TABLE 1

Physicochemical parameters to predict passive blood-brain barrier (BBB) permeability and in vitro transport activities of (breast cancer resistance protein (Bcrp) and P-glycoprotein (P-gp) for 19 compounds

Molecular weight (MW), the partition coefficient in octanol/water at pH 7.4 (LogD) at pH 7.4, and topologic van der Waals polar surface area (TPSA) of test compounds were obtained using ACD/PhysChem Suite (version 12, ACD/Laboratories, Toronto, Canada). The van der Waals surface area of the basic (vsa_base) was obtained using MOE 2010 (Chemical Computing Group, Montreal, QC, Canada). The calculation of the PS₁(1) and PS₁(2) of test compounds is described in Materials and Methods. Corrected flux ratio (CFR), which represents the ratio of transcellular transport in transporter-expressing and control cells, was obtained from a previous study (Kodaira et al., 2011). CFRs that showed statistical significance were included in the calculation; otherwise, CFR was regarded as 1. PS₂, PS₃, and PS₄ were calculated using fitted parameters.

Compound	Physicochemical Parameters				Clearance (ml/min per kg)									CFR		Substrate of P-gp and Bcrp
Compound	MW	cLogD pH 7.4	TPSA	vsa_base	Observed PS₁	PS₁ (1)	PS₂	PS₃	PS₄	PS₁ (2)	PS₂	PS₃	PS₄	Bcrp	P-gp	Substrate of P-gp and Bcrp
Antipyrine	188	0.441	23.55	0.00	4.32^{^a}	4.45	0.0276	0.00253	0.00	5.91	0.0274	0.00558	0	1.0	1.0	Nonsubstrate
Buspirone	386	1.19	69.64	0.00	—	5.70	0.0193	0.00324	0.00	3.64	0.0191	0.00343	0	1.0	1.0	Nonsubstrate
Caffeine	194	−0.628	58.44	0.00	4.32^{^a}	2.84	0.0272	0.00161	0.00	2.58	0.0270	0.00243	0	1.0	1.0	Nonsubstrate
Carbamazepine	236	1.90	46.33	0.00	6.91^{^b}	8.02	0.0247	0.00456	0.00	6.32	0.0245	0.00596	0	1.0	1.0	Nonsubstrate
Citalopram	324	1.35	36.26	0.00	4.18^{^b}	6.21	0.0211	0.00353	0.0	6.30	0.0209	0.00594	0	1.0	1.0	Nonsubstrate
Daidzein	254	2.11	66.76	0.00	—	8.72	0.0238	0.00495	89.3	4.93	0.0236	0.00465	50.5	1.8	1.0	Bcrp
Dantrolene	314	1.43	120.73	0.00	—	6.43	0.0214	0.00365	65.8	1.80	0.0212	0.00170	18.4	1.8	1.0	Bcrp
Diazepam	285	2.80	32.67	0.00	14.2^{^b}	11.5	0.0225	0.00653	0.00	10.0	0.0223	0.00943	0	1.0	1.0	Nonsubstrate
Flavopiridol	402	0.678	90.23	0.00	—	4.59	0.0189	0.00261	157	2.31	0.0188	0.00218	78.8	1.5	4.7	P-gp, Bcrp
Genistein	270	1.93	86.99	0.00	—	8.05	0.0231	0.00457	113	3.45	0.0229	0.00325	48. 6	2.1	1.0	Bcrp
Loperamide	477	3.63	43.78	0.00	—	15.6	0.0174	0.00886	619	10.7	0.0172	0.0101	425	1.0	6.3	P-gp
Midazolam	326	3.78	30.18	0.00	19.6^{^b}	17.2	0.0210	0.00977	0.0	13.7	0.0208	0.0129	0	1.0	1.0	Nonsubstrate
Phenytoin	252	2.52	58.20	0.00	3.51^{^b}	10.4	0.0239	0.00591	0.0	6.30	0.0237	0.00594	0	1.0	1.0	Nonsubstrate
Quinidine	324	0.947	45.59	0.00	0.172^{^a}	5.24	0.0211	0.00298	204	4.89	0.0209	0.00461	190	1.0	6.2	P-gp
Risperidone	410	1.86	61.94	0.00	6.12^{^b}	7.53	0.0187	0.00428	95.9	4.94	0.0186	0.00466	62.9	1.0	2.7	P-gp
Sertraline	306	3.04	12.03	5.68	31.6^{^b}	12.7	0.0217	0.00722	0.0	31.6	0.0215	0.0298	0	1.0	1.0	Nonsubstrate
Thiopental	242	2.99	90.29	0.00	—	12.7	0.0244	0.00722	0.00	4.43	0.0242	0.00418	0	1.0	1.0	Nonsubstrate
Verapamil	455	2.46	63.95	0.00	—	9.58	0.0178	0.00544	172	5.68	0.0176	0.00536	102	1.0	3.4	P-gp
Zolpidem	307	2.97	37.61	0.00	—	12.3	0.0216	0.00699	0.0	9.77	0.0215	0.00922	0	1.0	1.0	Nonsubstrate

Bcrp, breast cancer resistance protein; P-gp, P-glycoprotein.
↵^a These PS values observed at the BBB (observed PS₁) in rats were obtained by Liu et al. (2004).
↵^b These PS values obserbed at the BBB (observed PS₁) were obtained by Summerfield et al. (2007).