Cholesterol alters the binding of Ca2+ channel blockers to the membrane lipid bilayer
Mason, R.P.; Moisey, D.M.; Shajenko, L.
Molecular Pharmacology 41(2): 315-321
1992
ISSN/ISBN: 0026-895X PMID: 1531693 Document Number: 397614
X-ray diffraction and equilibrium binding techniques were used to study the effect of cholesterol on membrane binding of the charged 1,4-dihydropyridine (DHP) Ca2+ channel antagonist amlodipine and uncharged isradipine, nimodipine, and nitrendipine. Increases in membrane cholesterol content resulted in a marked decrease in DHP binding to cardiac phospholipid membranes, as expressed by the equilibrium partition coefficient (Kp greater than 10(4) and the slowest rate of dissociation and was affected least by membrane cholesterol content. The combination of electrostatic and hydrophobic bonding between amlodipine and membrane phospholipid may explain the high affinity of this drug for the membrane bilayer with normal and elevated cholesterol. The results of this study show that cholesterol content differentially affects the membrane-binding properties of the charged DHP amlodipine, compared with other Ca2+ channel blockers. These data help explain the biological distribution of these drugs and the distinct pharmacokinetics of amlodipine versus other Ca2+ channel blockers.