The role of drug-lipid interactions on the disposition of liposome-formulated opioid analgesics in vitro and in vivo.

UNLABELLED: Although liposome encapsulation prolongs the duration of action of epidurally administered drugs, little is known about how liposome encapsulation affects opioids differently, or about how lipid content of liposomes alters the bioavailability of epidurally-administered opioids. To address these issues, morphine, alfentanil, fentanyl, and sufentanil were loaded into D-alpha-dipalmitoyl phosphatidylcholine multilamellar liposomes, and incorporation efficiency and in vitro release rates were determined. We then determined epidural morphine and sufentanil liposomes, at two different lipid/opioid ratios, in vivo in a pig model in which epidural and intrathecal spaces were continuously sampled via microdialysis. Liposome encapsulation efficiency was significantly more for sufentanil (100%) than for the other opioids (25%-30%). The in vitro release rate was slowest for morphine, intermediate for fentanyl and alfentanil, and fastest for sufentanil. In vivo, morphine was released more slowly than sufentanil. It is most important to note that increasing the lipid content of morphine liposomes increased the proportion of drug reaching the intrathecal space. In contrast, increasing the lipid content of sufentanil liposomes did not alter intrathecal movement but did decrease movement into plasma. Therefore, increasing drug hydrophobicity and lipid content of the liposomes modulates drug distribution in vivo. IMPLICATIONS: The degree of interaction between opioids and lipid bilayers in liposome-formulated opioids dictates the rates at which epidurally-administered drugs distribute into the intrathecal compartment and blood in potentiating analgesic effects.

Lipid association improves the therapeutic index of lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] to suppress 36B-10 tumor growth in rats.

The therapeutic efficacy and tumor accumulation of a liposome formulation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), an effective agent used in the treatment of malignant brain tumors, was examined in an animal tumor model. Pharmacokinetic studies in normal and tumor-bearing rats indicated that a 2-fold greater plasma exposure was achieved with liposome-formulated CCNU compared with the free drug. In Fisher rats bearing s.c. tumors 36B-10, tumor growth was delayed substantially when liposomal CCNU was delivered compared with free-drug treatment. In single-dose treatments of 20, 35, and 50 mg/kg, tumor progression after each dose was reduced approximately 2-fold with liposomal compared with free CCNU (four animals in each treatment group). Multiple-dose treatments (given as three weekly doses with eight animals in each treatment group) with cumulative doses of 80 and 100 mg/kg of free and liposomal CCNU also resulted in a 2-fold reduction in tumor progression when compared with free-drug treatment. When drug levels in tumors relative to plasma were examined, it was observed that tumor drug concentrations did not exceed those found in plasma after administration of free CCNU; after administration of liposomal CCNU, however, tumor concentrations exceeded those in plasma by nearly 10-fold. These results suggest that the increased efficacy of liposome-formulated CCNU may be attributable to enhanced drug accumulation in tumor tissues.