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Psoriasis is a chronic inflammatory disease associated with several comorbidities, including depression. Previous studies have shown that inflammatory diseases downregulate the expression and suppress activity of CYP isoforms. Venlafaxine (VLX) is an antidepressant metabolized mainly by CYP2D6 to O-desmethylvenlafaxine (ODV), CYP3A to N-desmethylvenlafaxine (NDV), and CYP2D6 and CYP3A to N,O-didesmethylvenlafaxine (DDV). This study evaluated the influence of psoriasis on the enantioselective pharmacokinetics of VLX. Psoriasis patients (n = 13) and healthy volunteers (n = 11) phenotyped as CYP2D6 extensive (EM) or poor metabolizers (n = 1) received a single oral dose of 150 mg racemic VLX. Plasma concentrations of TNF-α, IFN-γ, IL-6, IL-8, and IL-17 cytokines were higher in EM psoriasis patients when compared with healthy volunteers. IL-6 plasma concentrations varied from 0.4 to 12.9 pg/mL (mean, 2.1 pg/mL) in healthy volunteers and from 0.4 to 29.3 pg/mL (mean, 4.2 pg/mL) in psoriatic patients. VLX pharmacokinetics are enantioselective in healthy volunteers and psoriasis patients phenotyped as EM. Higher AUC values for the (S)-VLX, (S)-NDV, and (S)-DDV enantiomers were observed in healthy volunteers, whereas higher AUC values for (S)-VLX and (R)-ODV were found in psoriasis patients phenotyped as EM. Psoriasis does not alter the pharmacokinetics of the VLX enantiomers probably because of the low levels of IL-6 plasma concentrations.