Metabolism of Selegiline Hydrochloride, a Selective Monoamine B-type Inhibitor, in Human Liver Microsomes

Abstract

The participation of cytochrome P-450 (CYP) isoforms in the metabolism of selegiline was investigated. Experiments using recombinant CYP isoforms expressed in human lymphoblastoid cells showed CYP2B6 to be the major CYP isoform involved with the metabolism of selegiline. CYP1A2 and CYP3A4 also contributed to the metabolism of selegiline but their catalytic activities were much less than that of CYP2B6. CYP2B6 had a higher affinity for both N-depropagylation (K(m)=21.4 microM) and N-demethylation (K(m)=25.2 microM) of selegiline than CYP3A4 and CYP1A2. In immunoinhibition studies using mixed human hepatic microsomes, selegiline N-depropagylation activity was most strongly inhibited by anti-CYP2B and anti-CYP3A antibodies, while selegiline N-demethylation activity was most inhibited by anti-CYP2B antibody. In CYP2B6-rich human hepatic microsomes, anti-CYP2B antibody had the strongest inhibitory effects on both activities. Selegiline inhibited CYP2B6-mediated (S)-mephenytoin N-demethylation activity and CYP2C19-mediated (S)-mephenytoin 4'-hydroxylation activity. These findings suggest that attention should be paid to the drug-drug interaction associated with CYP2B6 and CYP2C19. In conclusion, CYP2B6 participates in the metabolism of selegiline but the degree of its contribution varies with the level of its expression in human liver.

Interaction between Warfarin and Transdermal Selegiline: First Case Report and Literature Review

“…[13][14][15][16][17][18] Additionally, selegiline is a known potent inhibitor of CYP2C19, moderate inhibitor of CYP1A2, and may be a weak or competitive inhibitor of 2C9 and 3A4. [16][17][18] However, coadministration of low-dose transdermal selegiline did not alter the effects of warfarin titrated to a goal INR of 1.5 to 2 for 7 days in a small study of healthy volunteers. 11 We believe that this does not represent the true interaction potential of this combination given the low-intensity nature of the selegiline and warfarin therapy and does not rule out a potential mechanism to explain this drug-drug interaction.…”

“…8,[10][11][12][13][14] Several groups have assessed the in vitro metabolic activity of human liver microsomes on selegiline. [13][14][15][16][17][18] Likewise, several of these authors have assessed the in vitro inhibition ability of selegiline on the activity of several CYP450 isoenzymes embedded in the same microsomes. [16][17][18] Taavitsainen and colleagues 13 performed an in vitro analysis of the CYP450-catalyzed oxidative metabolism of selegiline to desmethylselegiline and l-methamphetamine in commercially prepared human liver microsomes.…”

“…[13][14][15][16][17][18] Likewise, several of these authors have assessed the in vitro inhibition ability of selegiline on the activity of several CYP450 isoenzymes embedded in the same microsomes. [16][17][18] Taavitsainen and colleagues 13 performed an in vitro analysis of the CYP450-catalyzed oxidative metabolism of selegiline to desmethylselegiline and l-methamphetamine in commercially prepared human liver microsomes. This group hypothesized that CYP1A2, 2C19, and 3A4 were the predominant metabolic pathways; accordingly, they repeated each analysis in the presence of furafylline, a known potent 1A2 inhibitor, ketoconazole, a known potent 3A4 inhibitor, and fluvoxamine, a known potent inhibitor of 1A2, 2C19, and 3A4.…”

“…Kamada 16 also performed a similar study to that of Hidestrand and Benetton; however, this group also assessed the inhibition potential of selegiline on several hepatic CYP450 isoenzymes. In this study, the y o for the N-demethylation phase of selegiline metabolism was 7.4, 215.6, and 1.7 mL/min/mcM for CY-P1A2, 2B6, and 3A4, respectively.…”

“…Furthermore, CYP2C9 and 3A4 metabolic activity was downregulated by 15% and 25%, respectively, when exposed to the 100 mcM concentration of selegiline. 16 Salonen and colleagues 17 also assessed the interaction potential of selegiline using methods similar to Kamada. They exposed human liver microsomes to known metabolic substrates of CYP1A2 (ethoxyresorufin), 2A6 (coumarin), 2B6 (bupropion), 2C9 (tolbutamide), 2C19 (mephenytoin), 2D6 (dextromethorphan), 2E1 (chlorzoxazone), and 3A4 (testosterone), and calculated the 50% of maximal inhibitory concentration (IC 50 ) of selegiline on each pathway at two different laboratories.…”