Liposomal and nonliposomal drug pharmacokinetics after administration of liposome-encapsulated vincristine and their contribution to drug tissue distribution properties

We have determined the pharmacokinetics of liposomal vincristine, in a Lewi s lung carcinoma solid tumor model in mice, with the aim of differentiating the contribution of liposomal and nonliposomal (released from liposomes) d rug pools to the overall pharmacokinetic profile. Two types of liposomal fo rmulations were used: one composed of 1,2 distearoyl-sn-glycero-3-phosphoch oline/cholesterol (Chol) (55/45; mol/mol) and the other composed of sphingo myelin/ cholesterol (SM/Chol; 55/45; mol/mol). Vincristine elimination from the circulation after injection of conventional, aqueous formulated vincri stine (C-VINC) was characterized by a short half-life (1.36 h), low plasma area under the plasma concentration-time curve (AUC) (0.59 mug . h/ml), and large volume of distribution (145 ml). Total drug elimination from the cir culation after liposomal vincristine injection using SM/Chol liposomes was characterized by a prolonged half-life (6.6 h), increased plasma AUC (213 m ug . h/ml) and small volume of distribution (2.0 ml). Our results indicate that greater than or equal to 98% of the total vincristine measured in the plasma of mice administered with liposomal vincristine was encapsulated wit hin the liposomes. The systemic exposure to free drug after administration of liposomal formulations was significantly lower than that observed after the injection of C-VINC. Plasma concentrations of free drug remained betwee n 0.025 and 0.05 mug/ml over 4 h of postinjection for both liposomal formul ations. In contrast, concentrations between 0.1 and 0.35 mug/ml were observ ed following C-VINC administration. Free plasma drug concentrations did not correlate with vincristine tissue distribution properties following admini stration of liposomal vincristine formulations. Rather, accumulation of vin cristine in tissues appeared to be influenced primarily by the drug retenti on properties of the liposome. While the reduced systemic exposure to free vincristine correlates with reduced toxicity, additional information (such as liposome drug release properties) may be necessary to correlate pharmaco kinetic behavior with antitumor activity.