CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as
a prodrug of SN-38, which is approximately 100-1000-fold more cytotoxic
than the parent drug. CPT-11 has shown a broad spectrum of antitumor
activity in preclinical models as well as clinically, with responses
observed in various disease types including colorectal, lung, cervical,
and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are
extremely complex and have been the subject of intensive investigation in
recent years. Both CPT-11 and SN-38 are known in an active lactone form
and an inactive carboxylate form, between which an equilibrium exists that
depends on the pH and the presence of binding proteins. CPT-11 is subject
to extensive metabolic conversion by various enzyme systems, including
esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as
well as CYP3A4, which forms several pharmacologically inactive oxidation
products. Elimination routes of CPT-11 also depend on the presence of
drug-transporting proteins, notably P-glycoprotein and canalicular
multispecific organic anion transporter, present on the bile canalicular
membrane. The various processes mediating drug elimination, either through
metabolic breakdown or excretion, likely impact substantially on
interindividual variability in drug handling. Strategies to individualize
CPT-11 administration schedules based on patient differences in enzyme or
protein expression or by coadministration of specific agents modulating
side effects are under way and may ultimately lead to more selective
chemotherapeutic use of this agent
