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: Mikko Gynther, Tiina M Kääriäinen, Jenni J Hakkarainen, Aaro J Jalkanen, Aleksanteri Petsalo, Marko Lehtonen, Lauri Peura, Jere Kurkipuro, Haritha Samaranayake, Seppo Ylä-Herttuala, Jarkko Rautio, Markus M Forsberg
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 43 Issue 1 Pg. 140-6 (Jan 2015) ISSN: 1521-009X [Electronic] United States
• PMID: 25349125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Ganciclovir

Topics

• Animals
• Blood-Brain Barrier (metabolism)
• Brain (metabolism)
• Brain Neoplasms (metabolism)
• Ganciclovir (metabolism, pharmacokinetics)
• Glioma (metabolism)
• Male
• Rats
• Tumor Cells, Cultured