Cellular pharmacology of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in mouse resident peritoneal macrophages, Kupffer cells, and hepatocytes.

Abstract

The in vitro and in vivo interaction of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ + (II) (L-NDDP) with mouse resident peritoneal macrophages (RPM), Kupffer cells (KC), and hepatocytes was studied. The peak in vitro uptake of L-NDDP by RPM was 12.5 ng elemental platinum/100 micrograms cell protein and constituted 0.2% of the platinum available for phagocytosis. The subsequent release of platinum by RPM was rapid initially, with a 20-fold increase over the first 4 h, followed by a plateau; ultrafilterable (free) platinum constituted 50% of the total platinum released at 24 h. The retained intracellular platinum in RPM at 24 h was close to 50% of that initially present. The peak in vitro uptake of L-NDDP by KC was 11.3 ng platinum/100 micrograms cell protein and amounted to 0.2% of the platinum available for phagocytosis. The release of platinum by KC was detectable only after 4 h of incubation and increased 3-fold over the next 14 h. The ultrafilterable platinum released by KC at 18 h was 40% of the total platinum released. The retained intracellular platinum in KC at 18 h was 33% of that initially present. The peak in vitro uptake of L-NDDP by hepatocytes was almost 50 ng platinum/100 micrograms cell protein and constituted 0.8% of the platinum available for intake. Following the i.v. injection of L-NDDP, hepatocytes contained up to 6-fold higher platinum concentrations than KC. This observation was supported by transmission electron microscopy showing a higher concentration of multilamellar vesicles within hepatocytes than in KC, 5 min after i.v. injection of L-NDDP. These findings suggest that L-NDDP becomes available to the liver following i.v. injection, that both macrophages and hepatocytes play a role in the metabolism of L-NDDP, and that Kupffer cells could mediate a sustained release of platinum in the liver following the interaction with L-NDDP, indicating the potential of L-NDDP for the treatment of tumors in the liver.

• Authors: J Lautersztain, R Perez-Soler, J Turpin, A R Khokhar, Z H Siddik, K Schmidt, G Lopez-Berestein
• Journal: Cancer research (Cancer Res) Vol. 48 Issue 5 Pg. 1300-6 (Mar 01 1988) ISSN: 0008-5472 [Print] United States
• PMID: 3342409 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Liposomes
• Organoplatinum Compounds
• bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II)
• Platinum

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• In Vitro Techniques
• Kupffer Cells (metabolism)
• Liposomes (administration & dosage)
• Liver (metabolism, ultrastructure)
• Macrophages (metabolism)
• Male
• Mice
• Organoplatinum Compounds (pharmacokinetics)
• Platinum (pharmacokinetics)