RESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/sangre , Hidrocarburo de Aril Hidroxilasas/genética , Infecciones por VIH/sangre , Infecciones por VIH/genética , Oxazinas/sangre , Oxidorreductasas N-Desmetilantes/genética , Adulto , Alquinos , Alelos , Animales , Área Bajo la Curva , Benzoxazinas , Western Blotting , Células COS , Chlorocebus aethiops , Ciclopropanos , Citocromo P-450 CYP2B6 , Exones/genética , Femenino , Genotipo , Humanos , Masculino , Plásmidos/genética , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Estudios Prospectivos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
The impact of thyroid dysfunction on the regulation, expression, and function of ABCB1 remains unclear. We therefore investigated ABCB1 mRNA expression and function in patients with thyroid dysfunction and studied the disposition of the ABCB1 substrate digoxin before and after treatment for thyroid disease. In patients with hypothyroidism, normalization of thyroid function was associated with a 1.8-fold increase in mRNA expression and a 26% increase in rhodamine efflux from CD56(+) cells. In hypothyroidism, digoxin clearance was significantly decreased, whereas bioavailability, volume of distribution, half-life time, and protein binding were unaltered. In hyperthyroidism, ABCB1 mRNA expression, rhodamine efflux, and disposition of digoxin were not significantly affected other than in relation to renal clearance. Experiments using the LS174T cell line indicated that the gene is a direct target of thyroid hormone receptors. In conclusion, thyroid abnormalities can exert significant effects on the expression of P-glycoprotein, thereby altering the disposition and action of drugs that are substrates of P-glycoprotein.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Cardiotónicos/farmacocinética , Digoxina/farmacocinética , Hipertiroidismo/metabolismo , Hipotiroidismo/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Administración Oral , Adulto , Anciano , Células CACO-2 , Cardiotónicos/administración & dosificación , Digoxina/administración & dosificación , Elementos de Facilitación Genéticos , Femenino , Regulación de la Expresión Génica , Humanos , Hipertiroidismo/tratamiento farmacológico , Hipertiroidismo/genética , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/genética , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Rodaminas/metabolismo , Hormonas Tiroideas/metabolismo , Transfección , Adulto JovenRESUMEN
The multidrug resistance protein 4 (MRP4) is an efflux transporter involved in the transport of endogenous substrates and xenobiotics. We measured MRP4 mRNA and protein expression in human livers and found a 38- and 45-fold variability, respectively. We sequenced 2 kb of the 5'-flanking region, all exons and intron/exon boundaries of the MRP4 gene in 95 patients and identified 74 genetic variants including 10 non-synonymous variations, seven of them being located in highly conserved regions. None of the detected polymorphisms was significantly associated with changes in the MRP4 mRNA or protein expression. Immunofluorescence microscopy indicated that none of the non-synonymous variations affected the cellular localization of MRP4. However, in cholestatic patients the MRP4 mRNA and protein expression both were significantly upregulated compared to non-cholestatic livers (protein: 299+/-138 vs 100+/-60a.u., P<0.001). Taken together, human hepatic MRP4 expression is highly variable. Genetic variations were not sufficient to explain this variability. In contrast, cholestasis is one major determinant of human hepatic MRP4 expression.