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

Abstract

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.

A Novel Approach for the Increased Delivery of Pharmaceutical Agents to Peritoneum and Associated Lymph Nodes

“…These studies have demonstrated a significantly prolonged retention time of the liposome-encapsulated chemotherapeutic agents in the peritoneum. These studies support the hypothesis that there is a marked pharmacological advantage for the treatment of intraperitoneal malignancies by encapsulating the intraperitoneally administered chemotherapeutic agent in a liposome (Vadiei et al, 1992;Daoud, 1994). Other studies demonstrate an improved toxicity profile.…”

“…In the last decade, research has been performed with intraperitoneally administered liposome-encapsulated anticancer agents (Malik et al, 1991;Vadiei et al, 1992;Daoud, 1994;Sharma et al, 1996Sharma et al, , 1997. These studies have demonstrated a significantly prolonged retention time of the liposome-encapsulated chemotherapeutic agents in the peritoneum.…”

Application of liposomal technologies for delivery of platinum analogs in oncology

“…4 Preclinical data showed that L-NDDP had a dramatically different biodistribution from that of NDDP, with accumulation of platinum in major organs, such as the liver, spleen, and lymph nodes. 43,44 In a preclinical toxicology and antitumor activity study, it was found that L-NDDP did not induce nephrotoxicity, but myelosuppression was the Abbreviations: MTD, maximum tolerated dose; NDDP, cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II); DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine; DMPG, 1,2-dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (sodium salt); HSPC, hydrogenated soy phosphatidylcholine; DSPe-PeG2000, 1,2-distearoyl-snglycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt); DPPG, 1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (sodium salt); NA, not available; DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine; DSPG, 1,2-distearoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (sodium salt); min, minutes. …”

Liposomally targeted cytotoxic drugs for the treatment of cancer

“…MLV composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) (ratio 7 : 3) containing the lipophilic platin cis-bis-neodecanoato trans-R,R-1,2 diaminocyclohexane platinum (II) (NDDP) have been shown to yield equivalent or increased tumours levels compared with unencapsulated cisplatin after intravenous administration . In addition, this agent appeared to have particularly attractive pharmacokinetics after intraperitoneal injection (Vadiei et al 1992), which has promoted its use as an intracavitary agent in patients with malignant eOE usions in early clinical trials (see below).…”

“…Other signi® cant toxicities included nausea, vomiting and diarrhoea, but there was no evidence of nephrotoxicity or ototoxicity. The favourable pharmacokinetics documented after intraperitoneal administration in mice (Vadiei et al 1992) have prompted studies of locoregional administration of this agent in patients with malignant eOE usions (Perez-Soler et al 1997, 1999. In the ® rst study, 21 patients with non-loculated malignant pleural eOE usions due to lung cancer, ovarian cancer and mesothelioma were treated with escalating doses of intrapleural liposomal NDDP (Perez-Soler et al 1997).…”