Fig 4.
Simulations show the effects of vascular content correction on the % magnitude of maximal P-gp inhibition (corrected versus uncorrected for vascular content contamination). With low brain penetrating P-gp substrates such as NFV (low brain: plasma ratio in the absence of P-gp inhibition), the increase in brain: plasma ratio of the P-gp substrate drug will be considerably underestimated when vascular content correction is not made. As in the case of NFV in this study, at 246.9 µM CsA blood concentration, we reported a 2110% increase in NFV brain: blood ratio without vascular content correction versus 6420% increase when correction is made (differences of 4320%). In contrast, for moderate or high brain penetrating P-gp substrate drugs such as cetirizine (C)40, docetaxel (D)41, fluphenazine (F)42, or verapamil (V)16, on inhibiting P-gp, the % increase in brain: plasma ratio of the drug is relatively unaffected by vascular content correction.