TY - JOUR
T1 - Pharmacokinetics and tissue distribution of liposome-encapsulated cis-bis-N-decyliminodiacetato-1,2-diaminocyclohexane-platinum (II)
AU - Lautersztain, J.
AU - Perez-Soler, R.
AU - Khokhar, A. R.
AU - Newman, R. A.
AU - Lopez-Berestein, G.
PY - 1986/11
Y1 - 1986/11
N2 - 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.
AB - 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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U2 - 10.1007/BF00262274
DO - 10.1007/BF00262274
M3 - Article
C2 - 3791565
AN - SCOPUS:0022974909
SN - 0344-5704
VL - 18
SP - 93
EP - 97
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -