The pharmacokinetics and tissue distribution of a lipophilic analogue of
cisplatin, cis-bis-N-decyl-iminodiacetato-1,2-diaminocyclohexane
platinum (II) (
N-decyl-IDP), were studied after the i.v. administration of the free
drug in
suspension in
phosphate-buffered saline (F-
N-decyl-IDP) and encapsulated in multilamellar
liposomes comprising dimyristoyl
phosphatidylcholine and
dimyristoyl phosphatidylglycerol at a molar ratio of 7:3 (L-
N-decyl-IDP). The encapsulation efficiency and stability at 14 days of L-
N-decyl-IDP were greater than 95%. The blood clearance of both forms of the
drug fit a two-compartment model. The peak blood level of elemental
platinum for L-
N-decyl-IDP was fourfold higher than for the free
drug (24.2 versus 6.1 micrograms/ml). In consequence, a fourfold difference in the volumes of distribution was observed (176 ml/kg for L-
N-decyl-IDP versus 608 ml/kg for F-
N-decyl-IDP).
Liposome encapsulation reduced the drug clearance by threefold; therefore, the CXT of L-
N-decyl-IDP was threefold higher than that of F-
N-decyl-IDP (1308 micrograms
platinum/ml per min versus 395 micrograms
platinum/ml per min). Tissue
platinum levels were significantly increased by
liposome encapsulation in the lung (33 versus 3.6 micrograms/g), spleen (38.3 micrograms/g versus none detected), and liver (16.2 versus 11.7 micrograms/g), and unchanged in the kidneys. Although only F-
N-decyl-IDP resulted in detectable levels of
platinum in the small bowel (70.5 micrograms/g), the stool excretion was similar for both forms of the
drug. The organ distribution changes secondary to
liposome encapsulation may result in an increased antitumor activity of
N-decyl-IDP in
tumors involving the lung, spleen, and liver, and avoidance of gastrointestinal toxicity.