PT - JOURNAL ARTICLE AU - Brandy L. Paris AU - Brian W. Ogilvie AU - Julie A. Scheinkoenig AU - Florence Ndikum-Moffor AU - Remi Gibson AU - Andrew Parkinson TI - In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran AID - 10.1124/dmd.109.028274 DP - 2009 Oct 01 TA - Drug Metabolism and Disposition PG - 2045--2054 VI - 37 IP - 10 4099 - http://dmd.aspetjournals.org/content/37/10/2045.short 4100 - http://dmd.aspetjournals.org/content/37/10/2045.full SO - Drug Metab Dispos2009 Oct 01; 37 AB - Milnacipran (Savella) inhibits both norepinephrine and serotonin reuptake and is distinguished by a nearly 3-fold greater potency in inhibiting norepinephrine reuptake in vitro compared with serotonin. We evaluated the ability of milnacipran to inhibit and induce human cytochrome P450 enzymes in vitro. In human liver microsomes, milnacipran did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 (IC50 ≥ 100 μM); whereas, a comparator with dual reuptake properties [duloxetine (Cymbalta)] inhibited CYP2D6 (IC50 = 7 μM) and CYP2B6 (IC50 = 15 μM) with a relatively high potency. Milnacipran inhibited CYP3A4/5 in a substrate-dependent manner (i.e., midazolam 1′-hydroxylation IC50 ≈ 30 μM; testosterone 6β-hydroxylation IC50 ≈ 100 μM); whereas, duloxetine inhibited both CYP3A4/5 activities with equal potency (IC50 = 37 and 38 μM, respectively). Milnacipran produced no time-dependent inhibition (<10%) of P450 activity, whereas duloxetine produced time-dependent inhibition of CYP1A2, 2B6, 2C19, and 3A4/5. To evaluate P450 induction, freshly isolated human hepatocytes (n = 3) were cultured and treated once daily for 3 days with milnacipran (3, 10, and 30 μM), after which microsomal P450 activities were measured. Whereas positive controls (omeprazole, phenobarbital, and rifampin) caused anticipated P450 induction, milnacipran had minimal effect on CYP1A2, 2C8, 2C9, or 2C19 activity. The highest concentration of milnacipran (30 μM; >10 times plasma Cmax) produced 2.6- and 2.2-fold increases in CYP2B6 and CYP3A4/5 activity (making it 26 and 34% as effective as phenobarbital and rifampin, respectively). Given these results, milnacipran is not expected to cause clinically significant P450 inhibition or induction. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics