Frijlink H W, Franssen E J, Eissens A C, Oosting R, Lerk C F, Meijer D K
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, The Netherlands.
Pharm Res. 1991 Mar;8(3):380-4. doi: 10.1023/a:1015857902238.
Naproxen and flurbiprofen form complexes with hydroxypropyl-beta-cyclodextrin; with stability constants of 2207 and 12515 M-1, respectively. However, only small fractions of the drug remain complexed when the drug-cyclodextrin complex is added to plasma in vitro. This result can be explained by albumin effectively competing with cyclodextrin for drug binding and by the simultaneous displacement of the drug from cyclodextrins by plasma cholesterol. Naproxen and flurbiprofen were administered intravenously to rats as cyclodextrin complexes. The disposition in the body of naproxen was not significantly altered by the complexation. This indicates that immediately after administration all drug is removed from the cyclodextrin complex. However, the initial distribution of flurbiprofen was changed upon complexation. Drug concentrations in liver, brain, kidney, and spleen were increased, indicating that hydroxypropyl-beta-cyclodextrin may improve the presentation of the flurbiprofen to biomembranes, as compared with plasma proteins. The effect was transient; 60 min after injection the differences in tissue concentration compared with controls were dissipated. Finally, the importance of protein binding in determining the mode of interaction of cyclodextrins on drug disposition is discussed.
萘普生和氟比洛芬与羟丙基-β-环糊精形成复合物，其稳定常数分别为2207 M⁻¹和12515 M⁻¹。然而，当药物-环糊精复合物在体外加入血浆时，只有一小部分药物保持复合状态。这一结果可以通过白蛋白与环糊精有效竞争药物结合以及血浆胆固醇同时将药物从环糊精中置换出来来解释。萘普生和氟比洛芬作为环糊精复合物静脉注射给大鼠。萘普生的体内处置并未因复合作用而发生显著改变。这表明给药后立即所有药物都从环糊精复合物中释放出来。然而，氟比洛芬的初始分布在复合后发生了变化。肝脏、脑、肾和脾中的药物浓度增加，这表明与血浆蛋白相比，羟丙基-β-环糊精可能改善了氟比洛芬向生物膜的递送。这种效应是短暂的；注射后60分钟，与对照组相比，组织浓度的差异消失。最后，讨论了蛋白质结合在确定环糊精与药物处置相互作用模式中的重要性。
