Pharmacokinetics of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) and cisplatin given i.v. and i.p. in the rat

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 (Vd_ss) 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.