Glucuronidation of SN-38, the active metabolite of irinotecan, by human hepatic microsomes

Pharmacol Toxicol. 1997 Feb;80(2):91-6. doi: 10.1111/j.1600-0773.1997.tb00289.x.


We have investigated the glucuronidation in vitro of SN-38, the active metabolite of irinotecan, a semi-synthetic anticancer drug derived from 20(S)camptothecin. Preparations of human hepatic microsomes (final concentration : 1 mg prot./ml), were incubated for 1 hr in 0.1 M Tris buffer, pH 7.4, containing 10 mM MgCl2, in the presence of UDP-glucuronic acid (4 mM), saccharolactone (4 mM), and a detergent. Microsomes from five livers were studied individually or as a pooled preparation. SN-38, either in its lactone or its carboxylate form, was added at a range of concentrations. The SN-38 beta-glucuronide formed was measured by HPLC with fluorometric detection. The glucuronidation reaction appeared linear over 1 hr in these conditions and Brij 35 at 0.5 mg/mg prot. was the best activator. The apparent parameters of the reaction were independent of the molecular form of the substrate. The half-saturation constant was 17-20 microM and Vmax was 60-75 pmol/min./mg prot. The interindividual variation of SN-38 glucuronidation was relatively low (ratio of 1.8 between extreme values). In addition, the effect of twelve drugs currently associated with irinotecan in clinics was evaluated in this system (drug concentration: 100 microM; SN-38 concentration: 5 microM). These produced little if any interference with SN-38 glucuronidation. Therefore, major interferences of this transformation by comedications are unlikely to occur in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / metabolism
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Biotransformation
  • Camptothecin / analogs & derivatives*
  • Camptothecin / metabolism
  • Camptothecin / pharmacokinetics
  • Detergents / pharmacology
  • Glucuronates / metabolism
  • Humans
  • Individuality
  • Irinotecan
  • Liver / metabolism
  • Microsomes, Liver / metabolism*


  • Antineoplastic Agents, Phytogenic
  • Detergents
  • Glucuronates
  • Irinotecan
  • Camptothecin