Ahn Sung-Hoon, Jeon Seng-Ho, Tsuruo Takashi, Shim Chang-Koo, Chung Suk-Jae
Department of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
J Pharm Sci. 2004 Feb;93(2):283-92. doi: 10.1002/jps.10546.
The objective of this study was to examine the kinetics of the distribution of dehydroevodiamine (DHED) in the rat brain. After an intravenous infusion of 15 min (dose of 1-10 mg/kg), the temporal profiles of the plasma levels of DHED declined in a multiexponential manner. Moment analysis indicated that the clearance and steady-state volume of distribution for DHED were not statistically different with the dose, indicating that the pharmacokinetics for DHED is linear in the range examined. Nonlinear regression analysis of DHED concentrations in the plasma and the brain revealed that the linear kinetics into and out from the brain reasonably described the data and that the clearances for influx into and efflux from the brain were comparable. Transport clearances for DHED across MBEC4 monolayers, an in vitro model of the blood-brain barrier, were also comparable for influx and efflux, and were independent of the medium concentration. The concentration of DHED in cerebrospinal fluid was negligible compared with that found in plasma, indicating that the drug is not primarily distributed to the brain via the blood-cerebrospinal fluid barrier. These observations indicate that DHED is transported from the systemic circulation to the brain via the blood-brain barrier by linear kinetics.
本研究的目的是考察去氢吴茱萸碱（DHED）在大鼠脑内的分布动力学。静脉输注15分钟（剂量为1 - 10 mg/kg）后，DHED的血浆浓度时间曲线呈多指数下降。矩量分析表明，DHED的清除率和稳态分布容积在不同剂量下无统计学差异，表明在所考察的剂量范围内，DHED的药代动力学呈线性。对血浆和脑内DHED浓度进行非线性回归分析发现，药物进出脑的线性动力学能合理地描述数据，且药物流入和流出脑的清除率相当。在血脑屏障体外模型MBEC4单层细胞中，DHED的转运清除率在流入和流出时也相当，且与培养基浓度无关。与血浆中发现的浓度相比，脑脊液中DHED的浓度可忽略不计，表明该药物并非主要通过血脑脊液屏障分布到脑内。这些观察结果表明，DHED通过血脑屏障以线性动力学从体循环转运至脑内。
