RESUMO
BACKGROUND: Irinotecan (CPT-11) is hydrolyzed by carboxyl esterase to the active metabolite SN-38 and oral irinotecan could undergo intestinal and hepatic activation. MATERNALS AND METHODS: Irinotecan was incubated with S9 fractions of human liver and intestinal tissues and the specific activity was determined based on the formation rate of SN-38. RESULTS: Irinotecan was hydrolyzed to SN-38 by hepatic and intestinal S9 fractions with mean (+/- SD) specific activities (pmoles/min/mg) of: liver (8.57 +/- 10.4, n = 8), duodenum (5.06 +/- 3.7, n = 4), jejunum (6.44 +/- 2.8, n = 5), ileum (4.81 +/- 2.4, n = 5), colon (1.93 +/- 1.5, n = 6) and rectum (0.82, n = 1). When incubated with S9 fractions obtained from tumor tissues, there appeared to be a decrease in SN-38 formation compared to matched normal liver and colon tissues. CONCLUSION: Irinotecan undergoes conversion to its active metabolite in human intestinal S9 fractions and there is variability in the extent of SN-38 formation. The localized intestinal activation of irinotecan to SN-38 may provide a rationale for the development of oral irinotecan for gastrointestinal malignancies but could also cause mucosal damage leading to toxicity.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Mucosa Intestinal/metabolismo , Neoplasias Intestinais/metabolismo , Neoplasias Hepáticas/metabolismo , Microssomos Hepáticos/metabolismo , Pró-Fármacos/farmacocinética , Biotransformação , Camptotecina/biossíntese , Camptotecina/farmacocinética , Hidrolases de Éster Carboxílico/metabolismo , Colo/metabolismo , Duodeno/metabolismo , Humanos , Hidrólise , Íleo/metabolismo , Irinotecano , Jejuno/metabolismo , Microssomos/metabolismo , Proteínas de Neoplasias/metabolismo , Especificidade de Órgãos , Reto/metabolismoRESUMO
We have developed a sensitive high-performance liquid chromatography (HPLC) assay to quantitate total and lactone forms of 20(S)camptothecin (CPT) in human plasma. Lactone and total CPT were extracted using solid-phase extraction and liquid-liquid extraction, respectively. The extracted lactone samples could be stored without immediate HPLC analysis. The two forms of CPT were quantitated by reversed-phase HPLC with fluorescence detection. The extraction efficiencies were about 100% and 92% for the total and lactone forms, respectively. The lower limit of quantitation was 5.74 nM for the two forms. The method was reproducible with a mean interday and intraday variability of 6% for total CPT and 4% and 6%. respectively, for lactone CPT. The assay could effectively quantitate lactone and total CPT in patients receiving single dose and multiple doses of oral CPT.