Table 1.

In vitro P-gp activity of entrectinib, larotrectinib, and crizotinib in LLC-PK1 cells stably transfected with human or mouse P-gp

			In vitro P-gp activity (human)					In vitro P-gp activity (mouse)
	ER	AP-ER	${\mathbf{P}}_{\mathbf{a}\mathbf{p}\mathbf{p}}^{\mathbf{A}\to \mathbf{B}}$ nM/sec ± SD	${\mathbf{P}}_{\mathbf{a}\mathbf{p}\mathbf{p}}^{\mathbf{B}\to \mathbf{A}}$ nM/sec ± SD	${\mathbf{P}}_{\mathbf{a}\mathbf{p}\mathbf{p},\mathbf{i}\mathbf{n}\mathbf{h}}^{\mathbf{A}\to \mathbf{B}}$ nM/sec ± SD	ER	AP-ER	${\mathbf{P}}_{\mathbf{a}\mathbf{p}\mathbf{p}}^{\mathbf{A}\to \mathbf{B}}$ nM/sec ± SD	${\mathbf{P}}_{\mathbf{a}\mathbf{p}\mathbf{p}}^{\mathbf{B}\to \mathbf{A}}$ nM/sec ± SD	${\mathbf{P}}_{\mathbf{a}\mathbf{p}\mathbf{p},\mathbf{i}\mathbf{n}\mathbf{h}}^{\mathbf{A}\to \mathbf{B}}$ nM/sec ± SD
Entrectinib	15 [++]	1.1 [-]	13.5 ± 3.4	197 ± 5	15.2 ± 1.9	26 [++]	1.5 [-]	9.90 ± 0.4	255 ± 19	14.6 ± 0.9
Larotrectinib	10 [++]	2.8 [+]	18.5	182 ± 37	51.9 ± 1.4	20 [++]	6.3 [+]	8.20 ± 0.7	161 ± 7	51.5 ± 2.1
Crizotinib	28 [++]	3.5 [+]	13.8 ± 0.3	388 ± 17	47.9 ± 10.5	29 [++]	4.9 [+]	12.0 ± 1.5	344 ± 16.8	58.6 ± 15.6
Digoxin a	11 [++]	3.9 [+]	10.9 ± 0.7	121 ± 7.3	42.0 ± 2.3	10 [++]	3.4 [+]	12.2 ± 1.0	125 ± 2.8	41.0 ± 3.8

[++] denotes very strong, [+] strong, or [-] weak substrate for P-gp. ^aDigoxin is an in vitro benchmark P-gp substrate, used as a control for the assay. ER was calculated from ${\mathrm{P}}_{\mathrm{a}\mathrm{p}\mathrm{p}}^{\mathrm{A}\to \mathrm{B}}\mathrm{a}\mathrm{n}\mathrm{d}{\mathrm{P}}_{\mathrm{a}\mathrm{p}\mathrm{p}}^{\mathrm{B}\to \mathrm{A}}$ (Equation 2); AP-ER was calculated from ${\mathrm{P}}_{\mathrm{a}\mathrm{p}\mathrm{p}}^{\mathrm{A}\to \mathrm{B}}\mathrm{a}\mathrm{n}\mathrm{d}{\mathrm{P}}_{\mathrm{a}\mathrm{p}\mathrm{p},\mathrm{i}\mathrm{n}\mathrm{h}}^{\mathrm{A}\to \mathrm{B}}$ (Equation 3). A→B, apical-to-basolateral direction; AP-ER, apical efflux ratio; B→A, basolateral-to-apical direction; ER, efflux ratio; P_app, apparent permeability; P_app,inh, apparent permeability in the presence of a P-gp inhibitor (zosuquidar); P-gp, P-glycoprotein; SD, standard deviation.