TABLE 4

Permeability in MDCK-MDR1 monolayers for LSN3207841(M2) and LSN3420637 (M16) and LSN3182170 (HCl salt of LY3202626, parent)

Compound		rD0, µM	Pe ± S.D. × 10⁻⁶ cm/s	% Cell ± S.D.	% Recovery	Pe _BL/AP	Pe _c/l	P-gp	P-gp Inhibition %		Comments
Compound		rD0, µM	Pe ± S.D. × 10⁻⁶ cm/s	% Cell ± S.D.	% Recovery	Pe _BL/AP	Pe _c/l	P-gp	5 µM	25 µM	Comments
M2	P-gp inhibited							Yes	0	0	Very slow Pe, very low % cell, inhibition unlikely
	A-B	3.5	1.1 ± 0.25	0.34 ± 0.00	102 ± 0.56	0.71	29
	B-A	3.3	0.80 ± 0.00	0.31 ± 0.00	100 ± 5.1
	P-gp active
	A-B	3.3	0.57 ± 0.05	0.30 ± 0.02	100 ± 1.4	21
	B-A	3.4	12 ± 0.26	0.27 ± 0.02	89 ± 3.6
M16	P-gp inhibited							Yes	1	21	Fast Pe, moderate % cell, inhibition unlikely
	A-B	3.5	53 ± 0.14	20 ± 0.18	154 ± 0.40	0.99	6.1
	B-A	2.8	53 ± 0.04	19 ± 0.73	130 ± 3.9
	P-gp active
	A-B	2.6	16 ± 2.1	11 ± 0.09	115 ± 5.7	6.0
	B-A	2.6	97 ± 0.62	7.9 ± 0.42	125 ± 4.1
Parent	P-gp inhibited							No	6	25	Fast Pe, high partitioning, inhibition unlikely
	A-B	2.1	19 ± 2.3	50 ± 0.53	92 ± 8.6	1.2	1.5
	B-A	2.4	21 ± 0.02	28 ± 0.00	97 ± 5.5
	P-gp active
	A-B	2.8	15 ± 0.13	49 ± 1.6	88 ± 0.25	1.8
	B-A	2.7	27 ± 1.1	27 ± 5.4	94 ± 1.4

rD0 is the measured concentration of recovered donor solution at t = 60 min. Pe is the apparent permeability coefficient (n = 2) with 60-min time interval: AB, BA>15, fast; AB, BA is 2–15, moderate; AB, BA is 1–2, slow; AB, BA is <1, very slow. % Cell is the amount extracted from cell with methanol relative to recovered mass: <1%, very low; 1%–5%, low; 6%–20%, moderate; 21%–89%, high; ≥90%, very high (invalidates Pe values because compound prefers lipid environment, assay artifact). %Recovery is the mass of D60 + cell60 + R60/D0 (measured concentration of donor solution at t = 0) × 100. If >100%, then D0 is underestimated. Pe _BL/AP is the ratio of Pe values in B-to-A and A-to-B directions; >3.0 + active efflux; Pe _C/I is the net efflux ratio = inhibited BA/AB and control BA/AB ratio. P-gp Yes (Y), No (N), or Unknown (U): if ≥3, Y; <3, N; if % Cell > 90, U. P-gp inhibition, two concentrations (5 and 25 µM) tested for calcein AM uptake assay in MDCK-MDR1 cells; % inhibition vs. LSN335984 (EC₅₀ = 0.15–0.3 µM), pending at 5 µM: 0–20, inhibition unlikely, 21–50, partial inhibition possible, >51%, partial inhibition likely.