Kinetic study on the mechanism of tissue distribution of vinblastine.
The purpose of present study was to analyze the factors involved in the tissue distribution of vinblastine (VBL). The specific binding of VBL to mouse tissue cytosol determined by a charcoal method correlated well with the tissue concentration of tubulin, a target protein for the pharmacological activity of Vinca alkaloids. The calculated tissue-to-plasma partition coefficients (Kp) in various tissues, based on the VBL binding to 100000 x g cytosols showed a good correlation with the corresponding in vivo Kp values of rats reported in the literature, however, the calculated Kp values were greatly underestimated. The total binding (including specific and non-specific bindings) to cytosols from the liver and kidney, determined with the ultrafiltration method, were approximately 5 times higher than those determined with the charcoal method for both tissues. However, the total bindings to cytosol cannot explain the high Kp values in vivo. Considering the intracellular distribution of VBL, it was found that cytosol is not the main binding component for VBL since approximately one-half of the VBL in the liver homogenate was associated with the nuclear fraction. The Kp value in the liver, calculated by considering the intracellular distribution, became close to the in vivo Kp value. It was concluded that the tissue distribution of VBL cannot be accounted for only by the binding to tubulin, and that the bindings to other intracellular components should also be included.
Wierzba
K
K
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Sugiyama
Y
Y
Iga
T
T
Hanano
M
M
D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D003078:Colchicine / Q000493:pharmacokinetics; D003600:Cytosol / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D011485:Protein Binding; D014018:Tissue Distribution; D014404:Tubulin / Q000378:metabolism; D014747:Vinblastine / Q000493:pharmacokinetics*
D014404:Tubulin; D014747:Vinblastine; D003078:Colchicine