Circadian phase dependent acute toxicity and pharmacokinetics of etidocaine in serum and brain of mice

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Abstract
The aim of this study was to investigate the possible influence of the time of administration on etidocaine acute toxicity and kinetics in mice. Different groups of adult male NMRI mice maintained under controlled environmental conditions (lights on 06.00–18.00) were injected at one of the following times: 10.00, 16.00,19.00,22.00,01.00 and 04.00 h with four doses of etidocaine at each time point to establish the acute toxicity (LD 50). To assess chronokinetics, a single 40 mg kg−1 i.p. dose of etidocaine was given to adult male NMRI mice at four fixed times: 10.00,16.00,22.00 and 04.00 h. Etidocaine serum levels were determined by GLC. The data showed significant 24 h variations of the Cmax only (highest value = 9.64 ± 1.31 μg mL−1 at 10.00 P < 0.05; amplitude, (maximum-minimum) mean × 100 = 84%) Vd, (amplitude = 59.7%), α and β phase elimination half-lives (amplitude = 52 and 35%, respectively), clearance (amplitude = 23%) and AUC°8 (amplitude = 22%) were not found to be significantly time dependent. Etidocaine kinetics in brain were determined similarly; a significant temporal variation was found for the elimination half life (amplitude, 161.9%) and AUC (amplitude, 133.2%) but not for Cmax. These data demonstrate a temporal pattern of etidocaine kinetics similar to those reported previously for other local anaesthetic agents, bupivacaine and mepivacaine. The temporal changes in etidocaine induced acute toxicity may result in part from its chronokinetic changes.

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