Influence of Time of Day on Propofol Pharmacokinetics and Pharmacodynamics in Rabbits

Abstract

This study evaluates the administration time-of-day effects on propofol pharmacokinetics and sedative response in rabbits. Nine rabbits were sedated with 5 mg/kg propofol at three local clock times: 10:00, 16:00, and 22:00 h. Each rabbit served as its own control by being given a single infusion at the three different times of day on three separate occasions. Ten arterial blood samples were collected during each clock-time experiment for propofol assay. A two-compartment model was used to describe propofol pharmacokinetics, and the pedal withdrawal reflex was used as the sedation pharmacodynamic response. The categorical data comprising the presence or absence of pedal withdrawal reflex was described by a logistic model. The typical volume of the central compartment equaled 7.67 L and depended on rabbit body weight. The elimination rate constant depended on drug administration time; it was lowest at 10:00 h, highest at 16:00 h, and intermediate at 22:00 h. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment, with the rate constant for the distribution to the effector compartment equal to 0.335 min⁻¹. Drug concentration had a large effect on the probability of anesthesia. The degree of anesthesia was largest at 10:00 h, lowest at 16:00 h, and intermediate at 22:00 h. In summary, both the pharmacokinetics and pharmacodynamics of propofol in rabbits depended on administration time. The developed population approach may be used to assess chronopharmacokinetics and chronopharmacodynamics of medications in animals and humans. (Author correspondence: [email protected])

Keywords:

• Anesthesia
• Chronopharmacodynamics
• Chronopharmacokinetics
• Circadian
• Propofol
• Rabbits

ACKNOWLEDGMENTS

This work is funded by the Department of Clinical Pharmacy and Biopharmacy, Karol Marcinkowski University of Medical Sciences, Poznań, Poland. One of the authors (Paweł Wiczling) was supported by the START fellowship and by a grant from Iceland, Liechtenstein, and Norway through the EEA Financial Mechanism via Homing Program from the Foundation for Polish Science.

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.