Effects of ethanol on the toxicokinetics of methamphetamine in rabbits

In the current study, the effects of ethanol (EtOH) on toxicokinetics of methamphetamine (MA) and its metabolite amphetamine (AP) were investigated. A single dose of MA hydrochloride at 15 mg/Kg was given intragastrically, either alone (MA group; n = 8) or in conjunction with 3 g/Kg EtOH (MA+EtOH group; n = 8) to rabbits. In placebo group, normal saline only was given (placebo group; n = 4). Plasma and urine samples were collected and analyzed by gas chromatography/mass spectrometry (GC/MS) for MA and AP. Toxicokinetic parameters of MA and AP were determined using WinNonlin. Our results showed that toxicokinetic profiles of MA and AP in the two experimental groups were both fitted to an open two-compartment model with first-order kinetics. These were not affected by co-administration of EtOH. However, concomitant intake of EtOH significantly increased MA plasma absorption constant (Ka) and maximum concentration (Cmax). The Ka of MA was increased from 0.679/h ± 0.023/h to 0.964/h ± 0.033/h (P < 0.05, the mean Cmax from 1.408 mg/L ± 0.072 mg/L to 1.676 mg/L ± 0.135 mg/L (P < 0.05), whereas the Tmax was significantly decreased from 1.620 h ± 0.062 h to 1.259h ± 0.033h (P < 0.05). In contrast, no significant difference was observed on MA elimination. Furthermore, the plasma AP area under the curve (AUC0-30 h) increased from 5.281 mg/h/L ± 0.264 mg/h/L to.13.052 mg/h/L ± 0.956 mg/h/L and Cmax increased from 0.315 mg/L ± 0.010 mg/L to 0.423 mg/L ± 0.042 mg/L (P < 0.01). Taken together, co-administration of EtOH with MA significantly accelerated MA absorption and subsequent metabolism to AP, but did not have significant effect on MA elimination.