Pharmacokinetics of intravenously administered stealth liposomal doxorubicin modulated with verapamil in rats

Abstract

Treatment of cancer through co-administration of anticancer drugs and multidrug resistance (MDR) modulators as a strategy to overcome drug resistance has been extensively explored. However, success has been limited by pharmacokinetic interactions because of non-specific blockade of P-glycoprotein (P-gp) in normal tissues or inability to reach relevant concentrations clinically. We hypothesized that stealth liposomal co-encapsulation of doxorubicin (DOX) with a P-glycoprotein inhibitor, verapamil (DARSLs), may overcome these limitations. Using intravenous (i.v.) administrations, the effects of verapamil (VER) either free (FV) or liposome co-encapsulated with DOX (DARSLs) on the pharmacokinetics and tissue distribution characteristics of DOX either as free (FD) or liposome-encapsulated (LD) were evaluated in normal rats. FV increased ( P<0.05) the plasma AUC of free DOX (FD). Preparations containing LD had significant prolonged systemic exposure and slow tissue distribution of DOX. LDFV (liposomal DOX with free verapamil) and DARSLs shared similar DOX pharmacokinetics but the latter showed slower DOX distribution in most tissues studied and slower ( P<0.05) DOX biliary transport. The addition of VER into LD in these two preparations significantly increased the AUC ( P<0.01) and reduced the clearance ( P<0.01) of DOX when compared to LD. Specifically, DARSLs reduced initial DOX distribution to the heart ( P<0.05) corresponding to initial alleviation ( P<0.05) of bradycardia when compared to other DOX with VER preparations. In conclusion, liposomal co-encapsulation of DOX with VER has promise of significant therapeutic advantages, and should be explored further in therapeutic studies with animal tumor xenograft models.