Plasma kinetics and uptake by the tumor of a cholesterol-rich microemulsion (LDE) associated to etoposide oleate in patients with ovarian carcinoma.

Objectives: Previously, we reported that etoposide oleate associated to a cholesterol-rich microemulsion (LDE) is taken up by malignant cells overexpressing low-density lipoprotein (LDL) receptors. The association is stable, preserves antiproliferative activity of the drug, and reduces toxicity to animals. Here, we determined in patients the plasma kinetics of LDE-etoposide oleate and verified whether the complex concentrates in ovarian carcinomas.

Methods: [(3)H]-etoposide oleate associated to LDE labeled with [(14)C]-cholesteryl oleate was intravenously injected into four ovarian carcinoma patients (50 +/- 8.7 years) 24 h before surgery. Blood samples were collected over a 24-h period to determine the radioactivity plasma decay curves, and the plasma fractional clearance rate (FCR) was calculated by compartmental analysis. Specimens of tumors and normal ovaries excised during the surgery were collected for lipid extraction and radioactive counting.

Results: FCRs of LDE label and of the drug were similar (0.0985 and 0.1722, respectively, P = 0.2422). [(14)C]-LDE uptake was 4.9 times and [(3)H]-etoposide oleate uptake was 4.1 times greater in the ovarian tumors than in the contralateral normal ovaries (LDE uptake, in cpm/g = 560 +/- 171 and 146 +/- 59; etoposide oleate uptake = 346 +/- 75 and 103 +/- 56, respectively).

Conclusions: Most of the drug is retained in the microemulsion particles until its removal from the circulation and internalization by the cells. In addition, LDE-etoposide oleate has the ability to concentrate in malignant ovarian tissues. Therefore, the complex may be used to direct and concentrate etoposide oleate in ovarian carcinomas.