Hirunpanich Vilasinee, Sato Hitoshi
Mahasarakham University, Kantharavichai, Mahasarakham, 44150, Thailand.
J Pharm Pharmacol. 2006 May;58(5):651-8. doi: 10.1211/jpp.58.5.0010.
This study investigated the effect of docosahexaenoic acid (DHA) on the metabolism of saquinavir by cytochrome P450 3A (CYP3A) in-vitro using rat liver microsomes and in-vivo using rats. DHA showed a concentration-dependent inhibition of in-vitro saquinavir metabolism with Km, Vmax and Ki values of 2.21 microM, 0.054 micromol h(-1) (mg protein)(-1) and 149.6 microM, respectively. After oral co-administration with 250 microg kg(-1) DHA, the bioavailability of saquinavir significantly increased approximately 4 fold (P < 0.01) without affecting the elimination half-life, as compared with the control. In contrast, oral administration of DHA did not affect the kinetic parameters of saquinavir administered intravenously. These results suggest that the inhibitory effect of DHA on saquinavir metabolism predominantly takes place in the gut and imply that DHA impairs the function of enteric, but not of hepatic, CYP3A. The pharmacokinetic interaction occurred only when DHA was taken simultaneously with oral administration of saquinavir. These results considered together with the lack of time-dependent saquinavir metabolism inactivation effects in-vitro, imply that the inhibitory effect of DHA is primarily reversible. It is concluded that DHA inhibited saquinavir metabolism in-vitro and enhanced the oral bioavailability of saquinavir in rats.
本研究使用大鼠肝微粒体在体外以及使用大鼠在体内研究了二十二碳六烯酸（DHA）对细胞色素P450 3A（CYP3A）介导的沙奎那韦代谢的影响。DHA对体外沙奎那韦代谢呈浓度依赖性抑制，其Km、Vmax和Ki值分别为2.21 microM、0.054 micromol h(-1)（mg蛋白）(-1)和149.6 microM。与对照组相比，口服250 microg kg(-1) DHA后，沙奎那韦的生物利用度显著增加约4倍（P < 0.01），且不影响消除半衰期。相反，口服DHA不影响静脉注射沙奎那韦的动力学参数。这些结果表明，DHA对沙奎那韦代谢的抑制作用主要发生在肠道，提示DHA损害肠道而非肝脏CYP3A的功能。仅当DHA与口服沙奎那韦同时服用时才会发生药代动力学相互作用。这些结果与体外缺乏沙奎那韦代谢的时间依赖性失活效应一起表明，DHA的抑制作用主要是可逆的。结论是，DHA在体外抑制沙奎那韦代谢并提高了大鼠体内沙奎那韦的口服生物利用度。
