Comparison of sublingual and oral prazepam in normal subjects. II. Pharmacokinetic and pharmacodynamic data

The pharmacokinetic profiles of oral and sublingual administrations of prazepam 20 mg to 5 normal volunteers were compared in order to explain the clinical observation that sublingual prazepam appears to exhibit sedative properties when compared to the same dose of oral prazepam. Blood samples for pharmacokinetic evaluation were collected just before drug intake and 7.5, 15, 22.5, 30, 45, 60, 90 min, 2, 3, 5, 6, 7, 8, 9, 10 and 24 h after drug intake. The study was performed in double-blind and crossover conditions. Serum levels of prazepam and its major metabolite N-desmethyl-diazepam were measured by HPLC. No prazepam was detected at a concentration higher than 20 ng/ml (limit of detection) whereas N-desmethyl-diazepam reached concentrations around 140 ng/ml. To correlate this observation with the clinical data, the affinity of prazepam and N-desmethyl-diazepam was compared measuring their ability to displace 50% of 3H-flunitrazepam bound to benzodiazepine receptors contained in synaptosomal preparation obtained from rat brain. N-desmethyl-diazepam was 17-fold more potent than prazepam. This data suggests that prazepam is a pro-drug which is transformed to the active compound N-desmethyl-diazepam and that the difference in clinical observation with both administrations could be correlated to N-desmethyl-diazepam concentration-time curves. Nevertheless, the comparison of the area under the N-desmethyl-diazepam serum concentration-time curves, the maximum concentrations, the times when the maximum concentrations were observed and the times needed to detect a significant level after oral and sublingual administration did not show statistical difference.(ABSTRACT TRUNCATED AT 250 WORDS)