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  1. Dong AN, Ahemad N, Pan Y, Palanisamy UD, Yiap BC, Ong CE
    Naunyn Schmiedebergs Arch Pharmacol, 2019 08;392(8):1015-1029.
    PMID: 31025144 DOI: 10.1007/s00210-019-01651-0
    One major source of inter-individual variability in drug pharmacokinetics is genetic polymorphism of the cytochrome P450 (CYP) genes. This study aimed to elucidate the enzyme kinetic and molecular basis for altered activity in three major alleles of CYP2D6, namely CYP2D6*2, CYP2D6*10 and CYP2D6*17. The E. coli-expressed allelic variants were examined using substrate (venlafaxine and 3-cyano-7-ethoxycoumarin[CEC]) and inhibitor (quinidine, fluoxetine, paroxetine, terbinafine) probes in enzyme assays as well as molecular docking. The kinetics data indicated that R296C and S486T mutations in CYP2D6*2 have caused enhanced ligand binding (enhanced intrinsic clearance for venlafaxine and reduced IC50 for quinidine, paroxetine and terbinafine), suggesting morphological changes within the active site cavity that favoured ligand docking and binding. Mutations in CYP2D6*10 and CYP2D6*17 tended to cause deleterious effect on catalysis, with reduced clearance for venlafaxine and CEC. Molecular docking indicated that P34S and T107I, the unique mutations in the alleles, have negatively impacted activity by affecting ligand access and binding due to alteration of the substrate access channel and active site morphology. IC50 values however were quite variable for quinidine, fluoxetine and terbinafine, and a general decrease in IC50 was observed for paroxetine, suggesting ligand-specific altered susceptibility to inhibition in the alleles. This study indicates that CYP2D6 allele selectivity for ligands was not solely governed by changes in the active site architecture induced by the mutations, but that the intrinsic properties of the substrates and inhibitors also played vital role.
    Matched MeSH terms: Venlafaxine Hydrochloride/pharmacokinetics
  2. Yee, A., Kanagasundram, S., Gill, J.S., Zainal, N.Z.
    MyJurnal
    Objective: This systematic review is aimed to quantitatively summarise the
    prevalence of sexual dysfunction among non-SSRI second generation
    antidepressants namely agomelatine, bupropion, duloxetine, venlafaxine, and
    mirtazapine.

    Methods: Relevant studies published from inception till
    December 2012 were identified by searching PubMed, OVID and Embase.
    We included all literatures encompassing randomized controlled, cohort,
    case-controlled and cross-sectional studies, which contained quantitative data
    for prevalence on all aspects of sexual dysfunction in depressive patients who
    were older than 18 years of age. Heterogeneity, publication bias and odds
    ratio were assessed thoroughly.

    Results: In the non-SSRI second generation
    antidepressant group which consisted of 17,316 subjects, various studies
    showed the range of sexual dysfunction prevalence between 0% and 67%.
    Sexual dysfunction in patients who took non-SSRI second generation
    antidepressants constituted a meta-analytical pooled prevalence of 15%, and
    36% in those who took SSRIs. The combined relative risk of sexual
    dysfunction in the non-SSRI second generation antidepressant group when
    compared with SSRI was 0.57.

    Conclusions: The pooled prevalence of sexual
    dysfunction in non-SSRI second generation antidepressant is lower than in
    SSRI antidepressants.
    Matched MeSH terms: Venlafaxine Hydrochloride
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