Venlafaxine and O-desmethylvenlafaxine concentrations in plasma and cerebrospinal fluid

To investigate whether drug concentrations of venlafaxine and its metabolite O-desmethylvenlafaxine in plasma can be considered as a surrogate marker of concentrations in brain/cerebrospinal fluid (CSF).

For therapeutic drug monitoring purposes, plasma and CSF concentrations of venlafaxine and O-desmethylvenlafaxine were measured between November 2011 and August 2013 in 16 depressive inpatients (ICD-10 diagnoses) who were treated with daily doses of venlafaxine extended release (dose range, 75-225 mg). Daily doses were correlated with plasma and CSF levels. The correlation between venlafaxine, O-desmethylvenlafaxine, and the active moiety (AM) in plasma and CSF was calculated.

Venlafaxine in plasma (P = .005) and CSF (P = .023) correlated significantly with the daily dose, while O-desmethylvenlafaxine and the active moiety (AM = venlafaxine + O-desmethylvenlafaxine) did not. The correlation between venlafaxine, O-desmethylvenlafaxine, and the AM in plasma and CSF was highly significant (P < .001). The calculated CSF/plasma ratio was 0.74 for venlafaxine, 0.88 for O-desmethylvenlafaxine, and 0.84 for the AM.

Venlafaxine and O-desmethylvenlafaxine were found to penetrate well into CSF in patients, which indicated good availability of the drug in the brain, although the findings on CSF concentrations do not allow calculation of concentrations at the target structure within the brain. CSF/plasma ratios for venlafaxine and its metabolite were high probably due to low plasma protein binding. The poor correlation of dose to concentrations in body fluids and the highly significant correlation of plasma to CSF concentrations indicate that plasma concentration is a much better marker of drug concentration in brain than the dose.