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Circadian phase-dependent pharmacokinetics and acute toxicity of mepivacaine
1Medical Pharmacology Laboratory, Faculty of Medicine, Marseille, France.
Abstract:
The aim of this study was to investigate the possible influence of the time of administration on mepivacaine acute toxicity and kinetics in mice. Four different groups of adult male NMRI mice maintained under controlled environmental conditions (lights on: = 0600-1800 h) were injected at one of the following times: 1000, 1600, 1900, 2200, 0100 and 0400 h with one of four doses of mepivacaine at each time point to establish the acute toxicity (LD50). To assess chronokinetics, a single 60 mg kg-1 i.p. dose of mepivacaine was given to adult male NMRI mice at four fixed times: 1000, 1600, 2200 and 0400 h. Mepivacaine plasma concentrations were determined by GLC. Our data showed significant 24 h variations in the following parameters: Highest tmax value = 0.366 +/- 0.073 h at 1000 h (P less than 0.005, amplitude, maximum-minimum/mean x 100, = 184%), highest Cmax/tmax ratio = 177.17 +/- 9.49 at 2200 h (P less than 0.005, amplitude = 192%), highest Vd = 0.842 +/- 0.23 L kg-1 at 2200 h (P less than 0.005, amplitude = 158%) and highest beta phase elimination half-life = 5.408 +/- 1.36 h at 2200 h (P less than 0.025, amplitude = 145%). Cmax (amplitude = 15%), AUC infinity 0 (amplitude = 24%) and clearance (amplitude = 23%) were not significantly time-dependent. These data demonstrate a temporal pattern of mepivacaine kinetics similar to those reported previously for bupivacaine. The temporal changes in mepivacaine-induced acute toxicity may result in part from its chronokinetic changes.
Insights
Mepivacaine toxicity and kinetics in mice show significant 24-hour variations, impacting its acute toxicity. These temporal changes in mepivacaine chronokinetics may influence its toxicity.
Area of Science:
- Pharmacology
- Chronobiology
- Toxicology
Background:
- Circadian rhythms influence drug metabolism and toxicity.
- Understanding the time-dependent effects of local anesthetics is crucial for safe administration.
Purpose of the Study:
- To investigate the influence of administration time on mepivacaine acute toxicity (LD50) and pharmacokinetics in mice.
- To determine if mepivacaine exhibits chronokinetic properties.
Main Methods:
- Adult male NMRI mice were administered varying doses of mepivacaine at different times to determine LD50.
- Pharmacokinetic parameters were assessed after a single dose at fixed time points.
- Mepivacaine plasma concentrations were analyzed using gas-liquid chromatography (GLC).
Main Results:
- Significant 24-hour variations were observed in tmax, Cmax/tmax ratio, Vd, and elimination half-life.
- Peak time to maximum concentration (tmax) was highest at 1000 h.
- Highest Cmax/tmax ratio, volume of distribution (Vd), and elimination half-life were observed at 2200 h.
- Maximum concentration (Cmax), area under the curve (AUC), and clearance showed no significant time dependency.
Conclusions:
- Mepivacaine exhibits significant chronokinetic variations in mice.
- Temporal changes in mepivacaine kinetics may contribute to variations in its acute toxicity.
- Findings suggest a potential for time-dependent efficacy and toxicity of mepivacaine, similar to bupivacaine.