Abstract
The potential for the modification of the pharmacokinetics of doxorubicin (DOX) concurrently administered with high-dose verapamil (VER) has been investigated in 17 patients with advanced neoplasms refractory to drugs belonging to the multidrug resistance spectrum. Steady-state concentration of DOX, systemic clearance and urinary excretion were analysed. No significant difference was found between the kinetic parameters estimated for DOX at different levels of VER and those reported for doxorubicin as single agent. It can be concluded that VER does not appear to modify DOX kinetics.
Highlights
Divirion of Experinental Oncology 1, Centro d Riferimento Oncologico, Aviano (PN), Italy Sy The potental for the m ion of the pharmacokinetics of doxorubicin (DOX) concurrently administcred with highoe vramil (VER) has be investigated in 17 patients with advanced as s refractory to drugs woning to the mulidrug resance spectrUmn Steady-state concentration of DOX, systemic canc and urmary excton wer analysed
No sgnifcant difference was found betwen the kinetic p s estimated for DOX at differt klve of VER and those reported for doxorubicin as single agenL It can be concded that VER does not appear to modify DOX kinetics
Experimental data suggest that multidrug resistance (MDR) in cancer may be overcome by using anti-cancer agents in combination with resistance-modifying agents (RMAs) such as verapamil (Tsuruo et al, 1983)
Summary
Experimental data suggest that multidrug resistance (MDR) in cancer may be overcome by using anti-cancer agents in combination with resistance-modifying agents (RMAs) such as verapamil (Tsuruo et al, 1983). We demonstrated that the best results in overcoming in vitro MDR to DOX require continuous VER exposure, at concentrations > Ipm and for a time roughly similar to the cells' repliation time (Boiocchi and Toffoli, 1992; Toffoli et al, 1993). Based on these in vitro results, we are trying to design clinical trials based on a continuous infusion of DOX and VER, which may be more effective than previous clinical trials. Eeven patients followed schedule A, four schedule B and two patients followed both schedules
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