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Abstract: The toxicity depending on both dose and administration route is the major obstacle to the development of brucine, a bioactive alkaloid from Semen Strychni. In this study, the apparent partition coefficient and plasma protein binding extent of brucine were determined. In addition, the dose-dependency of the pharmacokinetics of brucine was investigated. Three intravenous (2.5, 5 and 10mg/kg) and three oral (10, 20 and 40mg/kg) doses were administered to rats. After intravenous administration, the systemic clearance was reduced and AUC was nonlinearly increased as a function of dose. Upon oral administration, brucine was rapidly absorbed (Tmax <0.5h), which was consistent with previously reported high Caco-2 Papp values. The increase in AUC was proportional to the increase in dose. The oral bioavailability (F) did not vary with the dose (F=40.31%, 47.15% and 43.02% for 10, 20, 40mg/kg doses, respectively). However, the dose-proportionality was not observed with Cmax. The values of Cmax/Dose were calculated to be 92.92±45.83, 55.73±24.01 and 36.29±22.44μg/L for 10, 20 and 40mg/kg, respectively. The results of dose-dependent pharmacokinetic behavior under different administration routes may account for the significantly different toxicities of brucine between intravenous and oral administration. [Copyright &y& Elsevier]