Table 4.
Population parameter estimates and relative standard errors (%) of (R)-[11C]verapamil brain model are shown for all investigated brain regions
| |
Species |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| |
Rat |
Human |
|||||||||
| Brain region | WB*,a | WBb | CS | EC | SHipp | THipp | Th | Cer | FMC | WB*,a | WBb |
| OFV |
−604 |
−1676 |
−1420 |
−1652 |
−1500 |
−954 |
−1559 |
−1562 |
−1365 |
7799 |
−357 |
| Model parameters |
|
|
|
|
|
|
|
|
|
|
|
|
Vbr1 (ml) |
0.132 |
0.132 |
0.119 |
0.155 |
0.151 |
0.129 |
0.156 |
0.192 |
0.088 |
2.29 |
3.17 |
| (10.5) |
(11.3) |
(10) |
(11.4) |
(9.74) |
(27.2) |
(12.2) |
(19.2) |
(15.8) |
(−) |
(−) |
|
|
Vbr2 (ml) |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
13.0 |
18.4 |
| (−) |
(−) |
(−) |
(−) |
(−) |
(−) |
(−) |
(−) |
(−) |
(−) |
(−) |
|
|
Qin (ml·min−1) |
5.48 |
5.62 |
2.05 |
3.32 |
2.49 |
1.98 |
2.43 |
2.44 |
1.79 |
713 |
588 |
| (13.0) |
(12.5) |
(12.8) |
(16.8) |
(12.7) |
(24.5) |
(11.3) |
(14.2) |
(19.2) |
(−) |
(−) |
|
|
Qout (ml·min−1) |
3.56 |
3.60 |
3.45 |
3.91 |
4.56 |
2.99 |
4.39 |
3.01 |
1.97 |
1410 |
1080 |
| (12.6) |
(12.5) |
(12.5) |
(16.3) |
(12.5) |
(21.8) |
(11.3) |
(13.9) |
(19.1) |
(−) |
(−) |
|
|
Qbr (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 |
| (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 |
| (5.1) |
(4.61) |
(5.3) |
(6.25) |
(4.18) |
(14.4) |
(3.93) |
(5.72) |
(6.32) |
(−) |
(−) |
|
| Covariates |
|
|
|
|
|
|
|
|
|
|
|
| Effect of pilocarpine induced SE |
|
|
|
|
|
|
|
|
|
|
|
| EffSEc |
1.84 |
1.84 |
1.88 |
1.73 |
1.86 |
2.21 |
1.77 |
0.924 |
2.3 |
(−) |
(−) |
| (10.4) |
(11.7) |
(13.8) |
(13.5) |
(13.2) |
(24.7) |
(12.9) |
(20.5) |
(15.8) |
|
|
|
| Effect of tariquidar |
|
|
|
|
|
|
|
|
|
|
|
| Efftariquidar (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 |
| (5.84) |
(4.16) |
(3.89) |
(5.54) |
(5.49) |
(5.51) |
(5.33) |
(5.31) |
(4.42) |
(−) |
(−) |
|
| Efftariquidar (15 mg/kg)d |
0.168 |
0.135 |
0.101 |
0.215 |
0.101 |
0.134 |
0.103 |
0.148 |
0.155 |
(−) |
(−) |
| (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 |
|
|
|
|
|
|
|
|
|
|
|
| Effscand | (−) |
1.33 |
1.29 |
1.37 |
1.29 |
1.25 |
1.21 |
1.52 |
1.4 |
(−) |
2.28 |
| - | (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 Vbr2 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). cEffSE was a significant covariate on Vbr1. dThe effect of tariquidar, Efftariquidar, is on Qout the efflux clearance from the central brain compartment to the plasma compartment, while Effscan also takes into account changes occurring between scans (baseline or post-inhibition).