Application of a new MDCKII-MDR1 cell model to measure the extent of drug distribution in vitro at equilibrium for prediction of in vivo unbound brain-to-plasma drug distribution

Table 1 In vitro bidirectional transport of 16 reference compounds across MDCKII-MDR1

Compound	Permeability (P_app) (10^–6 cm/s)		Efflux ratio	Human P-gp substrate classification	Permeability classification
	P_app,AtoB	P_app,BtoA			P_app,AtoB
Altanserin	3.0 ± 0.6	3.4 ± 0.3	1.1	Unlikely	Moderate
Antipyrine	39 ± 1	48 ± 3	1.2	Unlikely	High
Atenolol	< LLOQ	< LLOQ	NA	NA	Low
Buspirone	21 ± 2	20 ± 3	0.9	Unlikely	High
Cimetidine	< LLOQ	2.5 ± 0.2	NA	Possible	Low
Citalopram	4.7 ± 0.4	7.7 ± 0.3	1.7	Possible	Moderate
Diphenhydramine	9.8 ± 1.3	16 ± 1	1.6	Possible	Moderate
Doxepin	2.0 ± 0.1	2.2 ± 0.1	1.1	Unlikely	Moderate
Fluoxetine	0.4 ± 0.1	0.4 ± 0.1	1.0	Unlikely	Low
Gabapentin	2.9 ± 0.7	1.6 ± 0.2	0.5	Unlikely	Moderate
Indomethacin	3.7 ± 0.5	2.7 ± 0.3	0.7	Unlikely	Moderate
Metoclopramide	24 ± 1	49 ± 3	2.0	Likely	High
N-desmethylclozapine*	2.1 ± 0.5	4.4 ± 0.3	2.1	Likely	Moderate
Propranolol	4.5 ± 0.4	3.7 ± 0.1	0.8	Unlikely	Moderate
Risperidone	8.5 ± 1.2	37 ± 4	4.4	Likely	Moderate
Way-100635	13 ± 1	17 ± 3	1.3	Unlikely	High

MDCKII-cells transfected with the human P-gp-transporter (hMDR1). Data represents mean ± SD of one test occasion of three individual filters, ‘n’ denotes test occasions, and ‘total N’ denotes the total number of replicates (n = 1, total N = 3). Recovery > 75% in total recovery (with monolayer accounted for)
^* Also tested with an inhibitor present given P_{app (A-B)}: 3.6 ± 0.2 and P_{app (B-A)}: 2.9 ± 0.5, with an ER of 0.8
Permeability classification: low: P_app < 1, moderate > 1 P_app < 10, and high: Papp > 10
P-gp substrate classification: likely P-gp substrates: ER > 2, possible substrates: ER > 1.5, and unlikely substrates: ER < 1.5
NA not available

ISSN: 2045-8118