Identification of the Cytochrome P450 and Other Enzymes Involved in the In Vitro Oxidative Metabolism of a Novel Antidepressant, Lu AA21004

Abstract

ABSTRACT:1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine (Lu AA21004) is a novel antidepressant that is currently in late-stage clinical development for major depressive disorder. In the present study, the metabolism of Lu AA21004 was investigated using human liver microsomes (HLM), human liver S9 fraction, and recombinant enzymes. Lu AA21004 was found in vitro to be oxidized to a 4-hydroxy-phenyl metabolite, a sulfoxide, an N-hydroxylated piperazine, and a benzylic alcohol, which was further oxidized to the corresponding benzoic acid [3-methyl-4-(2-piperazin-1-yl-phenysulfanyl)-benzoic acid (Lu AA34443)]. The formation of the 4-hydroxy-phenyl metabolite was catalyzed by CYP2D6 with some contribution from CYP2C9, whereas the formation of the sulfoxide was mediated by CYP3A4/5 and CYP2A6. CYP2C9 and CYP2C19 were the primary enzymes responsible for formation of the N-hydroxylated metabolite. The benzylic alcohol was formed by CYP2D6 only. The oxidation of the benzylic alcohol to the corresponding benzoic acid of Lu AA21004 was catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase, with some contribution from aldehyde oxidase. CYP2D6 was also capable of catalyzing the formation of the benzoic acid of Lu AA21004; however, its overall contribution to this pathway was negligible. Enzyme kinetic parameters revealed that the rate-limiting step in the formation of the benzoic acid from Lu AA21004 is the formation of the corresponding alcohol. Thus, the intrinsic clearance (V max /K m ) in HLM for metabolism of Lu AA21004 to the benzylic alcohol was 1.13 ؋ 10, whereas the subsequent metabolism of the benzylic alcohol to the benzoic acid of Lu AA21004 is characterized by an intrinsic clearance (V max /K m ) in S9 fraction of 922 ؋ 10 ؊6 l ⅐ min ؊1 ⅐ mg ؊1.

A Population Pharmacokinetic–Pharmacodynamic Meta‐Analysis of Vortioxetine in Patients with Major Depressive Disorder

“…In addition, even though potent CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine, quinidine) were not frequently taken by this population, they were recorded in the eCRF and included for covariate analysis, as vortioxetine is metabolized mainly through the CYP2D6 pathway [29].…”

“…In addition, even though potent CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine, quinidine) were not frequently taken by this population, they were recorded in the eCRF and included for covariate analysis, as vortioxetine is metabolized mainly through the CYP2D6 pathway [29].Base and covariate PK models development. Population PK analysis was conducted using the first-order conditional estimation with interaction method, as implemented in NONMEM â version 7 (ICON Development Solutions, Ellicott City, Maryland, USA) Level 1.0, accessed through the KIWI graphical interface version 1.0 (Cognigen Corporation Inc., Buffalo, NY, USA) at Takeda or S+NONMEM, a program developed by H. Lundbeck A/S based on the Perl and S-PLUS languages.…”

Vortioxetine: a review of efficacy, safety and tolerability with a focus on cognitive symptoms in major depressive disorder

“…CYP2D6 metabolism constitutes the primary metabolic pathway, converting vortioxetine to its major, pharmacologically inactive metabolite [3,5]. The enzymes alcohol dehydrogenase, aldehyde dehydrogenase and aldehyde oxidase also play a role in vortioxetine metabolism [6]. Furthermore, based on in vitro data, neither vortioxetine nor its metabolites exhibit clinically significant inhibition of any of the cytochrome P450 isozymes or the p-glycoprotein transporter [3].…”

Lack of effect of multiple doses of vortioxetine on the pharmacokinetics and pharmacodynamics of aspirin and warfarin

“…The study also evaluated the effects of vortioxetine coadministration on the pharmacokinetics of aspirin and vice versa. In period 1, 28 subjects were randomized to 1 of the 2 sequences in which vortioxetine 10 mg or matching placebo was administered once daily in the morning for 14 days (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14], followed by coadministration with aspirin 150 mg once daily for 6 days (days [15][16][17][18][19][20]. Following a 21-day washout, in period 2, subjects received the alternative treatment.…”

“…CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite Lu AA34443. 15 The plasma protein binding of vortioxetine in humans is 98%-99% and is independent of the investigated plasma concentrations of vortioxetine. 14 Vortioxetine pharmacological activity is due to the parent drug rather than to the metabolite.…”