title: Structure-activity relationships of P-glycoprotein interacting drugs: kinetic characterization of their effects on ATPase activity.
abstract: We have determined the kinetic parameters for stimulation and inhibition by 34 drugs of the P-glycoprotein ATPase in membranes derived from CR1R12 Chinese hamster ovary cells. The drugs chosen were sets of calmodulin antagonists, steroids, hydrophobic cations, hydrophobic peptides, chemotherapeutic substrates of P-glycoprotein, and some other drugs with lower affinity for P-glycoprotein. We studied how these kinetic parameters correlated with the partition coefficient and the Van der Waals surface area of the drugs. The maximum velocity of ATPase stimulation decreased with surface area and showed a suggestion of a maximum with increasing partition coefficient. The affinity of these drugs for P-glycoprotein showed no significant correlation with partition coefficient but was highly correlated with the surface area suggesting that binding between modulators and P-glycoprotein takes place across a wide interaction surface on the protein.
authors.affiliation: Department of Oncology, Herlev Hospital, University of Copenhagen, Denmark. T.Litman@mfi.ku.dk
authors.forename: T
authors.initials: T
authors.lastname: Litman
authors.forename: T
authors.initials: T
authors.lastname: Zeuthen
authors.forename: T
authors.initials: T
authors.lastname: Skovsgaard
authors.forename: W D
authors.initials: WD
authors.lastname: Stein
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology; D016466:CHO Cells / Q000187:drug effects; D006224:Cricetinae; D018432:Drug Resistance, Multiple; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000737:chemistry; D010640:Phenothiazines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013256:Steroids / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013696:Temperature; D014748:Vinca Alkaloids / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018943:Anthracyclines; D010455:Peptides; D004364:Pharmaceutical Preparations; D010640:Phenothiazines; D011804:Quinolines; D013256:Steroids; D014748:Vinca Alkaloids; D000251:Adenosine Triphosphatases