Irinotecan

Inhibits topoisomerase I, impeding DNA uncoiling leading to double-stranded DNA breaks.

Tradename Camptosar.

Topoisomerase I is an essential enzyme for eukaryotic DNA replication

Interferes with advancing replication or transcription forks, resulting in DNA breaks and cell death.

Metabolized in the liver in active metabolite 7-ethyl-10-hydroxycamptothecin with a low molecular weight and lipophilic properties, enabling it to cross the blood brain barrier.

A prodrug.and its cytotoxicity is primarily attributed to active metabolite, SN-38.

Alteration in the promoter area of the UGT1A1 gene predicts for toxicity.

Increased toxicity in 10% of the population who are homozygous for UGT1A128 a gene variant of UGT1A1, which results in decreased metabolism of SN-38, the active metabolite of irinotecan, to its inactive glucuronide conjugates.

SN-38 and irinotecan bind to the topoisomerase-DNA complex, preventing religation of single strand breaks in DNA and leads to apoptosis.

Hydrolyzed to SN-38 by carboxyl esterase found mainly in the liver but also the plasma and gastrointestinal tract

SN-38 is glucoronidated to SN-38 glucuronide, mainly in the liver, by uridine diphosphate glucoronosyltransferase (UGT) enzymes, primarily UGT1A1 isoenzyme.

Cleavage of SN-38 glucuronide back to SN-38 by bacterial beta-glucuronidase exposes the gastrointestinal brush border to SN-38 , which may contribute to diarrhea.

SN-38 is approximately 1,000 times a more potent topoisomerase I inhibitor than irinotecan.

Metabolism also affected by cytochrome P450 3A4 and drug transport via adenosine troposphere binding cassette transporter super family.

Plus fluorouracil/leucovorin (IFL) in colorectal cancer produces a 39% response rate with a 7 month median time to progression and a median overall survival of 14.8 months.

Utilized in small cell lung cancer and cervical cancer.

Common adverse effects include myelosuppression, diarrhea, nausea, vomiting and alopecia.

Adverse events include cholinergic syndrome.

Potent reversible inhibitor of acetylcholinesterase.

Activates nerve fibers and produces vagal reflexes at peripheral sites to trigger a cholinergic response.

Patients with a high microbiota metabotype have an elevated risk for irinotecan dependent adverse drug responses.

Dosage of 125 mg/m2 per week causes grade ¾ neutropenia in 29% of cases and diarrhea grade ¾ in 36% of individuals, while dosage of 300-350 mg/m2 every 3 weeks cause grade /4 neutropenia in 34% of patients and grade ¾ diarrhea in 19% (Fuchs).

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