Influence of membrane partitioning on inhibitors of membrane-bound enzymes

摘要: Membrane–water partitioning of inhibitors acyl-coenzyme A:cholesterol acyltransferase (ACAT) governs the concentration inhibitor that ACAT is exposed to and determines corresponding extent cholesterol esterification inhibition. Partitioning CI-976, CL 277,082, SaH 58-035 into rat liver microsomes containing was detected by shifts in level inhibition were independent but inversely dependent on microsome membrane concentration. The equilibrium distribution between aqueous phases derived directly from these data application a previously described method linear analysis. accuracy analysis based kinetic verified for CI-976 direct measurements [14C]CI-976 phospholipid membranes. results show are highly partitioned membranes factors exceeding 1 × 106. This result consistent with far greater influence content over volume activity. demonstrate size phase suspension must be taken account obtain accurate reproducible characterizations membrane-active molecules. Analyses membrane-dependent activity can used calculate membrane–water coefficient molecules such as inhibitors. © 2001 Wiley-Liss, Inc. American Pharmaceutical Association J Pharm Sci 90:1859–1867,