Brocks Dion R, Wasan Kishor M
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada.
J Pharm Sci. 2002 Aug;91(8):1817-26. doi: 10.1002/jps.10182.
The objective of this study was to determine the effect of lipids on the pharmacokinetics of halofantrine enantiomers. Rats were given (+/-)-halofantrine HCl 2 mg/kg i.v., or 7 mg/kg orally. Some rats were rendered hyperlipidemic by intraperitoneal administration of poloxamer 407 1 g/kg, followed by (+/-)-halofantrine HCl intravenously. In other normolipidemic rats, (+/-)-halofantrine was administered under fasted conditions, or after peanut oil given orally. Halofantrine enantiomer plasma concentrations were considerably (>10-fold) increased in hyperlipidemia. Decreases were noted in the clearance, volume of distribution and the unbound fraction in plasma of the hyperlipidemic rats. Peanut oil caused a significant 28% reduction in clearance of the (-), but not the (+) enantiomer (mean clearance reduced 11%) of halofantrine. After oral halofantrine, peanut oil resulted in a two- to threefold increase in the plasma area under the curves of halofantrine enantiomers. Halofantrine enantiomer pharmacokinetics are highly dependent upon plasma lipid concentrations. Oral lipids may result in a stereoselective interaction at the level of clearance. Because lipids may affect clearance of drugs that bind to lipoproteins, in determining bioavailability of such drugs in food-effect studies, reference intravenous groups should be included to separate true increase in bioavailability from the effects of decreased clearance.
本研究的目的是确定脂质对卤泛群对映体药代动力学的影响。给大鼠静脉注射2mg/kg的（±）-盐酸卤泛群，或口服7mg/kg。部分大鼠通过腹腔注射1g/kg泊洛沙姆407使其血脂升高，随后静脉注射（±）-盐酸卤泛群。在其他血脂正常的大鼠中，在禁食条件下或口服花生油后给予（±）-卤泛群。高脂血症时卤泛群对映体的血浆浓度显著升高（>10倍）。高脂血症大鼠的清除率、分布容积和血浆中未结合分数均降低。花生油使卤泛群（-）对映体的清除率显著降低28%，但（+）对映体未受影响（平均清除率降低11%）。口服卤泛群后，花生油使卤泛群对映体的血浆曲线下面积增加了两到三倍。卤泛群对映体的药代动力学高度依赖于血浆脂质浓度。口服脂质可能在清除率水平上导致立体选择性相互作用。由于脂质可能影响与脂蛋白结合的药物的清除率，在食物效应研究中确定此类药物的生物利用度时，应纳入静脉注射参考组，以区分生物利用度的真正增加与清除率降低的影响。
