Metabolism of Irinotecan to SN-38 in a Tissue-Isolated Tumor Model

Abstract

The objective of this study is to investigate the metabolism of the antitumor drug, irinotecan (CPT-11), to its active metabolite, SN-38, in tumor tissue. Using Walker 256 carcinoma, we prepared a tissue-isolated tumor model : tumor preparation was continuously perfused with Krebs-Henseleit bicarbonate buffer containing 4% bovine serum albumin (BSA) and CPT-11 (10 μg/ml), and the concentration of SN-38 in the perfusate was monitored using HPLC. The concentration of SN-38 in the perfusate was gradually increased to a level of 9.69 bng/ml 60 min after the start of perfusion. As a control, an aliquot of the perfusate was separately incubated; however, no significant increase in SN-38 levels was observed. At the end of the perfusion, a part of the tumor tissue was homogenized and the level of SN-38 was determined; the levels in tumor tissue were 2.2-4.5 times higher than in the perfusate. From above results, CPT-11 was found to be metabolized to its active metabolite, SN-38, in tumor tissue-a desirable feature of an antitumor prodrug. © 1995, The Pharmaceutical Society of Japan. All rights reserved.