PHARMACOKINETICS AND DISTRIBUTION OF LIPOSOMAL BUSULFAN IN THE RAT - A NEW FORMULATION FOR INTRAVENOUS ADMINISTRATION

The plasma pharmacokinetics and tissue distribution of busulfan (Bu) w ere investigated after intravenous injection of free Bu (D-Bu) and fre shly prepared liposomal Bu (L-Bu). Liposomal Bu was prepared using L-a lpha-phosphatidylcholine, 1,2-dioleolyl-sn-glycero-3-phosphate, and ch olesterol. The liposomes formed were unilamellar vesicles measuring 22 0 +/- 14 nm in diameter and containing a Bu concentration of 0.31 +/- 0.03 mg/ml. The half-life of Bu in the present formulation was determi ned to be 8.7 +/- 2.7 days at 4 degrees C. The liposomes in the new fo rmulation were stable for 20 days at 4 degrees C. After the intravenou s administration of L-Bu or D-Bu (dissolved in a mixture of DMSO, etha nol, and propylene glycol) to the rats a higher bone marrow exposure t o Bu as expressed in AUC marrow/ AUC blood was achieved using L-Bu as compared with D-Bu (1.59 and 0.83, respectively). A higher distributio n volume was observed for L-Bu as compared with D-Bu (1.39 versus 0.67 l/kg, respectively). The elimination half-lives were significantly lo nger in both blood and marrow after the administration of L-Bu as comp ared with D-Bu (2.52 and 3.08 versus 1.53 and 1.75 h, respectively). T he new liposomal Bu showed linear pharmacokinetics within the range of 0.5-3.5 mg/kg, which is comparable with that obtained for D-Bu. A sli ght difference was observed in systemic exposure to L-Bu as compared w ith D-Bu as expressed in AUC (9.93 and 11.82 mu g h ml(-1), respective ly). The distribution study using C-14-labeled Bu showed that the radi oactivity was significantly higher over 18 h in the bone marrow (3-fol d) and spleen (3-fold; P < 0.01) in a comparison of L-Bu with D-Bu. Ho wever in the brain, lungs, and heart the distribution of radioactivity after the administration of L-Bu was significantly lower (P < 0.05) t han that obtained using D-Bu. On the basis of the present study, the n ew formulation of liposomal Bu seems to be a promising preparation for clinical trails, since it appears to target bone marrow and spleen wi th no accumulation in the liver or other organs known for Bu toxicity.