N-desmethyladinazolam pharmacokinetics and behavioral effects following administration of 10-50 mg oral doses in healthy volunteers.
Results of previous studies suggest that N-desmethyladinazolam, the major metabolite of adinazolam in man, contributes substantially to psychomotor effects and sedation observed following adinazolam administration. Therefore, the pharmacokinetics and pharmacodynamics of N-desmethyladinazolam were explored following administration of single oral doses of placebo and solutions containing 10, 30, and 50 mg N-desmethyladinazolam mesylate in a double-blind, randomized, four-way crossover design to 15 healthy male volunteers. Plasma concentrations of N-desmethyladinazolam were determined by HPLC. Psychomotor performance tests (digit symbol substitution and card sorting by fours and suits), memory tests and sedation scoring were also performed following drug administration. N-Desmethyladinazolam pharmacokinetics were dose independent over this range. Dose-related performance effects were observed at 1, 2, and 6 h after dosing. Memory was likewise affected at 2 h. Psychomotor performance decrements correlated with log N-desmethyladinazolam plasma concentrations. Analysis of the relationship between percentage decrements in digit-symbol substitution and plasma N-desmethyladinazolam using the Hill equation revealed a EC50 of 325 ng/ml. These results establish the relationship between N-desmethyladinazolam plasma concentrations and performance effects; these data will be helpful in assessing the contribution of N-desmethyladinazolam to clinical effects observed after adinazolam administration.
Fleishaker
J C
JC
Clinical Pharmacokinetics Unit, Upjohn Company, Kalamazoo, MI 49007.
Smith
T C
TC
Friedman
H
H
Phillips
J P
JP
D000328:Adult; D001519:Behavior / Q000187:drug effects*; D001569:Benzodiazepines / Q000493:pharmacokinetics* / Q000494:pharmacology; D004311:Double-Blind Method; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008568:Memory / Q000187:drug effects; D008875:Middle Aged; D011597:Psychomotor Performance / Q000187:drug effects; D012016:Reference Values
D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; C050132:mono-N-demethyladinazolam