RESUMEN
The suitability of the capillary dried blood spot (DBS) sampling method was assessed for simultaneous phenotyping of cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) using a cocktail approach. Ten volunteers received an oral cocktail capsule containing low doses of the probes bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and fexofenadine (P-gp) with coffee/Coke (CYP1A2) on four occasions. They received the cocktail alone (session 1), and with the CYP inhibitors fluvoxamine and voriconazole (session 2) and quinidine (session 3). In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin. The concentrations of probes/metabolites were determined in DBS and plasma using a single liquid chromatography-tandem mass spectrometry method. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer. Minimally invasive one- and three-point (at 2, 3, and 6 h) DBS-sampling methods were found to reliably reflect CYP and P-gp activities at each session.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/sangre , Sistema Enzimático del Citocromo P-450/sangre , Pruebas con Sangre Seca , Preparaciones Farmacéuticas/sangre , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Administración Oral , Adulto , Bupropión/administración & dosificación , Bupropión/sangre , Bupropión/farmacocinética , Cafeína/administración & dosificación , Cafeína/sangre , Cafeína/farmacocinética , Cápsulas , Bebidas Gaseosas , Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Café , Inhibidores Enzimáticos del Citocromo P-450 , Dextrometorfano/administración & dosificación , Dextrometorfano/sangre , Dextrometorfano/farmacocinética , Inhibidores Enzimáticos/administración & dosificación , Estudios de Factibilidad , Flurbiprofeno/administración & dosificación , Flurbiprofeno/sangre , Flurbiprofeno/farmacocinética , Humanos , Isoenzimas , Masculino , Midazolam/administración & dosificación , Midazolam/sangre , Midazolam/farmacocinética , Omeprazol/administración & dosificación , Omeprazol/sangre , Omeprazol/farmacocinética , Preparaciones Farmacéuticas/administración & dosificación , Fenotipo , Proyectos Piloto , Valor Predictivo de las Pruebas , Espectrometría de Masa por Ionización de Electrospray , Especificidad por Sustrato , Espectrometría de Masas en Tándem , Terfenadina/administración & dosificación , Terfenadina/análogos & derivados , Terfenadina/sangre , Terfenadina/farmacocinética , Adulto JovenRESUMEN
Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.