13 research outputs found
Fexofenadine Brain Exposure and the Influence of Blood-Brain Barrier P-Glycoprotein After Fexofenadine and Terfenadine Administration
P-glycoprotein (P-gp) plays an important role in determining net brain
uptake of fexofenadine. Initial in vivo experiments with 24-h subcutaneous
osmotic minipump administration demonstrated that fexofenadine brain
penetration was 48-fold higher in mdr1a(–/–) mice than in
mdr1a(+/+) mice. In contrast, the P-gp efflux ratio at the
blood-brain barrier (BBB) for fexofenadine was only ∼4 using an in situ
brain perfusion technique. Pharmacokinetic modeling based on the experimental
results indicated that the apparent fexofenadine P-gp efflux ratio is
time-dependent due to low passive permeability at the BBB. Fexofenadine brain
penetration after terfenadine administration was ∼25- to 27-fold higher
than after fexofenadine administration in both mdr1a(+/+) and
mdr1a(–/–) mice, consistent with terfenadine metabolism
to fexofenadine in murine brain tissue. The fexofenadine formation rate after
terfenadine in situ brain perfusion was comparable with that in a 2-h brain
tissue homogenate in vitro incubation. The fexofenadine formation rate
increased ∼5-fold during a 2-h brain tissue homogenate incubation with
hydroxyl-terfenadine, suggesting that the hydroxylation of terfenadine is the
rate-limiting step in fexofenadine formation. Moreover, regional brain
metabolism seems to be an important factor in terfenadine brain disposition
and, consequently, fexofenadine brain exposure. Taken together, these results
indicate that the fexofenadine BBB P-gp efflux ratio has been underestimated
previously due to the lack of complete equilibration of fexofenadine across
the blood-brain interface under typical experimental paradigms