Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood–brain barriers studied with (R)-[11C]verapamil positron emission tomography

EJNMMI Research

Table 5 Comparison of volumes of distribution ( V _T ) values of naïve, 48-h SE rats, and humans obtained with Logan analysis, PK modeling, and nonlinear mixed effects modeling, respectively

Sample	Logan analysis ^a		PK modeling ^a(2T4K)		Nonlinear mixed effects modeling
Sample	WB*	Cer	WB*	Cer	WB*	WB	Cer
Control rats
Baseline	1.6 (16)	2.0 (19)	1.8 (16)	2.2 (18)	1.5 (18)	1.6 (18)	0.81 (20)
Post-inhibition	7.6 (13)	6.1 (9)	7.8 (14)	6.1 (9)	7.0 (19)	9.6 (18)	2.4 (21)
Increase after 3 mg/kg tariquidar^b	4.8-fold	3.1-fold	4.4-fold	2.8-fold	4.6-fold	6.2-fold	4.4-fold
48-h post SE rats
Baseline	1.4 (8)	1.3 (7)	1.5 (12)	1.5 (6)	1.5	1.6	0.81
Post-inhibition	7.4 (11)	3.5 (13)	7.6 (12)	3.6 (14)	7.0	9.6	2.4
Increase after 3 mg/kg tariquidar^b	5.5-fold	2.6-fold	5.1-fold	2.4-fold	4.6-fold	6.2-fold	4.4-fold
Human
Baseline scan	0.64 (1)		0.65 (6)	-	0.54 (−)	0.51 (−)	-
Post-inhibition	0.79 (1)		0.80 (2)	-	0.49 (−)	0.79 (−)	-
Increase after 2 mg/kg tariquidar^b	1.2-fold		1.2-fold	-	No difference	1.5-fold	-

V _T values were expressed as average and relative standard errors (%) for the WB region and Cer at baseline and post-inhibition scan. ^aLogan and 2T4K results were obtained from Bankstahl et al. [9] for rats and from Wagner et al. [30] for humans. ^bIncrease after tariquidar administration for NLME modeling is based on the estimated covariate effect Eff_tariquidar(1/Eff_tariquidar).