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

J. Lautersztain, Roman Perez-Soler, A. R. Khokhar, R. A. Newman, G. Lopez-Berestein

Research output: Contribution to journalArticle

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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 dimyristol 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 μg/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 μg platinum/ml per min versus 395 μg platinum/ml per min). Tissue platinum levels were significantly increased by liposome encapsulation in the lung (33 versus 3.6 μg/g), spleen (38.3 μg/g versus none detected), and liver (16.2 versus 11.7 μg/g), and unchanged in the kidneys. Although only F-N-decyl-IDP resulted in detectable levels of platinum in the small bowel (70.5 μg/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.

Original languageEnglish (US)
Pages (from-to)93-97
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume18
Issue number2
DOIs
StatePublished - Nov 1986
Externally publishedYes

Fingerprint

Pharmacokinetics
Tissue Distribution
Liposomes
Tissue
Platinum
Encapsulation
Pharmaceutical Preparations
Liver
((1R,2R)-1,2-diaminocyclohexane)platinum(II)
N-decyliminodiacetato-1,2-diaminocyclohexane-platinum(II)
Blood
Spleen
Lung
Phosphatidylglycerols
Phosphatidylcholines
Cisplatin
Toxicity
Tumors
Suspensions
Phosphates

ASJC Scopus subject areas

  • Pharmacology
  • Oncology
  • Cancer Research

Cite this

Pharmacokinetics and tissue distribution of liposome-encapsulated cis-bis-N-decyliminodiacetato-1,2-diaminocyclohexane-platinum (II). / Lautersztain, J.; Perez-Soler, Roman; Khokhar, A. R.; Newman, R. A.; Lopez-Berestein, G.

In: Cancer Chemotherapy and Pharmacology, Vol. 18, No. 2, 11.1986, p. 93-97.

Research output: Contribution to journalArticle

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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 dimyristol 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 μg/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 μg platinum/ml per min versus 395 μg platinum/ml per min). Tissue platinum levels were significantly increased by liposome encapsulation in the lung (33 versus 3.6 μg/g), spleen (38.3 μg/g versus none detected), and liver (16.2 versus 11.7 μg/g), and unchanged in the kidneys. Although only F-N-decyl-IDP resulted in detectable levels of platinum in the small bowel (70.5 μg/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.",
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