PHARMACOKINETICS AND TISSUE DISTRIBUTION OF ADRIAMYCIN AND ADRIAMYCINOL AFTER INTRAVENOUS ADMINISTRATION OF ADRIAMYCIN-LOADED NEUTRAL PROLIPOSOMES TO RATS

The pharmacokinetics and tissue distribution of adriamycin (ADM) and its metabolite, adriamycinol were investigated after intravenous (i.v.) injection of free ADM (treatment I), ADM-loaded neutral proliposomes (treatment II) and empty neutral proliposomes mixed manually with free ADM (treatment III), 16 mg per kg as free ADM, to rats, using HPLC assay. After 1 min i.v. infusion, the plasma concentrations of ADM (Cp), area under the plasma concentration-time curve (AUG, 159 vs 351 mu g min ml(-1)), terminal half-life (t(1/2), 65.2 vs 633 min), mean residence time (MRT, 27.5 vs 541 min) and apparent volume of distribution at steady state (V-ss, 2480 vs 22 800 ml kg(-1)) were significantly higher, however, the total body clearance (CL, 101 vs 45.6 ml min(-1) kg(-1)), renal clearance (CL(R), 9.81 vs 2.27 ml min(-1) kg(-1)), nonrenal clearance (CL(NR), 90.8 vs 42.8 ml min(-1) kg(-1)) and the amount of ADM excreted in urine (X(u), 496 vs 297 mu g) were significantly lower in treatment II than the values from treatment I. This could be due to the fact that some of the ADM-loaded liposomes (formed by hydration of ADM-loaded proliposomes) were entrapped in tissues and the rest were in plasma (higher MRT and V-ss in treatment II), and ADM was slowly released from ADM-loaded liposomes (higher t(1/2) in treatment II): In the present HPLC assay, the concentrations of ADM represent the sum of free ADM and ADM loaded in liposomes (higher C-p and AUC, slower CL in treatment II). After 1 min i.v. infusion, some pharmacokinetic parameters, such as t(1/2), MRT and X(u) were significantly different between treatments I and III, but not as distinct between treatments I and II. 30 min after i.v. infusion, the amount of ADM remaining in lymph node and the lymph node to plasma ratio were significantly higher in treatment II than in treatment I. This suggested that the i.v. administration of ADM-loaded proliposomes might have a better lymph node targeting ability than free ADM. The mean amount of ADM loaded in ADM-loaded proliposomes was 4.09 mg per g proliposome.