In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin.
OBJECTIVE
Antifungal prophylaxis is an important component of induction therapy for patients with acute myeloid leukemia (AML). Azole antifungal agents are increasingly used in this context. In vitro assays were performed to assess whether cytochrome P450 (CYP450) enzymes were affected by combinations of cytarabine or idarubicin with itraconazole or caspofungin.


METHODS
The high throughput microtiter assay was used to determine whether cytarabine, idarubicin and itraconazole or caspofungin were CYP450 isoenzyme substrates, inhibitors of CYP450 isoenzymes, and to determine potential CYP450 metabolism interactions between these agents.


RESULTS
Idarubicin is a substrate for CYP450 2D6 and 2C9. Cytarabine is a substrate of CYP450 3A4. Idarubicin inhibits CYP450 2D6, and cytarabine, itraconazole, and caspofungin inhibit CYP450 3A4. Cytarabine metabolism was significantly decreased when combined with caspofungin or itraconazole.


CONCLUSIONS
The inhibition of cytarabine metabolism may have important clinical implications. These in vitro findings warrant investigation with in vivo pharmacokinetic studies.
Colburn
Dawn E
DE
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. dcolburn@mdanderson.org
Giles
Francis J
FJ
Oladovich
Debra
D
Smith
Judith A
JA
D000208:Acute Disease; D000935:Antifungal Agents / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D000077336:Caspofungin; D003561:Cytarabine / Q000627:therapeutic use*; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D054714:Echinocandins; D006801:Humans; D015255:Idarubicin / Q000627:therapeutic use*; D017964:Itraconazole / Q000627:therapeutic use*; D007951:Leukemia, Myeloid / Q000150:complications / Q000188:drug therapy; D055666:Lipopeptides; D009181:Mycoses / Q000517:prevention & control*; D010455:Peptides / Q000627:therapeutic use*; D010456:Peptides, Cyclic; D013379:Substrate Specificity
D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D003561:Cytarabine; D017964:Itraconazole; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D000077336:Caspofungin; D015255:Idarubicin