title: Chronopharmacokinetic study with prolonged infusion of midazolam.
abstract: Physiological and temporal variation in the disposition of midazolam has been reported. In order to delineate the underlying mechanisms of these alterations, we infused in 5 healthy male volunteers for 26 hours midazolam at a rate of 0.025 mg/kg/h preceded by a bolus of 0.05 mg/kg. Thus, steady-state conditions were rapidly achieved. Plasma levels of midazolam were monitored on a 2-hourly basis during this period. In addition, the pharmacodynamic response to the new sedative/hypnotic benzodiazepine was characterised by a pencil tracking test, sedation index formed from visual analogue scales, and choice reaction time. In all subjects, small (4 to 16%) but clinically irrelevant fluctuations of steady-state plasma concentrations around 45 ng/ml were observed. During the night-time (11pm to 7am) plasma concentrations were slightly (p = 0.074) higher than during the daytime. Total plasma clearance varied from 563 to 823 ml/min. Plasma protein binding of midazolam was time independent. Since in only 1 of 5 subjects was a circadian rhythm observed, fluctuations in plasma midazolam concentrations under controlled and constant conditions are probably not of clinical significance.
mesh_terms: D000328:Adult; D001569:Benzodiazepines / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007263:Infusions, Parenteral; D007700:Kinetics; D008297:Male; D008874:Midazolam; D011597:Psychomotor Performance / Q000187:drug effects; D013997:Time Factors
chemical_list: D001569:Benzodiazepines; D008874:Midazolam