Population pharmacokinetic analysis of circadian rhythms in hepatic CYP3A activity using midazolam.
J Clin Pharmacol
; 54(10): 1162-9, 2014 Oct.
Article
en En
| MEDLINE
| ID: mdl-24782075
ABSTRACT
Diurnal changes in the activity of drug metabolizing enzymes may contribute to the variability in drug disposition and drug effects. The aim of this study was to quantify the circadian rhythmicity exhibited by hepatic CYP3A. A 10 µg/kg intravenous bolus dose, followed by a 30-hour 4 µg/kg/h intravenous infusion of midazolam, used as a probe substrate for hepatic CYP3A activity, was administered to 16 healthy volunteers (8 males and 8 females). Blood samples were drawn hourly for 24 hours after achieving steady state, and plasma concentrations of midazolam and its main metabolite 1-OH midazolam were determined. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. One-compartment pharmacokinetic models best described midazolam and 1-OH midazolam pharmacokinetic disposition. An unequivocal but minor diurnal pattern was identified in the midazolam plasma concentration profiles, which was described using a cosine function with a 24-hours period. The fluctuation in the relative CYP3A activity ranged between 10% above average around 1500, and 10% below average around 0300. None of the covariates tested had a significant impact on the parameters estimated. Although a diurnal pattern in hepatic CYP3A activity was identified, its magnitude suggests that it is small and without clinical significance for drug therapy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Midazolam
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Ritmo Circadiano
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Citocromo P-450 CYP3A
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Modelos Biológicos
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
J Clin Pharmacol
Año:
2014
Tipo del documento:
Article
País de afiliación:
Alemania