Biochemical, neurophysiological, and behavioral effects of Wy‐45,233 and other identified metabolites of the antidepressant venlafaxine

Abstract

Muth, E.A., J.A. Moyer, J.T. Haskins, T.H. Andree, and G.E. M. Husbands:Biochemical, neurophysiological, and behavioral effects of Wy-45,233 and other identified metabolites of the antidepressant venlafaxine. Drug Dev. Res. 23:191-199, 1991. Seven metabolites of venlafaxine, identified in several species, were examined for CNS pharmacological activity in rodents. The 0-desmethyl compound Wy-45,233, which is the major metabolite in man, had the greatest preclinical activity. This metabolite exhibited an antidepressant profile (monoamine uptake blockade, reversal of reserpine hypothermia, induction of pineal p-adrenergic subsensitivity) comparable to the parent drug, venlafaxine. This compound also inhibited serotonergic and noradrenergic firing rates like the parent compound, but with less potency. The cyclohexyl ring-hydroxylated metabolite 877 and the N-desmethyl metabolite Wy-45,494 were also active in reserpine hypothermia, but Wy-45,494 was a weaker inhibitor of serotonin uptake and both metabolites were weaker inhibitors of norepinephrine uptake than Wy-45,233. None of the seven metabolites tested exhibited significated binding at dopamine-2, muscarinic cholinergic, a-1 -adrenergic, histamine-1 , or opiate (k) receptors. These results suggest that Wy-45,233, the 0-desmethyl metabolite of venlafaxine, is an active metabolite which retains the benign side-effect profile of venlafaxine.

O- and N-demethylation of Venlafaxine In Vitro by Human Liver Microsomes and by Microsomes from cDNA-Transfected Cells Effect of Metabolic Inhibitors and SSRI Antidepressants

“…VF is biotransformed in the liver to O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (N,O-DV) (Muth et al 1991). ODV has a receptor affinity profile similar to its parent compound VF, while the latter two metabolites have little if any affinity for the above receptor sites (Muth et al 1991).…”

“…ODV has a receptor affinity profile similar to its parent compound VF, while the latter two metabolites have little if any affinity for the above receptor sites (Muth et al 1991). Previous studies have shown that the biotransformation of VF to ODV is mediated by CYP2D6, and NDV via CYP3A3 ր 4, and possibly a second enzyme (Otton et al 1996).…”

“…It has little to no affinity for ␣ -1 adrenergic, muscarinic, or histaminergic receptors, and does not inhibit monoamine oxidase (Muth et al 1986). VF is effective as an antidepressant (Schweizer et al 1994;Cunningham et al 1994), and may have utility in the treatment of panic disorder (Geracioti 1995), and attention-deficit disorder (Findling et al 1996).VF is biotransformed in the liver to O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (N,O-DV) (Muth et al 1991). ODV has a receptor affinity profile similar to its parent compound VF, while the latter two metabolites have little if any affinity for the above receptor sites (Muth et al 1991).…”

Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood

“…CYP2D6 catalyzes the metabolism of VEN to its main metabolite O-desmethylvenlafaxine (ODV) and CYP3A4 is the major enzyme responsible for formation of the minor metabolite N-desmethylvenlafaxine (NDV). Both metabolites are then further metabolized to N,O-didesmethylvenlafaxine (DDV), possibly by CYP2D6 [2,3]. ODV contributes to the overall pharmacological effect of VEN since it exhibits a pharmacological profile similar to that of VEN.…”

Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model

“…However, the R-enantiomer is a potent inhibitor of both serotonin and noradrenaline reuptake, whereas the S-enantiomer is more selective in inhibiting serotonin reuptake (Holliday et al 1995;Muth et al 1986). Venlafaxine is mainly metabolized by the cytochrome P450 (CYP) enzyme CYP2D6 to its major active metabolite Odesmethylvenlafaxine (Odm-venlafaxine) and to its two minor metabolites, Ndesmethylvenlafaxine (Ndm-venlafaxine) and N,O-didesmethylvenlafaxine (Ddmvenlafaxine) (Muth et al 1991;Muth et al 1986). …”