The comparative pharmacokinetics of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes was evaluated in rats at a dose of 6 mg/kg i.v. Doxorubicin was entrapped in cardiolipin liposomes by using 11.2 µmol of drug, 5.6 µmol of cardiolipin, 28.5 µmol of phosphatidylcholine, 19.5 µmol of cholesterol, and 11.1 µmol of stearylamine. The peak plasma concentration with free doxorubicin at 5 min was 1.7 µg/ml which was reduced to 0.3 µg/ml by 1 h. With cardiolipin liposomes, the peak plasma concentration of doxorubicin achieved at 5 min was 20.9 µg/ml. The plasma levels of doxorubicin decreased gradually and by 1 h the drug concentration in plasma was 10 µg/ml. The plasma levels of free doxorubicin and doxorubicin entrapped in liposomes were fitted to a 3-compartment computer model. The terminal half-life with free doxorubicin in plasma was 17.3 h whereas it was 69.3 h with drug entrapped in liposomes. The area under the plasma concentration curve with liposomal doxorubicin was 81.4 µg·h·ml-1 compared to 1.95 µg·h·ml-1 observed with free doxorubicin. The steady state volume of distribution with free doxorubicin was about 23-fold higher than liposomal doxorubicin. The terminal half-life with free doxorubicin in cardiac tissue was 17.9 h compared to 12.6 h with drug encapsulated in liposomes. The terminal half-lives in liver and spleen following administration of liposomal doxorubicin were 15- and 2.3-fold higher, respectively, compared to free drug; furthermore, the concentration × time values of liposomal doxorubicin in liver were 26-fold higher and in spleen 6-fold higher than the free drug. Free doxorubicin and doxorubicin entrapped in liposomes demonstrated 17 and 20% excretion in bile of the injected dose, respectively, in rats. The present studies demonstrate that liposomal encapsulation of doxorubicin significantly alters its pharmacokinetics in plasma and tissues compared to free drug.
↵1 This investigation was supported in part by Bristol Myers Co., New York, NY and USPHS Grant 5P30CA14626.
↵2 To whom requests for reprints should be addressed, at Division of Medical Oncology, Department of Medicine, Georgetown University, 3800 Reservoir Road, N.W., Washington, DC 20007.
- Received June 28, 1985.
- Revision received December 11, 1985.
- Accepted January 28, 1986.
- ©1986 American Association for Cancer Research.