In vitro assessment of cytochrome P450 inhibition and induction potential of azacitidine.
OBJECTIVE
To assess the potential inhibitory and inductive effects of azacitidine on cytochrome P450 isozymes in vitro.


METHODS
The inhibitory effects of azacitidine on various CYP isozymes were determined in human liver microsomes. In addition, the ability of azacitidine to induce CYP enzymes in cultured human hepatocytes was evaluated.


RESULTS
Azacitidine did not inhibit CYP2B6-, CYP2C8-, CYP2C9-, CYP2C19-, CYP2D6-, and CYP3A4-mediated activities in human liver microsomes up to a concentration of 100 microM, while weak inhibition (<30% inhibition) of CYP1A2 and CYP2E1 activities was observed at 100 microM azacitidine. In vitro azacitidine did not induce CYP1A2, CYP2C19, or CYP3A4/5 activities in cultured human hepatocytes.


CONCLUSIONS
Azacitidine is not an inhibitor or inducer of the cytochrome P450 isozymes tested; therefore, clinically relevant pharmacokinetic drug-drug interactions are unlikely to occur between azacitidine and co-administered substrates of these CYP isozymes.
Chen
Yong
Y
Non-Clinical Development, Celgene Corporation, Summit, NJ 07901, USA.
Liu
Lisa
L
Laille
Eric
E
Kumar
Gondi
G
Surapaneni
Sekhar
S
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology*; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology
D000964:Antimetabolites, Antineoplastic; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D001374:Azacitidine