Table 3.

Relation between the ability of MLs to inhibit the P-gp transport activity, to modulate ATPase activity and their lipophilicity.

	In LLCPK1-mdr1a cells	ATPase activity in P-gp overexpressing vesicles	ML lipophilicity
	IC50 (μM)	Calculated Ki (μM)	log Pa
Reference P-gp inhibitors
Valspodar	0.11	nd
Cyclodsporin	nd	0.015b
Verapamil	3.2	nd
Macrocyclic lactones
Ivermectin	0.44	0.05	4.8
Eprinomectin	0.50	0.02	4.4
Abamectin	0.11	0.02	5.3
Doramectin	0.31	0.03	5.6
Selamectin	0.60	1.0	6.3
Moxidectin	4.4	0.5	6

ATPase activity of P-gp was measured on membrane vesicles prepared from Chinese hampster cells overexpressing P-gp, in the presence of 5 mM ATP and ivermectin (0.05–100 μM). ATPase activity was first activated by verapamil (40 μM). IC₅₀ is defined as the ivermectin concentration that inhibits by 50% the activated ATPase activity. The K_i of ivermectin was calculated as follows:

$$K_{\text{i}}=\frac{{\mathrm{IC}}_{50}\times K_{\text{act}}}{K_{\text{act}}+(S^{\circ })}$$

where IC₅₀ was determined for ivermectin for each transporter inhibition assay; (S^○) was the concentration of the reference activator used in the inhibition assay; K_act was the concentration of the reference activator that allowed half maximum ATPase activation of the corresponding transporter.

^aHyperChem 7.0, HyperCube Inc.

^bGarrigues et al. (2002).