A high-performance liquid chromatographic method for the simultaneous determination of Venlafaxine ( Effexor ) and O-desmethylVenlafaxine ( Effexor ) in biological fluids.

A rapid, accurate, and sensitive high-performance liquid chromatographic (HPLC) method for simultaneous determination of Venlafaxine ( Effexor ) (V) and O-desmethylVenlafaxine ( Effexor ) (ODV) in plasma and urine has been developed. V and ODV are extracted from plasma using a liquid-liquid extraction procedure, chromatographed on a Supelcosil LC-8DB column, and quantitated by UV detection at 229 nm. Linearity was established over the range 10-500 ng/ml for V and 7.2-720 ng/ml for ODV using 1.0 ml of human, rat, dog, and mouse plasma. For urine, for both analytes, an analytical range 0.1-10.0 micrograms/ml was established. Accuracy of > +/- 10% about the theoretical mean was achieved for all matrices, with intra- and interday coefficients of variation for precision of < 10%. Endogenous components in plasma and/or urine or known metabolites of V do not interfere in the determination of the analytes. For both V and ODV a quantitation limit of 10 ng/ml for plasma was adequate for their estimation over a period of three half-lives, following administration of a pharmacologic dose in man, and the limit of 0.1 microgram/ml, for urine, can monitor excretion of as little as 0.5% of the dose.

Effects of Venlafaxine ( Effexor ) on extracellular 5-HT, dopamine and noradrenaline in the hippocampus and on peripheral hormone concentrations in the rat in vivo.

The purpose of the present study was to study the effect of an acute dose of the serotonin (5-HT) - noradrenaline (NA) reuptake inhibitor Venlafaxine ( Effexor ) on extracellular concentrations of 5-HT, NA and dopamine (DA) in the hippocampus and on the peripheral hormone concentrations in freely moving rats. Blood obtained from a catheter placed in the vena femoralis was analyzed for adrenocorticotropin (ACTH), beta-endorphins, prolactin (PRL), growth hormone (GH) and cortisol. Collections are referred to pre and post injection of 20 mg/kg of Venlafaxine ( Effexor ). Extracellular hippocampal NA and 5-HT as determined with in vivo microdialysis increased significantly after drug injection. PRL and ACTH were significantly affected by the drug. At the selected dose Venlafaxine ( Effexor ) is able to increase the release of 5-HT but also of NA in rat hippocampus. Due to the dual reuptake properties of the drug and the functional interconnection of the NA and the 5-HT systems, the observed effects on peripheral hormones are possibly mediated by a combined action of these 2 systems.

Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of Venlafaxine ( Effexor ).

INTRODUCTION: Melperone, a butyrophenone neuroleptic, is frequently used for its sleep-inducing properties. Despite its common use for more than 30 years, it is not yet characterized regarding its effects on cytochrome P450 s (CYPs). In an open pilot study, effects of melperone on the steady-state blood levels of Venlafaxine ( Effexor ), a recently introduced serotonin- and noradrenaline reuptake inhibiting antidepressant, were assessed. METHODS: The dose-corrected serum concentrations of Venlafaxine ( Effexor ) and O-desmethylVenlafaxine ( Effexor ) were analyzed retrospectively in a therapeutic drug-monitoring (TDM) database comprising 94 patients. In addition, three patients received Venlafaxine ( Effexor ) and melperone concomitantly and the serum concentrations of Venlafaxine ( Effexor ) and O-desmethylVenlafaxine ( Effexor ) were analyzed before, during, and after melperone co-medication. The effect of melperone on CYP2D6 was further assessed in seven patients by means of the dextromethorphan O-demethylation, which serves as a CYP2D6 probe reaction. RESULTS: Patients treated concomitantly with Venlafaxine ( Effexor ) and melperone had significantly higher (mean +/- SD) Venlafaxine ( Effexor ) (3.27 +/- 2.9 vs. 0.97 +/- 0.99 ng/ml per mg/d; p < 0.05) and lower O-desmethylVenlafaxine ( Effexor ) serum concentrations (0.69 +/- 0.35 vs. 1.51 +/- 0.9 ng/ml per mg/d; p < 0.01) compared to patients without melperone comedication. In the three patients, Venlafaxine ( Effexor ) serum concentrations increased, on average by 52 % during melperone co-medication, whereas O-desmethylVenlafaxine ( Effexor ) was decreased, on average by 29 %. Administration of melperone over three days elevated the ratio of dextromethorphan to dextrorphan from 0.044 +/- 0.04 to 0.09 +/- 0.083 (p < 0.05). DISCUSSION: This study pointed to an inhibitory effect of melperone on the O-demethylation of Venlafaxine ( Effexor ). Because the O-demethylation of Venlafaxine ( Effexor ) is almost exclusively catalyzed by CYP2D6 it is concluded that melperone is an inhibitor of CYP2D6. The hypothesis was further corroborated by the inhibitory effect of melperone on the dextromethorphan O-demethylation.

Effects of Venlafaxine ( Effexor ) on p90Rsk activity in rat C6-gliomas and brain.

The intracellular actions of the antidepressant, Venlafaxine ( Effexor ), were studied in C6-gliomas using a phosphoproteomics approach. Long-term pre-treatment of C6-gliomas with Venlafaxine ( Effexor ) followed by an acute challenge with isoproterenol (a beta-adrenoceptor agonist), resulted in increased p90Rsk phosphorylation (three-fold) versus control levels (isoproterenol alone). The effect of Venlafaxine ( Effexor ) pre-treatment on p90Rsk activity was dose-dependent (EC(50)=3.75nM) in C6 gliomas. In rat brain sections, intense immunoreactive phospho-p90Rsk labeling was observed for both neurons and glia, especially in cortical layers II/III and hippocampal formations. In vivo studies demonstrated an intense but similar distribution pattern of phospho-p90Rsk staining after chronic Venlafaxine ( Effexor ) dosing of rats compared to naives and no region-specific drug effect was observed in vivo. In conclusion, our findings suggest that some of the centrally-mediated benefits of Venlafaxine ( Effexor ) in depression may be due to its intracellular properties especially on the neuro-glial circuitry and MAPK/p90Rsk-dependent pathways at an early stage.