PT  - JOURNAL ARTICLE
AU  - Judith van Asperen
AU  - Olaf van Tellingen
AU  - Alfred H. Schinkel
AU  - Jos H. Beijnen
TI  - Comparative Pharmacokinetics of Vinblastine after a 96-Hour Continuous Infusion in Wild-Type Mice and Mice Lacking mdr1a P-Glycoprotein
DP  - 1999 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 329--333
VI  - 289
IP  - 1
4099  - http://jpet.aspetjournals.org/content/289/1/329.short
4100  - http://jpet.aspetjournals.org/content/289/1/329.full
SO  - J Pharmacol Exp Ther1999 Apr 01; 289
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics