GSK1034702 is a weak substrate for P-glycoprotein (PGP) (efflux ratio of 2.6 1 in MDCK cell line expressing human MDR1) and has displayed some species variability in brain-to-plasma ratios (brain/blood ratios of 0.4, 0.6 and 2.0 1, in mouse, rat and marmoset, respectively; GlaxoSmithKline (GSK) data on file).
Notably, we have reported before that the activity of KP1019 (the precursor of KP1339) is not limited by ABCG2, ABCC1 and ABCC2 but the metal drug is a weak substrate for ABCB1.
Both show activity with C6 to C14 saturated fatty acyl-ACP esters; however, C14 0 is a weak substrate of both enzymes and only FabF exhibits low activity with C16:0 [ 70].
Interestingly, the Vmax and kcat values for the Lys iPr) peptide (Vmax=0.152 μ ms−1, kcat=0.303 s−1) were higher than values for the other three peptides, although the Lys iPr) peptide is a weaker substrate than the Lys(Me/Et) and Lys(Me2) peptides in competition experiments.
Phenytoin is considered to be a (weak) P-gp substrate (37) and hence the results by Bankstahl et al. are in line with the results from the present study, i.e., that SE decreases the total brain concentrations and increases the free brain concentrations.
Mitoxantrone is often used as a fluorescent substrate in flow cytometry-based functional assays [7], [86], but it is also a weak substrate for P-gp.
Most AEDs are such a weak substrate of P-gp, that, in principle, the constitutive expression of that protein on BBB is not able to reduce the inflow of AEDs in a clinically important way [ 41]; however, the inborn or acquired excessive expression P-gp in BBB may critically reduce the penetration of AEDs to the brain, resulting in resistance to many AEDs [ 41– 41].
At baseline, substrate tracers such as R-[11C]verapamil display low brain concentrations with a distribution volume of around 1. [11C]phenytoin is supposed to be a weaker P-gp substrate, which may lead to higher brain concentrations at baseline.
A dosage of 14 mg/kg 11C]phenytoin in rhesus monkeys resulted in a high brain uptake, which is consistent with phenytoin being a weak P-gp substrate [18].
