title: Pharmacokinetics and distribution of liposomal busulfan in the rat: a new formulation for intravenous administration.
abstract: The plasma pharmacokinetics and tissue distribution of busulfan (Bu) were investigated after intravenous injection of free Bu (D-Bu) and freshly prepared liposomal Bu (L-Bu). Liposomal Bu was prepared using L-alpha-phosphatidylcholine, 1,2-dioleolyl-sn-glycero-3-phosphate, and cholesterol. The liposomes formed were unilamellar vesicles measuring 220 +/- 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 determined to be 8.7 +/- 2.7 days at 4 degrees C. The liposomes in the new formulation were stable for 20 days at 4 degrees C. After the intravenous administration of L-Bu or D-Bu (dissolved in a mixture of DMSO, ethanol, and propylene glycol) to the rats a higher bone marrow exposure to 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 distribution 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 longer in both blood and marrow after the administration of L-Bu as compared with D-Bu (2.52 and 3.08 versus 1.53 and 1.75 h, respectively). The 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 slight difference was observed in systemic exposure to L-Bu as compared with D-Bu as expressed in AUC (9.93 and 11.82 microg h ml(-1), respectively). The distribution study using 14C-labeled Bu showed that the radioactivity was significantly higher over 18 h in the bone marrow (3-fold) and spleen (2-fold; P < 0.01) in a comparison of L-Bu with D-Bu. However in the brain, lungs, and heart the distribution of radioactivity after the administration of L-Bu was significantly lower (P < 0.05) than that obtained using D-Bu. On the basis of the present study, the new formulation of liposomal Bu seems to be a promising preparation for clinical trials, since it appears to target bone marrow and spleen with no accumulation in the liver or other organs known for Bu toxicity.
authors.affiliation: Department of Clinical Pharmacology, Huddinge University Hospital, Sweden. Moustapha.Hassan@labtek.ki.se
authors.forename: M
authors.initials: M
authors.lastname: Hassan
authors.forename: Z
authors.initials: Z
authors.lastname: Hassan
authors.forename: C
authors.initials: C
authors.lastname: Nilsson
authors.forename: M A
authors.initials: MA
authors.lastname: Rehim
authors.forename: S
authors.initials: S
authors.lastname: Kumlien
authors.forename: B
authors.initials: B
authors.lastname: Elfsson
authors.forename: N
authors.initials: N
authors.lastname: Kållberg
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D004337:Drug Carriers; D006207:Half-Life; D007262:Infusions, Intravenous; D008081:Liposomes; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002250:Carbon Radioisotopes; D004337:Drug Carriers; D008081:Liposomes; D002066:Busulfan