On the pharmacokinetics of domperidone in animals and man. I. Plasma levels of domperidone in rats and dogs. Age related absorption and passage through the blood brain barrier in rats

Abstract

Domperidone, a novel gastrokinetic and antinauseant lacking central side-effects, was administered intravenously to male Wistar rats and orally to fasted rats of either sex and to 1- and 6-day old neonates at doses of 2.5 mg 14C-labelled drug/kg. The biphasic absorption of domperidone in fasted rats was extremely rapid suggesting a partial absorption from the stomach. The metabolism of domperidone was sex- and age-related: it was slower in the female rat and in the neonates. The elimination system for the metabolites was still immature in the 1-day old pups. The distribution of domperidone (and related metabolites) to the rat brain was limited, brain concentrations being lower than corresponding plasma levels in all cases. In 1-day old neonates, the blood-brain barrier was less obstructive to the passage of domperidone than in older rats. In Beagle dogs, domperidone pharmacokinetics were described by a two-compartment model with half-lives of distribution and elimination of 6 minutes and 2.45 hours respectively. The time-courses of the drug plasma levels were similar for single and repeated (once daily for 11 months) doses of 2.5, 10 and 40 mg/kg, indicating that chronic administration of domperidone, even at high dose levels, did not alter its pharmacokinetics. AUC-values increased proportionally with the dose pointing to linear pharmacokinetics over a wide dose range.