Pharmacokinetics of flutoprazepam, a novel benzodiazepine drug, in normal subjects.
The single dose pharmacokinetics of flutoprazepam and its active N-desalkyl metabolite were determined in 8 normal subjects by using newly developed, highly sensitive, GC-MS and HPLC techniques. Following a 2 mg dose of the drug, the concentrations of unchanged flutoprazepam in serum were extremely low (below 5 ng/ml at 2 h) and declined rapidly to undetectable levels within 6-9 h after dosing. At all sampling times, the serum concentration of the N-dealkylated metabolite (N-desalkylflurazepam) was much greater than that of the parent compound. This metabolite appeared in serum rapidly (within 2 h), reached a peak between 2 and 12 h and declined slowly, with an elimination half-life of about 90 h on average. The serum concentration of two additional putative metabolites (3-hydroxy-flutoprazepam and N-desalkyl-3-hydroxy-flutoprazepam) was below the limit of detection (2 ng/ml) in all samples. Mild CNS effects (documented by prolonged choice reaction time) were present at 2 and 4 h but were no longer detectable at 9 h. It is suggested that unchanged flutoprazepam is unlikely to contribute significantly to clinical effects and that the drug exerts its therapeutic activity through conversion to the slowly eliminated N-desalkyl metabolite.
Barzaghi
N
N
Department of Medical Pharmacology, University of Pavia, Italy.
Leone
L
L
Monteleone
M
M
Tomasini
G
G
Perucca
E
E
D000284:Administration, Oral; D000328:Adult; D001570:Benzodiazepinones / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005479:Flurazepam / Q000031:analogs & derivatives / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D011597:Psychomotor Performance; D011930:Reaction Time / Q000187:drug effects
D001570:Benzodiazepinones; D006993:Hypnotics and Sedatives; C029163:flutoprazepam; C033473:didesethylflurazepam; D005479:Flurazepam