Benzodiazepine hypnotics: time course and potency of benzodiazepine receptor occupation after oral application

Ex vivo benzodiazepine receptor occupation by six benzodiazepine hypnotics in the mouse brain was investigated with respect to the time course after oral administration and with respect to the in vitro potency as benzodiazepine receptor ligands. All drugs were administered as solutions. Receptor occupation, as indicated by the inhibition of specific [3H] flunitrazepam binding, occurs very rapidly after oral administration of all benzodiazepines tested with about 80% or even more of maximal inhibition already seen within 30 min after oral administration. However, the onset is somewhat faster with midazolam and temazepam than with the other four derivatives. The duration of benzodiazepine receptor occupation in the mouse brain differed markedly for the six benzodiazepines in agreement with their very different pharmacokinetics in this species. Except for midazolam, there was a good correlation between in vitro receptor affinity and ex vivo receptor occupancy, suggesting that all drugs except midazolam reach the receptor in the CNS similarly. Midazolam has a large first pass metabolism after oral administration which seems the reason for the lower ex vivo potency relative to the in vitro affinity. It is concluded that a fast onset of receptor occupation is a rather general property of benzodiazepines when administered orally as solutions.