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Research ArticleArticle

Brain Pharmacokinetics of Ganciclovir in Rats with Orthotopic BT4C Glioma

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 and Markus M. Forsberg
Drug Metabolism and Disposition January 2015, 43 (1) 140-146; DOI: https://doi.org/10.1124/dmd.114.059840
Mikko Gynther
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
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Tiina M. Kääriäinen
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
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Jenni J. Hakkarainen
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
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Aaro J. Jalkanen
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
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Aleksanteri Petsalo
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
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Marko Lehtonen
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
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Lauri Peura
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
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Jere Kurkipuro
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
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Haritha Samaranayake
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
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Seppo Ylä-Herttuala
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
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Jarkko Rautio
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
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Markus M. Forsberg
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
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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.

Footnotes

    • Received July 4, 2014.
    • Accepted October 27, 2014.
  • ↵1 Current affiliation: Aurealis Pharma Ltd., Kuopio, Finland.

  • This work was financially supported by the Finnish Funding Agency for Innovation (TEKES)/European Regional Development Fund (ERDF) [Grant 70043/10].

  • dx.doi.org/10.1124/dmd.114.059840.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (1)
Drug Metabolism and Disposition
Vol. 43, Issue 1
1 Jan 2015
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Research ArticleArticle

Brain Pharmacokinetics of Ganciclovir

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 and Markus M. Forsberg
Drug Metabolism and Disposition January 1, 2015, 43 (1) 140-146; DOI: https://doi.org/10.1124/dmd.114.059840

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Research ArticleArticle

Brain Pharmacokinetics of Ganciclovir

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 and Markus M. Forsberg
Drug Metabolism and Disposition January 1, 2015, 43 (1) 140-146; DOI: https://doi.org/10.1124/dmd.114.059840
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