title: Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship.
abstract: P-glycoprotein (P-gp) is involved in the ATP-dependant cellular efflux of a large number of drugs including ivermectin, a macrocyclic lactone (ML) endectocide, widely used in livestock and human antiparasitic therapy. The interactions of P-gp with ivermectin and other MLs were studied. In a first approach, the ability of ivermectin (IVM), eprinomectin (EPR), abamectin (ABA), doramectin (DOR), selamectin (SEL), or moxidectin (MOX) to inhibit the rhodamine123 efflux was measured in recombinant cells overexpressing P-gp. Then, the influence of these compounds on the P-gp ATPase activity was tested on membrane vesicles prepared from fibroblasts overexpressing P-gp. All the MLs tested increased the intracellular rhodamine123. However, the potency of MOX to inhibit P-gp function was 10 times lower than the other MLs. They all inhibited the basal and decreased the verapamil-stimulated P-gp ATPase activity. But SEL and MOX were less potent than the other MLs when competing with verapamil. According to the structural specificity of SEL and MOX, we conclude that the integrity of the sugar moiety is determinant to achieve the optimal interaction of macrocyclic lactones with P-gp. The structure-affinity relationship for interaction with P-gp is important information for improving ML bioavailability and reversal of multidrug resistance (MDR).
authors.affiliation: INRA-UR66, Laboratoire de Pharmacologie-Toxicologie, BP 3, 31931 Toulouse Cedex 9, France. lespine@toulouse.inra.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Lespine
authors.forename: Solenne
authors.initials: S
authors.lastname: Martin
authors.forename: Jacques
authors.initials: J
authors.lastname: Dupuy
authors.forename: Alain
authors.initials: A
authors.lastname: Roulet
authors.forename: Thierry
authors.initials: T
authors.lastname: Pineau
authors.forename: Stéphane
authors.initials: S
authors.lastname: Orlowski
authors.forename: Michel
authors.initials: M
authors.lastname: Alvinerie
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D002460:Cell Line; D003001:Cloning, Molecular; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D007783:Lactones / Q000737:chemistry / Q000493:pharmacokinetics*; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007783:Lactones; D047028:Macrocyclic Compounds