RESUMEN
Patients vary widely in their response to drugs. Having an understanding of the pharmacokinetic and pharmacodynamic properties of various medications is importantwhen assessing ethnic differences in drug response. Genetic factors can account for 20 to 95 percent of patient variability. Genetic polymorphisms for many drug-metabolizing enzymes and drug targets (e.g., receptors) have been identified. Although currently limited to a few pathways, pharmacogenetic testing may enable physicians to understand why patients react differently to various drugs and to make better decisions about therapy. Ultimately, this understanding may shift the medical paradigm to highly individualized therapeutic regimens.
Asunto(s)
Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Sistema Enzimático del Citocromo P-450/fisiología , Variación Genética , Preparaciones Farmacéuticas/metabolismo , Farmacogenética , Farmacocinética , Farmacología , Antiasmáticos/metabolismo , Asma/genética , Asma/fisiopatología , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Humanos , Fenotipo , Polimorfismo GenéticoRESUMEN
The purpose of this study was to characterize the effect of potent CYP2D6 inhibition byparoxetine on atomoxetine disposition in extensive metabolizers. This was a single-blind, two-period, sequential studyin 22 healthy individuals. In period 1, 20 mg atomoxetine bid was administered to steady state. In period 2, 20 mg paroxetine was administered qd for 17 days. On days 12 through 17, 20 mg atomoxetine bid were coadministered. Plasma pharmacokinetics of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine was determined at steady state in each treatment period. Plasma pharmacokinetics of paroxetine were determined after the 11th and 17th doses. Paroxetine increased C(ss,max), AUC0-12, and t1/2 of atomoxetine by approximately 3.5-, 6.5-, and 2.5-fold, respectively. After coadministration with paroxetine, increases in N-desmethylatomoxetine and decreases in 4-hydroxyatomoxetine concentrations were observed. No changes in paroxetine pharmacokinetics were observed after coadministration with atomoxetine. It was concluded that inhibition of CYP2D6 by paroxetine markedly affected atomoxetine disposition, resulting in pharmacokinetics similar to poor metabolizers of CYP2D6 substrates.
Asunto(s)
Inhibidores del Citocromo P-450 CYP2D6 , Paroxetina/farmacología , Propilaminas/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Simportadores/antagonistas & inhibidores , Administración Oral , Adulto , Área Bajo la Curva , Clorhidrato de Atomoxetina , Presión Sanguínea/efectos de los fármacos , Citocromo P-450 CYP2D6/genética , Interacciones Farmacológicas , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Fenoles/sangre , Éteres Fenílicos/sangre , Propilaminas/sangre , Método Simple Ciego , Factores de TiempoRESUMEN
AIMS: To examine the effects of an oral contraceptive containing ethinyloestradiol and norgestrel on intestinal and hepatic CYP3A activity using midazolam as a probe substrate. METHODS: In a nonblinded sequential study, nine healthy women received simultaneous doses of intravenous midazolam (0.05 mg kg(-1)) and oral 15N3-midazolam (3 mg) on days 0, 4, 6, 8, and 14. On study day 5, Ovral(50 microg ethinyloestradiol/500 microg norgestrel) was administered for 10 days. Serum and urine samples were assayed for midazolam, 15N3-midazolam and metabolites by liquid chromatography-mass spectrometry. A Digit Symbol Substitution Test (DSST) was used to assess changes in the pharmacodynamic activity of midazolam. RESULTS: Moderate (% CV 26-46) interindividual variability in the pharmacokinetics of midazolam were observed. Compared with baseline, AUC(0,infinity)iv ratios (95% CIs) after 2, 4, and 10 days treatment with OC were 89% (79, 101), 96% (85, 109), and 88% (77, 99), respectively. The AUC(0,infinity)oral ratios (95% CIs) were 101% (82, 125), 105% (85, 130), and 114% (92, 141), respectively, after 2, 4, and 10 days OC treatment compared with baseline. Concomitant administration of the oral contraceptive, Ovral for 2, 4 or 10 days did not significantly alter the area under the curve, clearance, or half-life of midazolam after either oral or intravenous administration. No alterations in pharmacodynamic effects of midazolam were observed between treatment days. Mean DSST scores strongly correlated with mean total midazolam blood concentrations (r = -0.936). CONCLUSIONS: Administration of Ovral for 10 days had no impact on intestinal or hepatic CYP3A activity as determined by midazolam metabolism.