Diurnal variation in the pharmacokinetics and brain distribution of morphine and its major metabolite

Abstract The pharmacokinetics and pharmacodynamics of drugs are influenced by daily fluctuations in physiological processes. The aim of this study was to determine the effect of dosing time on the pharmacokinetics and brain distribution of morphine. To this end, 4 mg/kg morphine was administered intravenously to Wistar rats that were either pre-treated with vehicle or tariquidar and probenecid to inhibit processes involved in the active transport of morphine. Non-linear mixed effects modelling was used to describe the concentration-time profiles of morphine and its metabolite M3G in plasma and brain tissue. We found that the concentrations of morphine in the brain and of M3G in plasma depended on the time of day, which could be quantified by a 24-hour rhythm in the efflux of morphine from brain tissue back into the circulation, with the lowest efflux during the two light-dark phase transitions with a difference between peak and trough of 20%. The active processes involved in the clearance of morphine and its metabolite M3G from plasma also showed 24-hour variation with the highest value in the middle of the dark phase being 54% higher than the lowest value at the start of the light phase. Hence, time of day presents a considerable source of variation in the pharmacokinetics of morphine, which could be used to optimize the dosing strategy of morphine.