Mechanisms of venoocclusive disease resulting from the combination of cyclophosphamide and roxithromycin.

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Kaufmann P, Haschke M, Torok M, Beltinger J, Bogman K, Wenk M, Terracciano L, Krahenbuhl S

Mechanisms of venoocclusive disease resulting from the combination of cyclophosphamide and roxithromycin.

Ther Drug Monit. 2006 Dec;28(6):766-74.

PubMed ID

17164692 [ View in PubMed

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Abstract

BACKGROUND: High doses (>or=500 mg/m) of cyclophosphamide are known to cause venoocclusive disease (VOD). The authors recently observed a patient treated with immunosuppressive cyclophosphamide doses (100 mg/day) and roxithromycin who developed VOD. Because roxithromycin inhibits cytochrome P450 (CYP) 3A4 and P-glycoprotein, the patient may have been exposed to higher cyclophosphamide and/or cyclophosphamide metabolite concentrations. METHODS: The effect of roxithromycin on the metabolism and toxicity of cyclophosphamide was studied using human hepatic microsomes and a human endothelial cell line. RESULTS: Cyclophosphamide or roxithromycin at concentrations from 0.05 to 500 micromol/L were not toxic to endothelial cells as assessed by lactate dehydrogenase (LDH) leakage assay. However, the combination of roxithromycin (500 micromol/L) and cyclophosphamide was toxic for all the tested cyclophosphamide concentrations (0.05 to 500 micromol/L) without clear concentration dependence (LDH ratio 38.3 +/- 11.0 [mean +/- SEM] for the combination with cyclophosphamide 0.05 micromol/L and 50.2 +/- 10.2 for the combination with cyclophosphamide 500 micromol/L; P

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Roxithromycin	P-glycoprotein 1	Protein	Humans	Unknown	Not Available	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Roxithromycin	Cytochrome P450 2B6	Protein	Humans	No	Inhibitor	Details