This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kehrer, D. F.S. Articles by Sparreboom, A. Search for Related Content PubMed PubMed Citation Articles by Kehrer, D. F.S. Articles by Sparreboom, A. Social Bookmarking                            What's this?

Modulation of Irinotecan Metabolism by Ketoconazole

From the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), University Hospital Rotterdam, the Netherlands.

Address reprint requests to Alex Sparreboom, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email: sparreboom{at}onch.azr.nl

PURPOSE: Irinotecan (CPT-11) is a prodrug of SN-38 and has been registered for the treatment of advanced colorectal cancer. It is converted by the cytochrome P450 3A4 isozyme (CYP3A4) into several inactive metabolites, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC). To investigate the role of CYP3A4 in irinotecan pharmacology, we evaluated the consequences of simultaneous treatment of irinotecan with a potent enzyme inhibitor, ketoconazole, in a group of cancer patients.

PATIENTS AND METHODS: A total of seven assessable patients was treated in a randomized, cross-over design with irinotecan (350 mg/m² intravenously for 90 minutes) given alone and followed 3 weeks later by irinotecan (100 mg/m²) in combination with ketoconazole (200 mg orally for 2 days) or vice versa. Serial plasma, urine, and feces samples were obtained up to 500 hours after dosing and analyzed for irinotecan, metabolites (7-ethyl-10-hydroxycamptothecin [SN-38], SN-38 glucuronide [SN-38G], and APC), and ketoconazole by high-performance liquid chromatography.

RESULTS: With ketoconazole coadministration, the relative formation of APC was reduced by 87% (P = .002), whereas the relative exposure to the carboxylesterase-mediated SN-38 as expected on the basis of dose (area under the plasma concentration-time curve normalized to dose) was increased by 109% (P = .004). These metabolic alterations occurred without substantial changes in irinotecan clearance (P = .90) and formation of SN-38G (P = .93).

CONCLUSION: Inhibition of CYP3A4 in cancer patients treated with irinotecan leads to significantly increased formation of SN-38. Simultaneous administration of various commonly prescribed inhibitors of CYP3A4 can potentially result in fatal outcomes, and up to four-fold reductions in irinotecan dose are indicated.

Presented, in part, at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications, Miami Beach, FL, October 29 to November 2, 2001.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J. M. van der Bol, R. H.J. Mathijssen, W. J. Loos, L. E. Friberg, R. H.N. van Schaik, M. J.A. de Jonge, A. S.Th. Planting, J. Verweij, A. Sparreboom, and F. A. de Jong Cigarette Smoking and Irinotecan Treatment: Pharmacokinetic Interaction and Effects on Neutropenia J. Clin. Oncol., July 1, 2007; 25(19): 2719 - 2726. [Abstract] [Full Text] [PDF]

				F. K. Engels, F. A. de Jong, A. Sparreboom, R. A. A. Mathot, W. J. Loos, J. J. E. M. Kitzen, P. de Bruijn, J. Verweij, and R. H. J. Mathijssen Medicinal Cannabis Does Not Influence the Clinical Pharmacokinetics of Irinotecan and Docetaxel Oncologist, March 1, 2007; 12(3): 291 - 300. [Abstract] [Full Text] [PDF]

				S. Mirkov, B. J. Komoroski, J. Ramirez, A. Y. Graber, M. J. Ratain, S. C. Strom, and F. Innocenti Effects of Green Tea Compounds on Irinotecan Metabolism Drug Metab. Dispos., February 1, 2007; 35(2): 228 - 233. [Abstract] [Full Text] [PDF]

				V. Uttamsingh, C. Lu, G. Miwa, and L.-S. Gan RELATIVE CONTRIBUTIONS OF THE FIVE MAJOR HUMAN CYTOCHROMES P450, 1A2, 2C9, 2C19, 2D6, AND 3A4, TO THE HEPATIC METABOLISM OF THE PROTEASOME INHIBITOR BORTEZOMIB Drug Metab. Dispos., November 1, 2005; 33(11): 1723 - 1728. [Abstract] [Full Text] [PDF]

				N. P.H. van Erp, S. D. Baker, M. Zhao, M. A. Rudek, H.-J. Guchelaar, J. W.R. Nortier, A. Sparreboom, and H. Gelderblom Effect of Milk Thistle (Silybum marianum) on the Pharmacokinetics of Irinotecan Clin. Cancer Res., November 1, 2005; 11(21): 7800 - 7806. [Abstract] [Full Text] [PDF]

				W. P. Yong, J. Ramirez, F. Innocenti, and M. J. Ratain Effects of Ketoconazole on Glucuronidation by UDP-Glucuronosyltransferase Enzymes Clin. Cancer Res., September 15, 2005; 11(18): 6699 - 6704. [Abstract] [Full Text] [PDF]

				R. H. J. Mathijssen, F. A. de Jong, R. H. N. van Schaik, E. R. Lepper, L. E. Friberg, T. Rietveld, P. de Bruijn, W. J. Graveland, W. D. Figg, J. Verweij, et al. Prediction of Irinotecan Pharmacokinetics by Use of Cytochrome P450 3A4 Phenotyping Probes J Natl Cancer Inst, November 3, 2004; 96(21): 1585 - 1592. [Abstract] [Full Text] [PDF]

				F. A. de Jong, S. Marsh, R. H. J. Mathijssen, C. King, J. Verweij, A. Sparreboom, and H. L. McLeod ABCG2 Pharmacogenetics: Ethnic Differences in Allele Frequency and Assessment of Influence on Irinotecan Disposition Clin. Cancer Res., September 1, 2004; 10(17): 5889 - 5894. [Abstract] [Full Text] [PDF]

				R. H. J. Mathijssen, S. Marsh, M. O. Karlsson, R. Xie, S. D. Baker, J. Verweij, A. Sparreboom, and H. L. McLeod Irinotecan Pathway Genotype Analysis to Predict Pharmacokinetics Clin. Cancer Res., August 1, 2003; 9(9): 3246 - 3253. [Abstract] [Full Text] [PDF]

				M. S H Lam and R. J Ignoffo A guide to clinically relevant drug interactions in oncology Journal of Oncology Pharmacy Practice, June 1, 2003; 9(2-3): 45 - 85. [Abstract] [PDF]

				J. D. Chester, S. P. Joel, S. L. Cheeseman, G. D. Hall, M. S. Braun, J. Perry, T. Davis, C. J. Button, and M. T. Seymour Phase I and Pharmacokinetic Study of Intravenous Irinotecan Plus Oral Ciclosporin in Patients With Fluorouracil-Refractory Metastatic Colon Cancer J. Clin. Oncol., March 15, 2003; 21(6): 1125 - 1132. [Abstract] [Full Text] [PDF]