Circadian phase-dependent pharmacokinetics and acute toxicity of mepivacaine

Abstract

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 < 0005, amplitude, maximum-minimum/mean × 100, = 184%), highest Cmax/tmax ratio = 177.17 ± 9.49 at 2200 h (P < 0005, amplitude = 192%), highest Vd = 0.842 ± 0.23 L kg−1 at 2200 h (P < 0005, amplitude = 158%) and highest β phase elimination half-life = 5.408 ± 1.36 h at 2200 h (P < 0.025, amplitude = 145%). Cmax (amplitude = 15%), AUCox (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.