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Drug Metabolism and Disposition Fast Forward
First published on June 28, 2007; DOI: 10.1124/dmd.106.014043

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Received for publication January 9, 2007.
Revised June 22, 2007.
Accepted for publication June 26, 2007.

Influence of Short-term use of Dexamethasone on the Pharmacokinetics of Ifosfamide in Patients

Svenja Kristin Bruggemann 1, Sonja Pfaffle 1, Stefan Oliver Peters 1, Thomas Wagner 1*

1 Universitatsklinikum Schleswig-Holstein Campus Lubeck

* Address correspondence to: E-mail: wagnerth{at}uni-luebeck.de

Abstract

Dexamethasone induces the hepatic cytochrome P450 3A and therefore, is predicted to change the pharmacokinetics, activities and side effects of drugs metabolized by cytochrome P450 3A. The aim of this study was to determine if the pharmacokinetics of the cytochrome-P450-3A-dependent oxazaphosphorine cytostatic drug ifosfamide is influenced by short-term antiemetic use of dexamethasone in patients. The peak-concentration and AUC were determined for the main substance and the metabolites 4-hydroxyifosfamide and chloroacetaldehyde in 8 patients who received two cycles of ICE-chemotherapy (ifosfamide 5 g/m2 day 1, carboplatin 300 mg/m2 day 1, etoposide 100 mg/m2 day 1-3). One cycle included concomitant administration of dexamethasone (40 mg over 30 min 16 hours and 1 hour prior to chemotherapy), whereas the other did not. The half-lives of ifosfamide, 4-hydroxyifosfamide and chloroacetaldehyde were shorter with concomitant administration of dexamethasone, but the differences were not statistically significant. In addition, there were no significant differences in the ifosfamide and active 4-hydroxyifosfamide peak-concentrations and AUCs when dexamethasone was included. After dexamethasone administration, the chloroacetaldehyde peak-concentration was slightly increased by 1.5-fold and the AUC by 1.3-fold, however, these increases were not statistically significant. In conclusion, dexamethasone comedication in ICE-chemotherapy did not change the ifosfamide pharmacokinetics. Thus, dexamethasone can be used safely as an antiemetic drug in ifosfamide chemotherapy.


Key words: anticancer agents, clinical pharmacokinetics, cytochrome P450, drug interactions, gas chromatography, HPLC, induction, metabolite kinetics, prodrugs, steroids


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A. Jarkowski III
Possible contribution of aprepitant to ifosfamide-induced neurotoxicity
Am. J. Health Syst. Pharm., December 1, 2008; 65(23): 2229 - 2231.
[Abstract] [Full Text] [PDF]


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