title: Brain pharmacokinetics of ganciclovir in rats with orthotopic BT4C glioma.
abstract: Ganciclovir (GCV) is an essential part of the Herpes simplex virus thymidine kinase (HSV-tk) gene therapy of malignant gliomas. The purpose of this study was to investigate the brain pharmacokinetics and tumor uptake of GCV in the BT4C rat glioma model. GCV's brain and tumor uptakes were investigated by in vivo microdialysis in rats with orthotopic BT4C glioma. In addition, the ability of GCV to cross the blood-brain barrier and tumor vasculature was assessed with in situ rat brain perfusion. Finally, the extent to which GCV could permeate across the BT4C glioma cell membrane was assessed in vitro. The areas under the concentration curve of unbound GCV in blood, brain extracellular fluid (ECF), and tumor ECF were 6157, 1658, and 4834 μM⋅min, respectively. The apparent maximum unbound concentrations achieved within 60 minutes were 46.9, 11.8, and 25.8 μM in blood, brain, and tumor, respectively. The unbound GCV concentrations in brain and tumor after in situ rat brain perfusion were 0.41 and 1.39 nmol/g, respectively. The highly polar GCV likely crosses the fenestrated tumor vasculature by paracellular diffusion. Thus, GCV is able to reach the extracellular space around the tumor at higher concentrations than that in healthy brain. However, GCV uptake into BT4C cells at 100 μM was only 2.1 pmol/mg of protein, and no active transporter-mediated disposition of GCV could be detected in vitro. In conclusion, the limited efficacy of HSV-tk/GCV gene therapy may be due to the poor cellular uptake and rapid elimination of GCV.
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland mikko.gynther@uef.fi.
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Kääriäinen
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Jenni J
authors.initials: JJ
authors.lastname: Hakkarainen
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Aaro J
authors.initials: AJ
authors.lastname: Jalkanen
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Aleksanteri
authors.initials: A
authors.lastname: Petsalo
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Lehtonen
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Peura
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Jere
authors.initials: J
authors.lastname: Kurkipuro
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Haritha
authors.initials: H
authors.lastname: Samaranayake
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
authors.affiliation: Faculty of Health Sciences, School of Pharmacy (M.G., T.M.K., J.J.H., A.J.J., A.P., M.L., L.P., J.R., M.M.F.) and A. I. Virtanen Institute for Molecular Sciences (J.K., H.S., S.Y.-H.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Forsberg
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D015774:Ganciclovir / Q000378:metabolism* / Q000493:pharmacokinetics*; D005910:Glioma / Q000378:metabolism*; D008297:Male; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D015774:Ganciclovir