Identification and kinetics of a beta-glucuronide metabolite of SN-38 in human plasma after administration of the camptothecin derivative irinotecan

Cancer Chemother Pharmacol. 1995;36(2):176-9. doi: 10.1007/BF00689205.

Abstract

Irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycampothecin) , also known as CPT-11, is a promising semi-synthetic derivative of camptothecin with significant activity against a range of tumor types. The pharmacokinetic behaviour of its principal and presumedly active metabolite, SN-38 (7-ethyl-10-hydroxy-camptothecin), displays wide inter-patient variation. During the high-performance liquid chromatographic (HPLC) analysis of plasma samples collected from a patient given CPT-11, we observed several unidentified peaks that were not present in pre-infusion samples. In this paper we describe the manner in which one of these was determined to be a beta-glucuronide of SN-38. The total plasma concentrations of this metabolite were quantified following digestion with beta-glucuronidase and were found to be greater than those of SN-38 in the patient studied. The elimination phases of the plasma concentration profile of SN-38 and its glucuronide were parallel, suggesting that the transformation of SN-38 to the glucuronide is the rate-limiting step in the elimination of SN-38 and could play a key role in its pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Antineoplastic Agents, Phytogenic / blood*
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Biotransformation
  • Camptothecin / analogs & derivatives*
  • Camptothecin / blood
  • Camptothecin / metabolism
  • Camptothecin / pharmacokinetics
  • Camptothecin / therapeutic use
  • Chromatography, High Pressure Liquid
  • Colonic Neoplasms / drug therapy
  • Female
  • Glucuronates / blood*
  • Glucuronidase
  • Humans
  • Irinotecan
  • Middle Aged
  • Time Factors

Substances

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