The influence of enaminones on the transport and oral bioavailability of P-glycoprotein substrate therapeutic agents.
The influence of enaminones on the transport and oral bioavailability of P-glycoprotein substrate therapeutic agents.
复制标题
烯胺酮对 P-糖蛋白底物治疗剂的转运和口服生物利用度的影响。
DOI：
10.1016/j.ijpharm.2003.12.020
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发表时间：
2004
影响因子：
5.8
通讯作者：
Eddington,NatalieD
中科院分区：
文献类型：
--
作者：
Salama,NohaN;Scott,KennethR;Eddington,NatalieD
ObjectiveThe enaminones have shown high P-gp affinity and may act as P-gp modulators. This study investigated the potential inhibition of the enaminones on paclitaxel efflux in vitro compared to cyclosporin A, a known P-gp inhibitor, and the effectiveness of select enaminones on paclitaxel oral absorption in rats.MethodsCaco-2 transport of [14C ]paclitaxel was evaluated in presence of various enaminones at 10−5M. Concentration–effect (10−10M to 10−4M) profiles for the enaminones, DM27 and/or DM40, with paclitaxel and cyclosporin A were determined. Male Sprague–Dawley (250–275g) rats were orally administered either [14C ]paclitaxel (30μCi/kg) or [14C ]paclitaxel/DM27 (7mg/kg) and blood samples were collected. Paclitaxel brain concentrations were measured.ResultsPapp(A–B)of [14C ]paclitaxel, with DM27 and DM40 at 10−5M, was significantly (P<0.05) higher versus control. DM27 produced a 360% and a 139% increase in Papp(A–B)Paclitaxeland Papp(A–B)Cyclosporin, respectively. DM40 displayed a 131% increase in Papp(A–B)Paclitaxelwhereas cyclosporin A produced a 213% increase in Papp(A–B)Paclitaxel. Rats in the DM27 group displayed large Vdss/F values (23.35 liters/kg versus 14.62 liters/kg) and lower AUC (5.47μg/mlmin versus 8.74μg/mlmin) versus control. However, significantly higher levels (2.25-fold) of paclitaxel were observed in the brains of the DM27 group.ConclusionThis study presents the enaminones as promising P-gp inhibitors with comparable potency to other P-gp inhibitors. Furthermore, the enaminones may improve conventional therapy when used in combination with P-gp substrate drugs.
