Metabolism of CPT‐11: Impact on Activity

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Abstract
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.

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