title: The influence of the time of day on midazolam pharmacokinetics and pharmacodynamics in rabbits.
abstract: BACKGROUND
  This study evaluates the time-of-day effect on midazolam and 1-OH midazolam pharmacokinetics, and on the sedative pharmacodynamic response in rabbits. Also, circadian fluctuations in rabbits' vital signs, such as the blood pressure, heart rate and body temperature were examined. The water intake was measured in order to confirm the presence of the animals' diurnal activity. The secondary aim involved the comparison of two methods of data analysis: a noncompartmental and a population modeling approach.
  
  
  METHODS
  Twelve rabbits were sedated with intravenous midazolam 0.35 mg/kg at four local times: 09.00, 14.00, 18.00 and 22.00 h. Each rabbit served as its own control by being given a single infusion at the four different times of the day on four separate occasions. The values of the monitored physiological parameters were recorded during the experiment and arterial blood samples were collected for midazolam assay. The pedal withdrawal reflex was used as the measurement of the sedation response. Two and one compartmental models were successfully used to describe midazolam and 1-OH midazolam pharmacokinetics. The categorical pharmacodynamic data were described with a logistic model.
  
  
  CONCLUSIONS
  We did not find any time-of-day effects for the pharmacokinetic and pharmacodynamics parameters of midazolam. For 1-OH midazolam, statistically significant time-of-day differences in the apparent volume of distribution and clearance were noticed. They corresponded well with the rabbits' water intake. The noncompartmental and model-based parameters were essentially similar. However, more information can be obtained from the population model and this method should be preferred in chronopharmacokinetic and chronopharmacodynamic studies.
authors.affiliation: Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Poznań, Poland. Electronic address: agnbienert@op.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bienert
authors.affiliation: Department of Teaching Anaesthesiology and Intensive Therapy, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Włodzimierz
authors.initials: W
authors.lastname: Płotek
authors.affiliation: Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Wiczling
authors.affiliation: Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Kostrzewski
authors.affiliation: Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kamińska
authors.affiliation: Department of Experimental Anaesthesiology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Billert
authors.affiliation: Department of Teaching Anaesthesiology and Intensive Therapy, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Damian
authors.initials: D
authors.lastname: Szczesny
authors.affiliation: Department of Forensic Medicine, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Czesław
authors.initials: C
authors.lastname: Zaba
authors.affiliation: Department of Forensic Medicine, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Teżyk
authors.affiliation: Department of Experimental Anaesthesiology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Buda
authors.affiliation: Department of Experimental Anaesthesiology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Bednarek
authors.affiliation: Department of Teaching Anaesthesiology and Intensive Therapy, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Roman
authors.initials: R
authors.lastname: Kaliszan
authors.affiliation: Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Edmund
authors.initials: E
authors.lastname: Grześkowiak
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008874:Midazolam / Q000493:pharmacokinetics* / Q000494:pharmacology; D008954:Models, Biological; D011817:Rabbits; D013997:Time Factors
chemical_list: D051544:Cytochrome P-450 CYP3A; D008874:Midazolam
keywords: Chronopharmacodynamics; Chronopharmacokinetics; Circadian rhythm; Midazolam; Rabbits