Pharmacokinetics and tissue distribution of liposome-encapsulated cis-bis-N-decyl-iminodiacetato-1,2-diaminocyclohexane-platinum (II).
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.
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D002945:Cisplatin / Q000378:metabolism; D007700:Kinetics; D008081:Liposomes / Q000008:administration & dosage*; D008297:Male; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000378:metabolism*; D010984:Platinum / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D008081:Liposomes; D009944:Organoplatinum Compounds; C051114:N-decyliminodiacetato-1,2-diaminocyclohexane-platinum(II); D010984:Platinum; D002945:Cisplatin