Comparative pharmacokinetics of vinblastine after a 96-hour continuous infusion in wild-type mice and mice lacking mdr1a P-glycoprotein

To determine the tissue-specific impact of P-glycoprotein on the accumulati on of a substrate drug, we have studied the tissue distribution of vinblast ine in mdr1a(-/-) and wild-type mice at approximately similar, relatively l ow plasma levels. Vinblastine was administered as a 96-h continuous infusio n at dose rates of 1 to 10 mu g/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 concen trations were observed in the brains of mdr1a(-/-) mice (p less than or equ al to .014), whereas a 2-fold increase was found in the heart (p = .014) an d the intestinal tissues (p less than or equal to .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 intestina l tissues, P-glycoprotein does not protect individual organs against vinbla stine. Given its polarized cell-specific and organ-specific distribution an d its affinity for a broad range of compounds, it is suggested that P-glyco protein has mainly evolved to provide a general protection of the complete organism against potentially toxic substrates by inhibiting their uptake an d by mediating their transport from the internal to the external environmen t. For the clinical application of reversal agents, these data indicate tha t, in general, a blockade of endogenous P-glycoprotein will probably not re sult in an increased accumulation of the coadministered anticancer drug in complete organs, but, possibly, only in classes of cells making up a fracti on of an organ.