Vol. 298, Issue 3, 1206-1212, September 2001

Liposomal and Nonliposomal Drug Pharmacokinetics after Administration of Liposome-Encapsulated Vincristine and Their Contribution to Drug Tissue Distribution Properties

Rajesh Krishna¹ , Murray S. Webb² , Ginette St. Onge and Lawrence D. Mayer

Department of Advanced Therapeutics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada (R.K., G.St.O., L.D.M.); Division of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (R.K., L.D.M.); and Inex Pharmaceuticals Corporation, Burnaby, British Columbia, Canada (M.S.W.)

We have determined the pharmacokinetics of liposomal vincristine, in a Lewis lung carcinoma solid tumor model in mice, with the aim of differentiating the contribution of liposomal and nonliposomal (released from liposomes) drug pools to the overall pharmacokinetic profile. Two types of liposomal formulations were used: one composed of 1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol (Chol) (55/45; mol/mol) and the other composed of sphingomyelin/cholesterol (SM/Chol; 55/45; mol/mol). Vincristine elimination from the circulation after injection of conventional, aqueous formulated vincristine (C-VINC) was characterized by a short half-life (1.36 h), low plasma area under the plasma concentration-time curve (AUC) (0.59 µg · h/ml), and large volume of distribution (145 ml). Total drug elimination from the circulation after liposomal vincristine injection using SM/Chol liposomes was characterized by a prolonged half-life (6.6 h), increased plasma AUC (213 µg · h/ml) and small volume of distribution (2.0 ml). Our results indicate that 98% of the total vincristine measured in the plasma of mice administered with liposomal vincristine was encapsulated within 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 between 0.025 and 0.05 µg/ml over 4 h of postinjection for both liposomal formulations. In contrast, concentrations between 0.1 and 0.35 µg/ml were observed following C-VINC administration. Free plasma drug concentrations did not correlate with vincristine tissue distribution properties following administration of liposomal vincristine formulations. Rather, accumulation of vincristine in tissues appeared to be influenced primarily by the drug retention 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 pharmacokinetic behavior with antitumor activity.