Dirson Grégoire, Fernandez Christine, Hindlet Patrick, Roux Françoise, German-Fattal Michèle, Gimenez François, Farinotti Robert
Clinical Pharmacy Unit (EA 2706; Barrières et passage des medicaments), University of Paris-Sud XI, 5 rue Jean-Baptiste Clément, Châtenay-Malabry, 92296, France.
Pharm Res. 2006 Jul;23(7):1525-32. doi: 10.1007/s11095-006-0279-5. Epub 2006 Jun 21.
This work characterizes the interactions between efavirenz (EFV) and P-glycoprotein (P-gp/ABCB1) at the blood-brain barrier (BBB) and predicts the possible consequences on the brain uptake of coadministered P-gp substrates.
The uptake of EFV was measured in whole brains of rat and mdr1a-/- and mdr1a+/+ mice, and in GPNT cells (rat brain endothelial cell line) with and without P-gp inhibitors (PSC833, S9788, Quinidine). The effect of a single dose or multiple doses of EFV on the P-gp functionality was evaluated in vivo and in vitro by measuring the brain and cell uptake of digoxin, completed by the analysis of the P-gp expression at the rat BBB after repeated administrations of EFV.
Inhibition of P-gp did not alter the uptake of EFV in rat brain and GPNT cells. The EFV brain/plasma ratio in mdr1a-/- mice, lacking the expression of P-gp, was not different from that in mdr1a+/+ mice. Moreover, a single dose of EFV did not modify the uptake of digoxin in rat brain and GPNT cells. Finally, the 3-day exposure of GPNT cells to EFV did not have any effect on the uptake of digoxin. Similarly, the 7-day treatment with EFV did not change the uptake of digoxin in rat brain nor the expression of P-gp at the BBB.
EFV is strongly distributed in the brain, but is neither a substrate nor an inhibitor of the P-gp at the blood-brain barrier. On the other hand, EFV did not induce P-gp, allowing to sustain the brain accumulation of associated P-gp substrates such as protease inhibitors. These findings make EFV suitable for combinations circumventing the brain HIV-1 residency.
本研究旨在表征依非韦伦（EFV）与血脑屏障（BBB）处的P-糖蛋白（P-gp/ABCB1）之间的相互作用，并预测其对同时给药的P-gp底物脑摄取的可能影响。
在大鼠、mdr1a-/-和mdr1a+/+小鼠的全脑中，以及在有或没有P-gp抑制剂（PSC833、S9788、奎尼丁）的GPNT细胞（大鼠脑内皮细胞系）中测量EFV的摄取。通过测量地高辛的脑摄取和细胞摄取，并在重复给予EFV后分析大鼠血脑屏障处的P-gp表达，在体内和体外评估单剂量或多剂量EFV对P-gp功能的影响。
抑制P-gp不会改变大鼠脑和GPNT细胞中EFV的摄取。缺乏P-gp表达的mdr1a-/-小鼠的EFV脑/血浆比值与mdr1a+/+小鼠的无差异。此外，单剂量的EFV不会改变大鼠脑和GPNT细胞中地高辛的摄取。最后，GPNT细胞暴露于EFV 3天对地高辛的摄取没有任何影响。同样，EFV治疗7天不会改变大鼠脑中地高辛的摄取，也不会改变血脑屏障处P-gp的表达。
EFV在脑中分布广泛，但既不是血脑屏障处P-gp的底物，也不是其抑制剂。另一方面，EFV不会诱导P-gp，从而能够维持相关P-gp底物（如蛋白酶抑制剂）的脑内蓄积。这些发现使EFV适用于规避脑内HIV-1驻留的联合用药方案。
