unbound drug concentrations, as it is the unbound drug concentration that drives transport processes (BBB transport, intra-brain distribution, unbound brain concentrations) and target interactions that lead to drug effects (69, 70).
Within the brain, distribution is ubiquitous and uniform.
In PET studies using cynomolgus and rhesus monkeys, 11 C]N-methyl-SSR504734 showed high brain uptake and a regional brain distribution consistent with other GlyT1 PET ligands [19 21].
Characteristics of PAO include excellent blood-brain barrier permeability, peak levels of brain distribution within 5 minutes after intravenous injection, and maintenance of steady-state levels over a subsequent period of a several hours.
Both subtypes have a discrete brain distribution that overlaps in numerous brain regions, including the POM and bed nucleus of the stria terminalis (BST) in quail [28], [29].
Similarly, alteration in renal elimination resulted in increased brain distribution (brain-to-plasma ratio: 10.98 vs. 6.88).
4. Bauer M, Wulkersdorfer B, Karch R, Philippe C, Jager W, Stanek J, et al. Effect of P-glycoprotein inhibition at the blood-brain barrier on brain distribution of (R -[11 C]veR -[11l in elderly versus young subjeC]verapamil
Calculations of brain distribution are often performed by modeling the brain compartment as an effect compartment (15, 45).
In vivo brain distribution studies showed that brain-to-plasma concentration ratio of dasatinib was significantly higher in Mdr1a/b −/−Bcrp1 −/− than in Mdr1a/b −/− mice and increased in wild-type mice with co-administration with Ko143 [137].
However, our recent results obtained from murine brain distribution studies using direct brain perfusion show that P-gp restricts the accumulation of [H]cortisol in specific brain regions, such as hypothalamus, and does not restrict the access of [H]corticosterone in any brain regions sampled (13).
