Topoblock Mechanism of Action

Pharmacotherapeutic group: Antineoplastic.
Pharmacology: Pharmacodynamics: Mechanism of action: Irinotecan inhibits Topoisomerase-I, an enzyme involved in DNA replication.
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase -I which relieves torsional strain in DNA by inducing reversible single-strained breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase- I DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replicating enzymes interact with the ternary complex formed by topoisomerase-I DNA and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-stranded breaks.
Pharmacokinetics: After the intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in a multiexponential manner, with a terminal elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hrs. Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins(95%bound). The plasma protein to which irinotecan and SN-38 predominantly binds is albumin. Irinotecan has a large mean value of distribution, ranging between 104-211 t/m² after I.V. infusion of 100–350mg/m². Both irinotecan and SN-38 are subject to pH dependent hydrolysis of active closed lactoning structure to an active open ring carboxylate. The AUC ratio of active closed ring form versus total varied from3 3.9% to 44% and from 44.7% to 64% respectively for irinotecan and SN-38.
Metabolism and Excretion: The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in liver. SN-38 subsequently undergoes conjugation to form a glucuronide metabolite. Mean residence time was generally between 9-12 hrs. independent of dose. The elimination of irinotecan was triphasic. The first elimination phase lasting 1.2 to 2.5 hours. SN-38 generally had a longer half-life 7.7 to 17 hours.10 to 26% of the administered dose of irinotecan and 0.18 to 0.26% of SN-38 were eliminated in the urine over a 24 hours period.