Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Sep;84(3):393-402.
doi: 10.1038/clpt.2008.63. Epub 2008 Apr 16.

Pharmacogenetic pathway analysis of irinotecan

G L Rosner  1 , J C Panetta, F Innocenti, M J Ratain
Affiliations

Pharmacogenetic pathway analysis of irinotecan

G L Rosner et al. Clin Pharmacol Ther. 2008 Sep.

Abstract

Irinotecan, a chemotherapeutic agent against various solid tumors, is a prodrug requiring activation to SN-38. Irinotecan's complex pharmacokinetics potentially allow for many genetic sources of variability. We explored relationships between pharmacokinetic pathways and polymorphisms in genes associated with irinotecan's metabolism and transport. We fitted a seven-compartment pharmacokinetic model with enterohepatic recirculation (EHR) to concentrations of irinotecan and metabolites SN-38, SN-38 glucuronide (SN-38G), and aminopentanoic acid (APC). Principal component analysis (PCA) of patient-specific parameter estimates produced measures interpretable along pathways. Nine principal components provided good characterization of the overall variation. Polymorphisms in genes UGT1A1, UGT1A7, and UGT1A9 had strong associations with a component corresponding to the irinotecan-to-SN-38 pathway and SN-38 recirculation and to a component relating to SN-38-to-SN-38G conversion and elimination of SN-38G. The component characterizing irinotecan's compartments was associated with HNF1alpha and ABCC2 polymorphisms. The exploratory analysis with PCA in this pharmacogenetic analysis was able to identify known associations and may have allowed identification of previously uncharacterized functional polymorphisms.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Pharmacokinetic model with enterohepatic recirculation (EHRT). The numbers in the lower right corner of the compartments identify each compartment.
Figure 2
Figure 2
Example fit of model to one patient’s concentration-time data for irinotecan (a), SN-38 (b), SN-38G (c), and APC (d).
Figure 3
Figure 3
Biplot showing the first two PCs after rotation. The numbers in the graph refer to patients (numbered consecutively). The scales of the axes refer to the PC scores (see text) for each patient. Each arrow is labeled with the corresponding parameter from the pharmacokinetic model (Figure 1).
Figure 4
Figure 4
The first two PCs as pharmacokinetic pathways with associated polymorphisms.
See this image and copyright information in PMC

References

    1. Rivera F, Vega-Villegas ME, Lopez-Brea MF. Chemotherapy of advanced gastric cancer. Cancer Treat Rev. 2007;33:315–324. - PubMed
    1. Markman M. New, expanded, and modified use of approved antineoplastic agents in ovarian cancer. Oncologist. 2007;12:186–190. - PubMed
    1. MacCallum C, Gillenwater HH. Second-line treatment of small-cell lung cancer. Curr Oncol Rep. 2006;8:258–264. - PubMed
    1. Kumar A, Wakelee H. Second-and third-line treatments in non-small cell lung cancer. Curr Treat Options Oncol. 2006;7:37–49. - PubMed
    1. Garcia-Carbonero R, Supko JG. Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res. 2002;8:641–661. - PubMed

Publication types

MeSH terms