Biopharmaceutical Characterization, Metabolism, and Brain Penetration of the Triple Reuptake Inhibitor Amitifadine
Frank P. Bymaster,
Pierre V. Tran,
Randall D. Marshall.
Amitifadine (EB-1010, formerly DOV 21,947) is a serotonin-preferring triple reuptake inhibitor that is a drug
candidate for major depressive disorder. We investigated several relevant biopharmaceutic and drug-like characteristics of
amitifadine using in vitro methodology and additionally determined the in vivo brain to plasma ratio of the drug in rats.
Amitifadine was highly plasma protein bound with over 99% of drug bound to human plasma proteins. Using Caco-2 cell
lines, amitifadine was bidirectionally highly permeable and showed no evidence of active secretion. Amitifadine was
metabolized slowly by human hepatocytes and the major metabolite was the lactam EB-10101. In vitro studies using
human liver microsomes demonstrated that EB-10101 was formed by monoamine oxidase A (MAO-A) and a NADPHdependent
enzyme, possibly a cytochrome P450 (CYP) isoform. Amitifadine was a moderate inhibitor of the human
isoforms of the major drug metabolizing enzymes CYP2D6, CYP3A4, CYP2C9, and CYP2C19 (IC50 = 9 - 100 μM), but
was a potent inhibitor of human CYP2B6 (IC50 = 1.8 μM). The brain to plasma ratio for amitifadine varied from 3.7 - 6.5
at various time points, indicating preferential partitioning into rat brain versus plasma. The low affinity for the major drug
metabolizing CYP enzymes and metabolism by multiple pathways may reduce pharmacokinetic drug-drug interactions
and effects of enzyme polymorphisms. Overall, these studies suggest that amitifadine has drug-like characteristics
favorable for drug development.
Keywords: Amitifadine, antidepressant, brain penetration, CYP P450, metabolism, plasma protein binding, triple reuptake
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