Irinotecan (CPT-11) is a semi-synthetic camptothecin with a broad spectrum of clinical activity. It is a prodrug that is cleaved by esterases to the potent topoisomerase I poison, SN-38. In humans, this activation is relatively inefficient, but this may result in a more protracted formation of SN-38 lactone. Some intratumoral activation may also occur, but the significance of this process is uncertain. CPT-11 is metabolized by cytochrome P450 3A to yield a number of comparatively inactive compounds. SN-38 is glucurono-conjugated in the liver, and this metabolite, although inactive, may participate in the enterohepatic cycling of SN-38 after hydrolysis in the intestinal lumen. Overall, the production of SN-38 from CPT-11 is the result of the complex interplay of several metabolic pathways and the source of considerable interpatient variability.