Evaluation of the pharmacodynamics and pharmacokinetics of brucine following transdermal administration

Abstract

Before the design of brucine-containing transdermal formulations, the pharmacodynamics and pharmacokinetics of brucine following transdermal administration should be evaluated. In this study, the effect of addition of ethanol on solubility of bruicne was investigated and 20% ethanol was added into PBS to obtain 10mg/mL brucine solution. Then three transdermal doses (10, 20 and 40 mg/kg) were administered to mice to evaluate pharmacological activity. It had been demonstrated that brucine possessed analgesic and anti-inflammatory activity in a dose-dependent manner. Cytotoxicities of brucine against various tumor cells including skin tumor cell were also compared in vitro. Brucine was found to possess antitumor activity in a concentration and time-dependent manner and gastrointestinal tumor cells seemed to be more sensitive to brucine. Then in vitro skin permeation behavior and in vivo pharmacokinetics following transdermal administration were further investigated. The cumulative amounts of brucine across mouse skin in vitro were found to be higher than 90%. The absolute bioavailability of brucine was determined to be 40.83%. And compared with intravenous administration, MRT and T1/2 values were increased about 8~12-fold by transdermal route. Moreover, fluctuations of drug levels were found to be significantly decreased in tissues, especially in brain. Finally, no dermal toxicity of brucine was observed. The results of this study indicated that transdermal administration might be beneficial for the sustained efficacy and reduced toxicity of brucine.