Oxime Derivatives of the Intermediary Oncostatic Metabolites of Cyclophosphamide and Ifosfamide: Synthesis and Deuterium Labeling for Applications to Metabolite Quantification

Ludeman, Susan M.; Shulman-Roskes, Ellen M.; Wong, K; Han, Sung Y.; Anderson, Lawrence W.; Strong, John M.; Colvin, O. Michael

doi:10.1002/jps.2600840403

Cited by 14 publications

(10 citation statements)

References 21 publications

(1 reference statement)

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“…CYP P450 is predominantly responsible for phase 1 metabolism in the liver, as is the case with cyclophosphamide. 6,7,[13][14][15][16] The genetic polymorphisms in certain CYP P450 isozymes, including CYP2B6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5, can contribute to the interanimal variability commonly seen among dogs receiving cyclophosphamide. 6,7,[14][15][16] In some cases, these polymorphisms were found to be predictors for intoxication and clinical response.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Cyclophosphamide after Oral and Intravenous Administration to Dogs with Lymphoma

Warry

Hansen

Gustafson

et al. 2011

Veterinary Internal Medicne

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Background Cyclophosphamide is an alkylating chemotherapeutic drug administered IV or PO. It is currently assumed that exposure to the active metabolite, 4-hydroxycyclophosphamide (4-OHCP), is the same with either route of administration. Objectives To characterize the pharmacokinetics of cyclophosphamide and 4-OHCP in dogs with lymphoma when administered PO or IV. Animals Sixteen client-owned dogs with substage A lymphoma were enrolled in the study. Eight dogs received cyclophosphamide IV and 8 received it PO. Methods Prospective randomized clinical trial was performed. Blood was collected from each dog at specific time points after administration of cyclophosphamide. The serum was evaluated for the concentration of cyclophosphamide and 4-OHCP with mass spectrometry and liquid chromatography. Results Drug exposure to cyclophosphamide measured by area under the curve (AUC)0–inf is significantly higher after intravenous administration (7.14 ± 3.77 μg/h/mL) compared with exposure after oral administration (P-value < .05). No difference in drug exposure to 4-OHCP was detected after IV (1.66 ± 0.36 μg/h/mL) or PO (1.42 ± 0.64 μg/h/mL) administered cyclophosphamide. Conclusions and Clinical Importance Drug exposure to the active metabolite 4-OHCP is equivalent after administration of cyclophosphamide either PO or IV.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Cyclophosphamide after Oral and Intravenous Administration to Dogs with Lymphoma

Warry

Hansen

Gustafson

et al. 2011

Veterinary Internal Medicne

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“…1; ref. 27), which is stable in the trapping solution for weeks at room temperature and indefinitely at À20jC, and can be quantified by gas chromatography/mass spectrometry (GC/MS) or liquid chromatography/tandem mass spectrometry (LC/MS/MS) as a measure of the concentration of 4-OH-CPA in the original blood sample (26,27). Using this methodology, ''4-OH-CPA'' levels refer to aggregate concentrations of 4-OH-CPA, aldophosphamide, and any other species that reversibly interconvert with these metabolites (e.g., iminophosphamide and glutathione adducts; ref.…”

Section: Matrigel Plug Perfusion Assay and Circulating Endothelial Prmentioning

confidence: 99%

“…28). The syntheses of 4-hydroperoxy-CPA (4-OOH-CPA; synthetic precursor of 4-OH-CPA) and ''PBOX-d 4 '' (internal standard with four deuterium atoms in chloroethyl side chains) used in GC/MS and LC/MS/MS analyses have been reported (27). These materials are also available commercially: Qventas, Inc. (4-OOH-CPA) and Dr. Ulf Niemeyer, IIT, Universität Bielefeld GmbH, part NIOMECH, Bielefeld, Germany (4-OOH-CPA and PBOX-d 4 ).…”

Section: Matrigel Plug Perfusion Assay and Circulating Endothelial Prmentioning

confidence: 99%

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Emmenegger

Shaked

Man

et al. 2007

Molecular Cancer Therapeutics

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Prolonged, frequently administered low-dose metronomic chemotherapy (LDM) is being explored (pre)clinically as a promising antiangiogenic antitumor strategy. Although appealing because of a favorable side effect profile and mostly oral dosing, LDM involves new challenges different from conventional maximum tolerated dose chemotherapy. These include possible altered pharmacokinetic characteristics due to long-term drug exposure potentially resulting in acquired resistance and increased risk of unfavorable drug interactions. We therefore compared the antitumor and antivascular effects of LDM cyclophosphamide (CPA) given to mice that had been pretreated with either LDM CPA or normal saline, obtained blood 4-hydroxy-CPA (activated CPA) concentrations using either gas chromatography/mass spectrometry or liquid chromatography/tandem mass spectrometry in mice treated with LDM CPA, and measured hepatic and intratumoral activity of enzymes involved in the biotransformation of CPA and many other drugs [i.e., cytochrome P450 3A4 (CYP3A4) and aldehyde dehydrogenase]. Exposure of mice to LDM CPA for z8 weeks did not compromise subsequent activity of LDM CPA therapy, and biologically active 4-hydroxy-CPA levels were maintained during long-term LDM CPA administration. Whereas the effects on CYP3A4 were complex, aldehyde dehydrogenase activity was not affected. In summary, our findings suggest that acquired resistance to LDM CPA is unlikely accounted for by altered CPA biotransformation. In the absence of reliable pharmacodynamic surrogate markers, pharmacokinetic parameters might become helpful to individualize/optimize LDM CPA therapy. LDM CPA-associated changes of CYP3A4 activity point to a potential risk of unfavorable drug interactions when compounds that are metabolized by CYP3A4 are coadministered with LDM CPA. [Mol Cancer Ther 2007;6(8):2280 -9]

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“…The mixture was stirred at RT (36 h); product was isolated according to literature procedures. 8,18 The product was obtained as a flocculent, light brown solid (0.87 g, 59%). …”

Section: Methodsmentioning

confidence: 99%

Labeled oxazaphosphorines for applications in MS studies. Synthesis of deuterium labeled cyclophosphamides and ifosfamides

Springer

Colvin

Ludeman

2007

Labelled Comp Radiopharmac

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Oxime Derivatives of the Intermediary Oncostatic Metabolites of Cyclophosphamide and Ifosfamide: Synthesis and Deuterium Labeling for Applications to Metabolite Quantification

Cited by 14 publications

References 21 publications

Pharmacokinetics of Cyclophosphamide after Oral and Intravenous Administration to Dogs with Lymphoma

Pharmacokinetics of Cyclophosphamide after Oral and Intravenous Administration to Dogs with Lymphoma

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Labeled oxazaphosphorines for applications in MS studies. Synthesis of deuterium labeled cyclophosphamides and ifosfamides

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