The influence of the time of day on midazolam pharmacokinetics and pharmacodynamics in rabbits

Abstract

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.

Pharmacokinetics of midazolam and its major metabolite 1‐hydroxymidazolam in the ball python (Python regius) after intracardiac and intramuscular administrations

“…However, the V ss was not higher in the current study compared to that of mammalian and avian species, with values as high as 2.99 L/kg in rabbits receiving 0.35 mg/kg IV (Bienert et al, 2014) and 4.83 L/kg in turkeys receiving 5 mg/kg IV (Cortright, Wetzlich, & Craigmill, 2007). This variability likely reflected the differences in body composition, plasma protein binding, and organ blood flow, which also highlights the limitations of extrapolating these values across taxa.…”

“…Plasma concentrations of the metabolite 1‐hydroxymidazolam reached their peak 22.33 ± 20.26 hr following IC administration of midazolam. The difference between the IC t max of midazolam and its major metabolite in ball pythons (22.33 hr) was substantially longer than in rabbits (0.28 hr) (Bienert et al, ) and sheep (0.28 hr) (Simon et al, ), which suggests slow hepatic metabolism or low hepatic blood flow. In humans, prolonged sedation can occur with the accumulation of 1‐hydroxymidazolam in patients with compromised renal function (Bauer et al, ; Spina & Ensom, ).…”

Comparative pharmacokinetics and bioavailability of intranasal and rectal midazolam formulations relative to buccal administration in rabbits

“…Furthermore, recent data concerning the molecular clock, which regulates the circadian rhythmicity in mammals, provide better insight into the nature of the circadian rhythms in rabbits, which led to the circadian uctuation of midazolam's clearance. 36 Hence, the comparisons of CYP3A activity between rabbits and human and the gender differences between male and female rabbits are of great value. According to our current ndings, it can be assumed that the hepatic CYP3A activity of male rabbit is closer to that of humans than female rabbits.…”

A Pharmacokinetic-Pharmacodynamic Study of Intravenous Midazolam and Flumazenil in Adult New Zealand White—Californian Rabbits (Oryctolagus cuniculus)

“…The PK of midazolam previously reported in rabbits is consistent with our results, with a half-life of 30 min and weight-normalized V d and Cl of 0.83 L/kg and 19 mL/min/kg, respectively. 6 Important differences in dosage (0.35 compared with 1.2 mg/kg) could explain the small discrepancies in PK data between studies. Metabolism of midazolam by the liver leads to the production of an active metabolite, 1-OH-midazolam.…”