Pharmacology: Pharmacodynamics: Mechanism of Action: Irinotecan inhibits Topoisomerase-I, an enzyme involved in DNA replication.
Clinical Pharmacology: 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.
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 100 times potent as irinotecans an inhibitor of topoisomerase-I purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2 to 2000 fold. However, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan. The precise contribution of SN-38 to the activity of irinotecan is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. A pH dependent equilibrium exist between the two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favours the hydroxy acid anion form. Administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.
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.
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.