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

Müllauer, Julia; Kuntner, Claudia; Bauer, Martin; Bankstahl, Jens P; Müller, Markus; Voskuyl, Rob A; Langer, Oliver; Syvänen, Stina

doi:10.1186/2191-219X-2-58

EJNMMI Research

Table 4 Population parameter estimates and relative standard errors (%) of ( R )-[ ¹¹ C]verapamil brain model are shown for all investigated brain regions

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

	Species
	Rat									Human
Brain region	WB ^*,a	WB ^b	CS	EC	SHipp	THipp	Th	Cer	FMC	WB ^*,a	WB ^b
OFV	−604	−1676	−1420	−1652	−1500	−954	−1559	−1562	−1365	7799	−357
Model parameters
V _br1 (ml)	0.132	0.132	0.119	0.155	0.151	0.129	0.156	0.192	0.088	2.29	3.17
V _br1 (ml)	(10.5)	(11.3)	(10)	(11.4)	(9.74)	(27.2)	(12.2)	(19.2)	(15.8)	(−)	(−)
V _br2 (ml)	2	2	2	2	2	2	2	2	2	13.0	18.4
V _br2 (ml)	(−)	(−)	(−)	(−)	(−)	(−)	(−)	(−)	(−)	(−)	(−)
Q _in (ml·min⁻¹)	5.48	5.62	2.05	3.32	2.49	1.98	2.43	2.44	1.79	713	588
Q _in (ml·min⁻¹)	(13.0)	(12.5)	(12.8)	(16.8)	(12.7)	(24.5)	(11.3)	(14.2)	(19.2)	(−)	(−)
Q _out (ml·min⁻¹)	3.56	3.60	3.45	3.91	4.56	2.99	4.39	3.01	1.97	1410	1080
Q _out (ml·min⁻¹)	(12.6)	(12.5)	(12.5)	(16.3)	(12.5)	(21.8)	(11.3)	(13.9)	(19.1)	(−)	(−)
Q _br (ml·min⁻¹)	0.115	0.115	0.114	0.111	0.113	0.108	0.129	0.118	0.12	1.26	1.71
Q _br (ml·min⁻¹)	(3.2)	(3.05)	(3.43)	(3.71)	(3.87)	(4.63)	(3.45)	(3.24)	(3.58)	(−)	(−)
Residual error brain	0.404	0.382	0.44	0.387	0.421	0.571	0.016	0.407	0.454	0.295	0.27
Residual error brain	(5.1)	(4.61)	(5.3)	(6.25)	(4.18)	(14.4)	(3.93)	(5.72)	(6.32)	(−)	(−)
Covariates
Effect of pilocarpine induced SE
Eff_SE ^c	1.84	1.84	1.88	1.73	1.86	2.21	1.77	0.924	2.3	(−)	(−)
Eff_SE ^c	(10.4)	(11.7)	(13.8)	(13.5)	(13.2)	(24.7)	(12.9)	(20.5)	(15.8)
Effect of tariquidar
Eff_tariquidar (3 mg/kg or 2 mg/kg)^d	0.219	0.161	0.114	0.233	0.119	0.15	0.12	0.226	0.194	0.993	0.483
Eff_tariquidar (3 mg/kg or 2 mg/kg)^d	(5.84)	(4.16)	(3.89)	(5.54)	(5.49)	(5.51)	(5.33)	(5.31)	(4.42)	(−)	(−)
Eff_tariquidar (15 mg/kg)^d	0.168	0.135	0.101	0.215	0.101	0.134	0.103	0.148	0.155	(−)	(−)
Eff_tariquidar (15 mg/kg)^d	(5.22)	(6.94)	(7.71)	(6.56)	(9.3)	(7.61)	(9.01)	(8.65)	(7.74)	-	-
Effect of scan on tariquidar induced P-gp inhibition
Eff_scan ^d	(−)	1.33	1.29	1.37	1.29	1.25	1.21	1.52	1.4	(−)	2.28
Eff_scan ^d	-	(5.67)	(6.78)	(5.47)	(7.1)	(6.21)	(6.08)	(6.97)	(6.06)	-	(−)

All (R)-[¹¹C]verapamil plasma model parameter estimates outlined in Figure 2, obtained from final plasma model were fixed and the parameter estimate for the second brain compartment V _br2 was fixed in rats to 2 ml. Parameters are given for the whole brain excluding (WB^*) and including (WB) the increase of (R)-[¹¹C]verapamil brain uptake during and after treatment with tariquidar, corpus striatum (CS), entorhinal cortex (EC), septal hippocampus (SHipp), temporal hippocampus (THipp), thalamus (TH), cerebellum (Cer), and frontal motor cortex (FMC) for rat; WB^* and WB for human. ^aWB^* is the whole brain region excluding data from 60 to 140 min rat or 40 to 120 min human (baseline and post-inhibition scan are considered, as used for kinetic modeling). ^bWB is the whole brain region including data from 60 to 140 min rat or 40 to 120 min human (baseline, during, and after tariquidar, and post-inhibition scan are considered). ^cEff_SE was a significant covariate on V _br1. ^dThe effect of tariquidar, Eff_tariquidar, is on Q _out the efflux clearance from the central brain compartment to the plasma compartment, while Eff_scan also takes into account changes occurring between scans (baseline or post-inhibition).

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