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Tumor and normal tissue pharmacokinetics of perifosine, an oral anti-cancer alkylphospholipid

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Abstract

Clinical use of anti-cancer alkylphospholipids is limited by gastrointestinal toxicity. However, new interest has emerged since it was shown that these drugs enhance the cytotoxic effect of conventional chemotherapy and radiotherapy in preclinical models. The aim of this study was to characterize the pharmacokinetic profile of perifosine, an oral analog of alkylphosphocholine (APC), and to compare in vitro drug uptake with in vivo drug accumulation in three human-derived squamous cell carcinomas (A431, HNXOE and KB). In vitro, KB cells showed a remarkably high uptake and sensitivity for perifosine compared with A431 and HNXOE cells. In vivo, perifosine reached a clinically relevant plasma concentration in mice after a single oral dose of 40 mg/kg. Perifosine was not metabolized and displayed slow elimination, with a terminal half-life of 137 (± 20) hours and an apparent volume of distribution of 11.3 l/kg. Comparable tumor accumulation was observed for A431 and HNXOE tumors, whereas perifosine uptake by KB xenografts was substantially higher. Tissue distribution occurred throughout the whole body reaching high perifosine levels in the gastro-intestinal tract, while heart and brain tissue contained relatively low levels. Based on its stability and relatively high tumor uptake in vivo, perifosine is an attractive candidate for further evaluation, e.g. as radiosensitizer.

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Authors and Affiliations

  1. Division of Experimental Therapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Stefan R. Vink

  2. Department of Radiation Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Stefan R. Vink & Marcel Verheij

  3. Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Jan H. M. Schellens

  4. Faculty of Pharmaceutical Sciences, University of Utrecht, The Netherlands

    Jan H. M. Schellens

  5. Division of Cellular Biochemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Wim J. van Blitterswijk & Marcel Verheij

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Vink, S.R., Schellens, J.H.M., van Blitterswijk, W.J. et al. Tumor and normal tissue pharmacokinetics of perifosine, an oral anti-cancer alkylphospholipid. Invest New Drugs 23, 279–286 (2005). https://doi.org/10.1007/s10637-005-1436-0

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  • DOI: https://doi.org/10.1007/s10637-005-1436-0

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