We studied the liposome formulation characteristics of eight new lipophilic antitumour agents that have demonstrated a broad spectrum of antitumour activity in preclinical in vitro and in vivo screening models. Multilamellar vesicles were prepared by using standard evaporation/hydration methods. The drug to lipid weight ratio was 1:15 in all cases. Different combinations of DMPC, DMPG and cholesterol were used. The quality of the liposomal formulations was evaluated by calculating the percentage drug bound to the liposome phase and assessing the morphology of the liposome phase by optic microscopy, to rule out the presence of drug crystals or drug/lipid microaggregates. Good liposomal preparations were obtained with hexamethylmelamine, penclomedine, mitindomide, and fazarabine. However, with taxol, batracylin, trimelamol, and diaziquone, the presence of crystals of free drug or microaggregates of lipid/drug complex was observed in all preparations, independently of lipid composition. In general, mixtures of DMPC:DMPG at a molar ratio between 7:3 and 9:1, and the addition of 5 per cent cholesterol (w/w) gave the optimal results. In vitro cytotoxicity studies of free and liposomal drugs against L1210 cells showed changes in both directions after liposome entrapment, thus suggesting that liposome entrapment may alter drug cellular uptake or may result in chemical modifications of the entrapped drug. Because of the limited number of compounds studied we were unable to identify general chemical characteristics required for an enhanced liposome formation and drug entrapment.

The pharmacokinetics of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) and cisplatin (CDDP) were studied after i.v. and i.p. administration of an equimolar dose (11 and 5 mg/kg for L-NDDP and CDDP, respectively) in the rat. The systemic absorption following i.p. administration was faster in rats receiving CDDP than in those receiving L-NDDP. Peak serum platinum (Pt) levels were observed at 30 min and 12 h after the i.p. administration of CDDP and L-NDDP, respectively. Administration by the i.v. route did not significantly alter the serum Pt levels for either compound. However, serum Pt levels were 2-3 times greater in animals treated with L-NDDP than in those treated with CDDP. The estimated pharmacokinetic parameters for each drug were independent of the route of administration, except for the clearance (Cl) of CDDP, which increased 2-fold following i.p. administration. In addition, significant differences in pharmacokinetic parameters were observed between drug-treatment groups that were independent of the route of administration: the serum Pt area under the concentration-time curve (AUC) was higher and the volume of distribution at steady state (Vdss) was lower in rats receiving L-NDDP. Pt levels measured at 6 h in the peritoneal fluid, peritoneal tissue, and intestine of rats receiving i.p. L-NDDP were higher than those observed in rats receiving either i.v. L-NDDP or CDDP by either route. Pt levels measured in the liver and spleen of rats receiving L-NDDP were independent of the route of administration and were significantly higher than those determined in rats treated with CDDP. In contrast, kidney Pt levels were lower in rats receiving L-NDDP than in rats receiving CDDP by either route. These results suggest that the prolongation of the mean retention time of L-NDDP in the peritoneum achieved after i.p. administration without compromising the systemic distribution of the drug may result in a significant enhancement of the therapeutic efficacy of L-NDDP against malignancies confined to the peritoneal cavity as compared with that of i.p. CDDP.

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