STRUCTURE-ACTIVITY-RELATIONSHIPS OF P-GLYCOPROTEIN INTERACTING DRUGS - KINETIC CHARACTERIZATION OF THEIR EFFECTS ON ATPASE ACTIVITY

We have determined the kinetic parameters for stimulation and inhibiti on by 34 drugs of the P-glycoprotein ATPase in membranes derived from CR1R12 Chinese hamster ovary cells. The drugs chosen were sets of calm odulin antagonists, steroids, hydrophobic cations, hydrophobic peptide s, 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 W aals surface area of the drugs. The maximum velocity of ATPase stimula tion 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 coeff icient but was highly correlated with the surface area suggesting that binding between modulators and P-glycoprotein takes place across a wi de interaction surface on the protein.