biosíntesis , ARN/genética , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Receptores de Esteroides/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/efectos de los fármacosRESUMEN
To assess the association of CYP2B6 allelic diversity with efavirenz (EFV) pharmacokinetics, we performed extensive genotyping of 15 relevant single nucleotide polymorphism in 169 study participants, and full resequencing of CYP2B6 in individuals with abnormal EFV plasma levels. Seventy-seven (45.5%) individuals carried a known (CYP2B6*6, *11, *15, or *18) or new loss/diminished-function alleles. Resequencing defined two new loss-of-function alleles: allele *27 (marked by 593T>C [M198T]), that results in 85% decrease in enzyme activity and allele *28 (marked by 1132C>T), that results in protein truncation at arginine 378. Median AUC levels were 188.5 microg h/ml for individuals homozygous for a loss/diminished-function allele, 58.6 microg h/ml for carriers, and 43.7 microg h/ml for noncarriers (P<0.0001). Individuals with a poor metabolizer genotype had a likelihood ratio of 35 (95% CI, 11-110) of presenting very high EFV plasma levels. CYP2B6 poor metabolizer genotypes explain to a large extent EFV pharmacokinetics and identify individuals at risk of extremely elevated EFV plasma levels.