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Pharmacokinetics and tissue distribution of liposome-encapsulated cis-bis-N-decyl-iminodiacetato-1,2-diaminocyclohexane-platinum (II).

Abstract
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.
AuthorsJ Lautersztain, R Perez-Soler, A R Khokhar, R A Newman, G Lopez-Berestein
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 18 Issue 2 Pg. 93-7 ( 1986) ISSN: 0344-5704 [Print] Germany
PMID3791565 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Liposomes
  • Organoplatinum Compounds
  • N-decyliminodiacetato-1,2-diaminocyclohexane-platinum(II)
  • Platinum
  • Cisplatin
Topics
  • Animals
  • Antineoplastic Agents (administration & dosage, metabolism)
  • Cisplatin (metabolism)
  • Kinetics
  • Liposomes (administration & dosage)
  • Male
  • Organoplatinum Compounds (administration & dosage, metabolism)
  • Platinum (metabolism)
  • Rats
  • Rats, Inbred Strains
  • Tissue Distribution

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