Organ-specific carboxylesterase profiling identifies the small intestine and kidney as major contributors of activation of the anticancer prodrug CPT-11

摘要: The activation of the anticancer prodrug CPT-11, to its active metabolite SN-38, is primarily mediated by carboxylesterases (CE). In humans, three CEs have been identified, which human liver CE (hCE1; CES1) and intestinal (hiCE; CES2) demonstrate significant ability hydrolyze drug. However, while kinetic parameters CPT-11 hydrolysis measured, actual contribution each enzyme activate drug in biological samples has not addressed. Hence, we used a combination specific inhibition conventional chromatographic techniques determine amounts, hydrolytic activity, present within liver, kidney, lung specimens. These studies confirm that hiCE demonstrates most efficient for activation, however, due high levels hCE1 are expressed latter can contribute up 50% total this tissue. Conversely, duodenum, jejunum, ileum where expression very low, greater than 99% conversion SN-38 was hiCE. Furthermore, analysis microsomal extracts indicated more proficient obtained from smokers. Overall, our plays role even though it 100-fold less at hiCE, intestine kidney likely major contributors production vivo.