Irinotecan metabolism

Although irinotecan metabolism generates at least 20 metabolites, many of them are found at trace levels in patients. Clinically relevant metabolites of irinotecan are the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), inactive glucuro-nide SN-38G, and inactive aminopentane carboxylic acid (7-ethyl-10[4-N-(5-amino-pentanoic acid)-l-piperidino]carbonyloxycamptothecin, APC) (Figure 14.5). 

Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A. Effects of St. John s wort on irinotecan metabolism. J Natl Cancer Inst 2002 94(16) 1247-1249. 

Mathijssen RH, Sparreboom A, Dumez H, van Oosterom AT, de Bruijn EA. Altered irinotecan metabolism in a patient receiving phenytoin. Anticancer Drugs 2002 13(2) 139-40. 

Metabolism of Irinotecan - Activating and Inactivating Pathways and Their Clinical Relevance... 

Metabolic fate of irinotecan in humans correlation of glucuronidation with diarrhea. Cancer Res 1994 54 3723-3725. 

Iyer L, King CD, Whitington PF et al. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998 101 847-854. 

UGTIAI has an important role in the metabolism of irinotecan, etoposide, epiru-bicine, and tipifamib. Irinotecan is a camptothecin derivative used in the treatment of metastatic colon cancer. Irinotecan is a prodrug since it is activated to Ethyl-10-hydroxycamptothecin (SN-38) by carboxyl esterase to exert its antitumor activity mediated by the inhibition of topoisomerase I. SN-38 undergoes UGTIAI-catalyzed glucuronide conjugation to form the inactive SN-38 glucuronide (SN-38G). 

In conclusion, the homozygous or heterozygous genotype for UGTIAI 28 may be a significant risk factor for severe irinotecan toxicity. The example of irinotecan demonstrates clearly how polymorphisms in an inactivating metabolic pathway may affect the adverse events and therapeutic outcome in cancer chemotherapy. 

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Use aprepitant with caution in patients receiving concomitant medicinal products, including chemotherapy agents that are primarily metabolized through CYP3A4 (docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine). 

A full characterization of the metabolic pathways of CPT-11 in human cancer patients has not been undertaken. The incomplete recovery of the irinotecan dose based on urine and bile determinations of irinotecan, SN-38, and SN-38 glucuronide suggests the presence of additional unidentified metabolites. Recently, a major metabolite, 7-ethyl-10-[4-A-(5-aminopenatoic acid)-l-piperidino]carbonyloxycamptothecin, has been identified in dogs and humans, suggesting the presence of an additional metabolic pathway (18). Renal clearance has not been reported to be a major route of elimination for these compounds in humans. 

GuptaE,LestingiTM,Mick R, Ramirez J, Vokes EE, Ratain MJ. Metabolic fate of irinotecan in humans correlation of glucuronidation with diarrhea. Cancer Res 1994 54(14) 3723-3725. 

Irinotecan has demonstrated a broad spectrum of activity in vitro and in vivo, and synergistic effects have been observed when it is administered in combination with other antineoplastic agents. Clinically irinotecan is now an active agent in patients with colorectal carcinoma. Irinotecan is metabolized by carboxylesterase to an active metabolite. It is cleared by hepatic metabolism and biliary excretion with a terminal elimination half-life of approximately 15 hours. The principal toxicities associated with irinotecan are diarrhoea and leucopenia. 

They cause substantial DNA damage in tumor cells, preventing tumor growth. Topotecan has been evaluated in metastatic ovarian cancer. Irinotecan is a prodrug that is metabolized to a topoisomerase I inhibitor it has been used in the treatment of colon and... 

UGT 2 UGT2B7 IPD Reduced metabolism in 10-15% (W) population Ibuprofen, Naproxen, Irinotecan... 

Mathijssen RH, van Alphen RJ, Verweij J et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 2001 21%2-2194. 

Curran et al. have developed an efficient access to 2 and its analogs,3 which provides the first direct synthesis of the prodrug irinotecan (1) without passing through the toxic molecule 3 as in prior studies.4 The latter is the active antitumor agent, which is formed in vivo by metabolism from 1. 

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