Drug Metabolism and Disposition Fast Forward
First published on June 28, 2007; DOI: 10.1124/dmd.106.014043
0090-9556/07/3510-1721-1724$20.00
DMD 35:1721-1724, 2007
SHORT COMMUNICATION
Influence of Short-Term Use of Dexamethasone on the Pharmacokinetics of Ifosfamide in Patients
Svenja Kristin Brüggemann,
Sonja Pfäffle,
Stefan Oliver Peters, and
Thomas Wagner
Department of Internal Medicine, Section of Hematology/Oncology, University of Lübeck, Lübeck, Germany
(Received January 9, 2007;
accepted June 26, 2007)
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Abstract
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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 whether 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 area under the curve (AUC) were determined for the parent compound and the metabolites 4-hydroxyifosfamide and chloracetaldehyde in eight patients who received two cycles of ICE chemotherapy (ifosfamide 5 g/m2 day 1, carboplatin 300 mg/m2 day 1, etoposide 100 mg/m2 days 1-3). One cycle included concomitant administration of dexamethasone (40 mg over 30 min, 16 h and 1 h before chemotherapy), whereas the other did not. The half-lives of ifosfamide, 4-hydroxyifosfamide, and chloracetaldehyde 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 chloracetaldehyde 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.
Dexamethasone (DEX) is frequently used as an antiemetic with highly emetogenic chemotherapy regimens, enhancing the antiemetic potential of 5-hydroxytryptamine3 antagonists (Perez, 1998
). DEX is known to induce hepatic cytochrome P450 3A via the SXR nuclear receptor (Xie et al., 2000) and thus could alter the pharmacokinetics, activities, and side effects of other cytochrome P450-dependent drugs, including oxazaphosphorine cytostatic ifosfamide (IFO) and cyclophosphamide. Both these prodrugs require hepatic activation to form 4-hydroxymetabolites (Furlanut and Franceschi, 2003). For IFO, a second metabolic pathway catalyzed by cytochromes P450 3A4 and 2B6 (Granvil et al., 1999; Huang et al., 2000) leads to the release of chloracetaldehyde (CAA). CAA is responsible for some side effects of IFO (Nicolao and Giometto, 2003; Aleksa et al., 2004) and has been reported to exert cytotoxic effects on tumor cells in vitro and in vivo, by inhibition of DNA synthesis and induction of DNA strand breaks (Brüggemann et al., 1997, 2006; Börner et al., 2000; Brueggemann et al., 2002). Changes in the metabolism of IFO could result in unpredictable antitumor activities and side effects. Using cyclophosphamide in male rats, Yu et al. (1999) found DEX to increase the CAA values almost 10-fold compared with the controls without DEX administration. The peak levels and AUC of 4-hydroxycyclophosphamide were reduced by DEX administration. In humans, CAA generation is low after cyclophosphamide administration (Yu et al., 1999), but considerably increased with IFO. However, so far, there are no published reports documenting the influence of DEX on IFO metabolism in cancer patients.
The aim of this study was to test whether short-term use of DEX as an antiemetic influences the pharmacokinetics of the oxazaphosphorine cytostatic IFO in patients and, thereby, to determine whether these drugs can be safely combined without changing the metabolism, antitumoral potentials, and side effects of ifosfamide.
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Materials and Methods
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Patients. Nine patients (six males, three females), 18 to 70 years of age, 0 to 2 on the World Health Organization performance scale, took part in this prospective randomized trial. All patients suffered from solid tumors (five bronchial carcinomas, one breast cancer, one neuroendocrine tumor, one hepatic metastasized cancer of unknown primary origin, and one neuroendocrine cancer of unknown primary origin with axillar, cervical, infraclavicular, mediastinal, and abdominal metastases) and had a life expectancy of 3 months or more, and the indication for IFO-containing polychemotherapy. Patients with florid gastric or duodenal ulcer were excluded from the study, and one patient dropped out because of antiepileptic medication, which is known to influence hepatic cytochrome P450. The study was approved by the ethics committee of the University of Lübeck and was carried out in accordance with the Declaration of Helsinki. All patients gave their written informed consent before the start of the therapy.
Patient Therapy. To minimize inter- and intraindividual differences, the patients received two cycles of ICE polychemotherapy (IFO 5 g/m2 day 1, carboplatin 300 mg/m2 day 1, and etoposide 100 mg/m2 days 1-3 with 8 mg of ondansetron as standard antiemetic before chemotherapy) and were randomized to receive DEX concomitantly in cycle 1 or 2. When DEX was administered, 40 mg were infused over 30 min, 16 h and 1 h before chemotherapy. Three milliliters of blood were taken from a venous catheter 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 24, and 30 h after the start of IFO infusion, and IFO, 4-hydroxyifosfamide (4-OH-IFO), and CAA were measured as described below.
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FIG. 1. Pharmacokinetics of IFO (a) and the metabolites 4-OH-IFO (b) and CAA (c) after ifosfamide-containing chemotherapy with or without DEX (n = 8; mean ± S.D.).
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IFO Assay. For IFO determination, the blood samples were centrifuged and the plasma was spiked with an internal standard solution containing the oxazaphosphorine derivative trofosfamide (for details see Kurowski and Wagner, 1993). After dichloromethane extraction, IFO was measured by gas chromatography with an HP5 column (Hewlett Packard, Palo Alto, CA; 5% phenylmethylsilicone) and helium serving as carrier gas. Temperatures of the oven, injector, and detector were set at 130°C (heated to 210°C), 190°C, and 300°C. LOQ and LOD were 1.5 µM and 0.5 µM, respectively. Interassay CV at 50 µM was 5.2% (for more details see Kurowski and Wagner, 1993).
CAA Assay. To determine the CAA concentrations, the blood samples were processed as described by Kurowski and Wagner (1993). In brief, CAA was measured by gas chromatography with an electron capture detector, a capillary column (HP5, cross-linked with 5% phenylmethylsilicone), and helium serving as carrier gas. LOQ and LOD were 1.0 µM and 0.33 µM, respectively. Interassay CV at 5 µM was 13.7% (for more details see Kurowski and Wagner, 1993).
4-OH-IFO Assay. To measure 4-OH-IFO, the blood samples were processed as described previously (Alarcon, 1968) with minor modifications. The derivatization mixture with fluorescent 7-hydroxyquinoline was separated by high performance liquid chromatography without the extraction procedure and quantified by fluorescence detection (see Bohnenstengel et al., 1997). LOQ and LOD were 0.16 µM and 0.05 µM, respectively. Interassay CV at 2 µM was 5.7% (for more details see Kurowski and Wagner, 1993).
Calculations and Statistical Evaluation. The terminal half-life (t
), the highest measured concentration (Cmax), the time point of highest concentration (tmax), and the area under the concentration-time curve (AUC0-24 and AUC0-
) were calculated with the TOPFIT 2.0 program (version 2.0, Heinzel et al., 1993). The Wilcoxon-Test (Wilcoxon matched pair signed rank statistic) was used for statistical evaluation.
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Results and Discussion
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DEX is known to induce hepatic cytochrome P450 3A via the SXR nuclear receptor (Xie et al., 2000). Used as an antiemetic, DEX could alter the pharmacokinetics, activities, and side effects of cytochrome P450-dependent oxazaphosphorine cytostatic IFO. Therefore, the pharmacokinetics of the prodrug IFO and the active metabolites 4-OH-IFO and CAA were determined after ICE chemotherapy, with or without concomitant DEX administration (Fig. 1). The plasma concentrations were similar for IFO and 4-OH-IFO, respectively, and no significant differences were identified in the peak concentrations and AUC (see Table 1). The standard deviations can probably be explained by the known high interindividual differences in cytochrome P450 activities (Lamba et al., 2002). Small differences cannot be ruled out; however, statistically significant and clinically relevant differences were not observed in IFO and 4-OH-IFO peak concentrations and AUC between the two groups. The half-lives of all three substances were shorter when DEX was administered, but the differences were not statistically significant (Table 1). In contrast to IFO and 4-OH-IFO, the CAA peak concentration and AUC were increased 1.5- and 1.3-fold, respectively, with concomitant DEX administration. However, due to the number of patients and the high standard deviation, these increases could not be statistically confirmed (Fig. 1; Table 1).
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TABLE 1 Pharmacokinetics of IFO and the metabolites 4-OH-IFO and CAA after ifosfamide-containing chemotherapy with or without DEX n = 8. Values are mean (±S.D.).
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The IFO, 4-OH-IFO, and CAA AUCs of each patient are shown in Fig. 2. The individual AUC ratios after ICE chemotherapy without, versus with, DEX ranged from 0.64 to 1.95, 0.63 to 2.01, and 0.27 to 1.64 for IFO, 4-OH-IFO, and CAA, respectively. No differences were observed between administering DEX in cycle 1 or 2.
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FIG.2. AUC0- of IFO (a), 4-OH-IFO (b), and CAA (c) of patients 1 to 8 with or without concomitant application of DEX.
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Currently, there is no information about the pharmacokinetics of ifosfamide after short-term use of dexamethasone in humans. Our results contrast those from animal studies in rats (Brain et al., 1998) in which a proportional decrease in the AUCs for both IFO metabolites was observed after DEX administration with no net impact on the fraction of IFO undergoing 4-hydroxylation. Furthermore, our results differ from those of Yu et al. (1999), who found that DEX pretreatment enhances the CAA levels. These authors reported that Cmax of CAA was increased 
8.5-fold, whereas the AUC of CAA was increased 4-fold. The concomitant peak level and AUC of 4-hydroxycyclophosphamide were reduced when DEX was given before the cyclophosphamide application. However, unlike in rats, in humans the generation of CAA is low after cyclophosphamide treatment (Yu et al., 1999).
Wang et al. (2004a,b) investigated the pharmacokinetics of carboplatin and gemcitabine after DEX pretreatment in mice. They found small but significant differences in the plasma pharmacokinetics of gemcitabine. The plasma AUC of gemcitabine was decreased by 40% with the DEX pretreatment, as a result of a reduced half-life (Wang H et al., 2004a). These data are inconsistent with earlier results from the same group, which did not show significant changes in the gemcitabine pharmacokinetics (Wang et al., 2004b). In both studies, DEX pretreatment resulted in no significant changes in the carboplatin pharmacokinetics and AUC.
In this study, we compared the pharmacokinetics of IFO and its metabolites in patients, with or without the short-term use of DEX as an antiemetic. Taken together, our results show that DEX administration before chemotherapy has no important effect on the IFO pharmacokinetics, which suggests that DEX may be safely used with ifosfamide chemotherapy. The induction of cytochrome P450 3A by DEX may require 2 to 3 days, and therefore, the long-term use of DEX could induce significant changes. However, there are no data to document the effects of continuous DEX application; for example, in the therapy of cerebral metastases in bronchial carcinoma.
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Acknowledgments
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We thank Heike Albrecht for skillful technical assistance.
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Footnotes
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doi:10.1124/dmd.106.014043.
ABBREVIATIONS: DEX, dexamethasone; SXR, steroid and xenobiotic receptor; IFO, ifosfamide; 4-OH-IFO, 4-hydroxyifosfamide; CAA, chloracetaldehyde; AUC, area under the curve; ICE, ifosfamide 5 g/m2 day 1, carboplatin 300 mg/m2 day 1, etoposide 100 mg/m2 days 1-3; LOQ, limit of quantification; LOD, limit of detection; AUC0-24 and AUC0-, areas under the concentration-time curve.
Address correspondence to: Thomas Wagner, Department of Internal Medicine, Section of Hematology/Oncology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. E-mail: wagnerth{at}uni-luebeck.de
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Abstract
Materials and Methods
