Irinotecan is an active cytotoxic agent for various cancers, and is converted to SN-38, its most active metabolite, by carboxylesterase converting enzyme (CCE) in vivo. Although the primary metabolic site is in the liver, ex vivo studies have proven that irinotecan is also converted to SN-38 in intestines, plasma and tumor tissues. The present study attempted to elucidate the in vitro conversion efficiency in human plasma, and to examine possible inter-individual variability and its clinical significance. Plasma samples were taken from 57 patients with lung cancer, 3 patients with benign pulmonary diseases and 9 healthy volunteers. After addition of 157 µ µ µ µM irinotecan to plasma, time courses of SN-38 concentration, measured by high-performance liquid chromatography (HPLC), were investigated. All subjects showed linear increase in SN-38 concentration during the first 60-min period, followed by a plateau. Mean and standard deviation of the conversion rate in the first 60 min were 515.9 ± ± ± ±50.1 pmol/ml/h (n = = = =69), with a coefficient of variation of 0.097. Although most of the subjects showed comparable conversion rates, 3 subjects had significantly higher conversion rates. In conclusion, the results of this study suggest that the enzyme activity of CCE in human plasma may show inter-individual variability. rinotecan, a camptothecin analogue, has recently been introduced into clinical practice and used for treatment of various cancers including lung, colorectal, pancreatic and ovarian cancer. It is a pro-drug that is converted to SN-38 by carboxylesterase converting enzymes (CCE), 1) and SN-38 has 100-to 1000-fold higher cytotoxic activity when compared to the original chemical form.2, 3) In addition, irinotecan and its metabolites have an extremely complex pharmacokinetic profile that is dependent on many enzymes involved in metabolism and transporters associated with intestinal absorption and hepatobiliary secretion mechanisms. 4)The dose-limiting toxicity of the agent includes bone marrow suppression and diarrhea. These adverse effects are occasionally severe not only in high-risk patients, and can even be fatal, especially when diarrhea is accompanied by neutropenia. 5-8)One of the major clinical issues with this drug is that its toxicity and pharmacokinetic parameters ostensibly show inter-patient variability, 4,9) and the toxicity is not necessarily correlated to the pharmacokinetic parameters. 4) Therefore, predicting its toxicity in any given patient has been difficult in contrast to other agents such as carboplatin, for which a sophisticated method for individualizing dosing is available. 10)As one of the mechanisms underlying this inter-individual variability of irinotecan metabolism, Ando et al. 11,12) demonstrated that bilirubin UDP-glucuronosyltransferase 1 gene promoters with excessive TATAA elements were responsible for reduced conjugation of SN-38 to SN-38-glucuronide (SN-38G), resulting in a reduction of SN-38 detoxication in the liver. However, it is still unresolved whether this mec...