Blood–brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein

Abstract

, Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein, 2010, European Neuropsychopharmacology, (20), 9, 632-640 Blood-brain barrier penetration of the enantiomers of venlafaxine in mice lacking P-gp Karlsson et al. 2 AbstractAccording to in vitro studies the enantiomers of venlafaxine display different degrees of serotonin and noradrenaline reuptake inhibition. Therefore, clarification of the enantiomeric drug distribution between serum and brain is highly warranted. To elucidate if P-glycoprotein (P-gp) in a stereoselective manner transports venlafaxine and its metabolites out of the brain we used abcb1ab double-knockout mice that do not express P-gp. A single dose of racemic venlafaxine (10 mg/kg bw) was intraperitoneally injected to knockout (-/-) and wildtype (+/+) mice. Serum and brain samples were collected 1, 3, 6 and 9 h following drug administration for analysis by LC/MS/MS. One to six hours post-dose, the brain concentrations of venlafaxine, O-desmethylvenlafaxine and N-desmethylvenlafaxine were 2-3, 2-6 and 3-12 times higher in abcb1ab (-/-) mice compared to abcb1ab (+/+) mice, respectively. No major differences in the serum and brain disposition of the S-and R-enantiomers of venlafaxine and its metabolites were found between the groups. We conclude that P-gp decreases the penetration of the S-and R-enantiomers of venlafaxine and its major metabolites into the brain. No evidence of a stereoselective P-gp mediated transport of these substances was observed.

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment

“…However, venlafaxine has been reported to induce the expression of P-gp (Doran et al, 2005;Ehret et al, 2007) an effect not seen in our previous acute and chronic venlafaxine studies in the wild-type mouse (Karlsson et al, 2011;Karlsson et al, 2010). In another recently published study, venlafaxine was found to induce the expression of P-gp but no effect on induction was seen for desvenlafaxine (i.e.…”

“…In the present study, the ratio of citalopram concentration in brain between abcb1ab (-/-) mice and wild-type mice was 3.1 (1 h, acute). We showed recently for the antidepressant venlafaxine that the ratio of concentration in brain between abcb1ab (-/-) mice and wild-type mice ranges between 2.0 and 3.7 for the mother compound (Karlsson et al, 2011;Karlsson et al, 2010). These ratios might not be considered very high compared with some substances with higher affinity for P-gp e.g.…”

“…The two mouse genes are supposed to exhibit similar characteristics as the human isoform. Accordingly, the abcb1ab knockout mouse model has been a valuable tool to identify drugs that are P-gp substrates (Doran et al, 2005;Karlsson et al, 2011;Karlsson et al, 2010;Kirschbaum et al, 2008;Uhr et al, 2000;Wang et al, 2004).…”

“…According to both in vitro and in vivo data P-gp may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies (Ejsing et al, 2007;Linnet and Ejsing, 2008;O'Brien et al, 2012). While there is evidence that venlafaxine and paroxetine are substrates of P-gp (Karlsson et al, 2010;, the results are contradictory for citalopram (Rochat et al, 1999;. showed that the brain concentrations of racemic citalopram in wild-type mice were lower than the brain concentrations in P-gp knockout mice, suggesting that citalopram is actively exported out of the brain by P-gp.…”

Lack of Evidence for Involvement of P-Glycoprotein in Brain Uptake of the Centrally Acting Analgesic, Tramadol in the Rat

“…Several researches have focused on the effect of P-gp in the brain distribution of different CNS-active or CNS-reactive therapeutic agents with the key finding being the role of P-gp as an efflux transporter limiting the brain penetration of its substrates (15)(16)(17).…”