Abstract
To determine the tissue-specific impact of P-glycoprotein on the accumulation of a substrate drug, we have studied the tissue distribution of vinblastine in mdr1a(−/−) and wild-type mice at approximately similar, relatively low plasma levels. Vinblastine was administered as a 96-h continuous infusion at dose rates of 1 to 10 μg/h, which were delivered by a s.c.-implanted osmotic pump. Drug concentrations were determined in plasma and tissues by HPLC. In comparison to wild-type mice, 4.4- to 9.6-fold higher drug concentrations were observed in the brains ofmdr1a(−/−) mice (p ≤ .014), whereas a 2-fold increase was found in the heart (p= .014) and the intestinal tissues (p ≤ .028). No or only slight differences were observed in all other tissues. These results indicate that, except for the brain and, to a lesser extent, the heart and the intestinal tissues, P-glycoprotein does not protect individual organs against vinblastine. Given its polarized cell-specific and organ-specific distribution and its affinity for a broad range of compounds, it is suggested that P-glycoprotein has mainly evolved to provide a general protection of the complete organism against potentially toxic substrates by inhibiting their uptake and by mediating their transport from the internal to the external environment. For the clinical application of reversal agents, these data indicate that, in general, a blockade of endogenous P-glycoprotein will probably not result in an increased accumulation of the coadministered anticancer drug in complete organs, but, possibly, only in classes of cells making up a fraction of an organ.
Footnotes
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Send reprint requests to: Judith van Asperen, Drug Metabolism Department, Covance Laboratories Ltd., Otley Road, Harrogate, North Yorkshire HG3 1PY, United Kingdom.
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↵1 This work has been presented at the 10thNCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, the Netherlands, 1998 (abstract 570).
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↵2 Present address: Drug Metabolism Department, Covance Laboratories Ltd., Otley Road, Harrogate, North Yorkshire HG3 1PY, United Kingdom.
- Abbreviations:
- Css
- steady state plasma concentration
- LLQ
- lower limit of quantitation
- Received August 5, 1998.
- Accepted December 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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