@entity4540 (GCV) is an essential part of the @entity778 ( @entity778 ) @entity1014 kinase (tk) gene therapy of @entity11 . The purpose of this study was to investigate the brain pharmacokinetics and @entity5 uptake of GCV in the BT4C @entity35 @entity11 model. GCV's brain and @entity5 uptakes were investigated by in vivo microdialysis in @entity35 with orthotopic BT4C @entity11 . In addition, the ability of GCV to cross the blood-brain barrier and @entity5 vasculature was assessed with in situ @entity35 brain perfusion using. Finally, the extent to which GCV could permeate across BT4C @entity11 cell membrane was assessed in vitro. The areas under the concentration curve of unbound GCV in blood, brain and @entity5 extracellular fluid were 6157  M min, 1658  M min and 4834  M min, respectively. The apparent maximum unbound concentrations achieved within 60 min were 46.9  M, 11.8  M and 25.8  M in blood, brain and @entity5 , respectively. The unbound GCV concentrations in brain and @entity5 after in situ @entity35 brain perfusion were 0.41 nmol/g and 1.39 nmol/g, respectively. The highly polar GCV likely crosses the fenestrated @entity5 vasculature by paracellular diffusion. Thus, GCV is able to reach the extracellular space around the @entity5 at higher concentrations than that in healthy brain. However, GCV uptake in BT4C @entity11 cells at 100  M was only 2.1 pmol/mg protein and no active transporter mediated disposition of GCV could be detected in vitro. In conclusion, the limited efficacy of @entity778 -tk/GCV gene therapy may be due to the poor cellular uptake and rapid elimination of GCV.

Brain Pharmacokinetics of @entity4540 in XXXX with Orthotopic BT4C @entity11 .

@entity778 :: ('MESH:D015658', 'Disease') :: ['Herpes simplex virus', 'HSV'] @entity35 :: ('10116', 'Species') :: ['rat', 'rats'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor'] @entity11 :: ('MESH:D005910', 'Disease') :: ['glioma', 'malignant gliomas'] @entity1014 :: ('MESH:D013936', 'Chemical') :: ['thymidine'] @entity4540 :: ('MESH:D015774', 'Chemical') :: ['Ganciclovir']
@entity35 :: (10116,Species) :: ['Rats']
