PHARMACOKINETIC STUDY OF INTRAPERITONEALLY ADMINISTERED ETOPOSIDE AGAINST PERITONITIS CARCINOMATOSA

Abstract

Etoposide is becoming important in primary and salvage therapy for ovarian cancer. In the present study, we administered etoposide (100-300 mg/subject) intraperitoneally to six patients suffering from cancerous peritonitis, particularly that resulting from ovarian cancer, to investigate the bioavailability and pharmacokinetics of this drug. The peak etoposide level in the ascites was 80 μg/ml. Twelve hours after intrapertoneal administration (i. p.), more than 10 μg/ml of etoposide was still found in ascites. The serum level after administration of 100 mg i. p. reached approximately 4 μg/ml within 30 minutes, and 1 μg/ml of etoposide was still found in serum after 24 hours. The etoposide levels in ascites and serum after 300 mg i. p. were higher than those after 100 mg i. p. When the peritoneum was intact, the area under the curve (AUC) of etoposide in ascites was low (164 μg・h/ml), and the peritoneal clearance (Clp) was high. In contrast, in advanced cancerous peritonitis, the AUC in ascites was high (500 μg・h./ml) and the Clp was low. The AUC of etoposide in the ascites of patients with cancerous peritonitis was more than five-fold greater than that of patients with an intact peritoneum, while MRT (mean residence time) was 15-fold, and VRT (variance of residence time) was 300-fold greater. The AUC ratio in intact peritoneum was 4.1, and that in cancerous peritonitis ranged from 17.8 to 27.1. AUC, MRT and VRT of etoposide transported into the blood were slightly higher in advanced cases than in those with intact peritoneum. These findings indicate that intraperitoneal etoposide han not only a direct anticancer effect in the abdominal cavity but also shows effects via the vascular system of the tumor.