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

Karlsson, Louise; Hiemke, Christoph; Carlsson, Björn; Josefsson, Martin; Ahlner, Johan; Bengtsson, Finn; Schmitt, Ulrich; Kugelberg, Fredrik C.

doi:10.1007/s00213-010-2148-5

Cited by 24 publications

(20 citation statements)

References 59 publications

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“…Brain entry of venlafaxine and its demethylated metabolites Odesmethyl-venlafaxine and N-desmethyl-venlafaxine has previously been shown to be limited by P-gp using knockout mice with brain penetration enhancement ratios between 2 and 4 in mice lacking P-gp after subchronic minipump treatment (Uhr et al, 2008;Karlsson et al, 2011). In the current experiments, similar enhancement ratios were observed in mice.…”

Section: Discussionsupporting

confidence: 79%

Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice

Bundgaard¹,

Jensen²,

Garmer³

2011

Drug Metab Dispos

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ABSTRACT:The experiments described herein compared the extent of in vivo P-glycoprotein (P-gp)-mediated brain efflux between rats and mice for a set of known central nervous system compounds. With use of newly introduced genetically modified mdr1a-deficient rats and their gene-competent counterparts, the brain to plasma distribution was assessed and compared with the distribution pattern in mdr1a-deficient and wild-type mice. Four compounds (aripiprazole, citalopram, risperidone, and venlafaxine) were administered using a continuous subcutaneous osmotic minipump infusion paradigm. Steady-state brain and plasma concentrations of the compounds, including selected metabolites (9-hydroxyrisperidone, O-desmethyl-venlafaxine and N-desmethyl-venlafaxine) were measured in mdr1a-deficient rats and mice and their wild-type counterparts along with their free fractions to determine total and unbound brain to plasma distribution between genotypes within and between species. The results revealed qualitative as well as quantitative similarities between P-gp functionality in vivo at the blood-brain barrier level in rats and mice. All compounds tested were shown to have a significantly higher brain to plasma distribution in both mdr1a-deficient rats and mice compared with that in their wild-type counterparts. Moreover, the relative enhancement in extent of brain penetration between mdr1a-deficient and wild-type rats could be directly correlated to the enhancement ratios obtained in mice. From the unbound brain to unbound plasma distributions, the impact of P-gp on the overall brain penetration capabilities showed minor differences between rats and mice for the compounds tested. In conclusion, a comparable functional role of P-gp between rats and mice with respect to brain efflux mediated by this transporter is suggested.

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Section: Discussionsupporting

confidence: 79%

Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice

Bundgaard¹,

Jensen²,

Garmer³

2011

Drug Metab Dispos

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“…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.…”

Section: And R-citalopram and Its Metabolites In Abcb1ab (-/-) Knocmentioning

confidence: 57%

“…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.…”

Section: And R-citalopram and Its Metabolites In Abcb1ab (-/-) Knocmentioning

confidence: 98%

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

Karlsson¹,

Carlsson²,

Hiemke³

et al. 2013

European Neuropsychopharmacology

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According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the S-enantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp. P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10 mg/kg) or escitalopram (5 mg/kg). Serum and brain samples were collected 1-6 h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. In brain, 3-fold higher concentrations of S-and R-citalopram, and its metabolites, were found in abcb1ab (-/-) mice than in abcb1ab (+/+) mice after both acute and chronic citalopram treatments. After escitalopram treatment, the S-citalopram brain concentration was 3-5 times higher in the knockout mice than in controls. The results provide novel evidence that the enantiomers of citalopram are substrates of P-gp. Possible clinical and toxicological implications of this finding need to be further elucidated.

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“…This information is especially important seeing that P-gp is expressed in the intestinal epithelium and brain vascular endothelium, which can influence the oral bioavailability and the distribution of VEN and ODV to the brain (biophase) [35,54,56]. Recently, Karlsson et al (2011) found that the brain concentrations of VEN and some of its metabolites were two-to four-fold times higher in P-gp knockout vs. wild-type mice. These data show that the expression of P-gp plays an important role in limiting brain access of VEN and its metabolites [58].…”

Section: Pharmacokinetic Propertiesmentioning

confidence: 96%

Venlafaxine pharmacokinetics focused on drug metabolism and potential biomarkers

Magalhães¹,

Alves²,

LLerena

et al. 2014

Drug Metabolism and Drug Interactions

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Venlafaxine (VEN) is one of the safest and most effective drugs used in the treatment of selective serotonin reuptake inhibitors-resistant depression, and thereby it is nowadays one of the most commonly prescribed antidepressants. Nevertheless, patients treated with antidepressant drugs including VEN have exhibited large inter-individual variability in drug outcomes, possibly due to the influence of genetic and nongenetic factors on the drug pharmacokinetics and/or pharmacodynamics. Among them, an increased interest has emerged over the last few years on the genetic and/or phenotypic profile for drug-metabolizing cytochrome P450 isoenzymes and drug transporters such as potential predictive pharmacokinetic-based biomarkers of the variability found in drug biodisposition and antidepressant response. The integration of some of these key therapeutic biomarkers with classic therapeutic drug monitoring constitutes a promising way to individualization of VEN's pharmacotherapy, offering to clinicians the ability to better predict and manage pharmacological treatments to maximize the drug effectiveness. Thus, this review provides an extensive discussion of the pharmacokinetics of VEN focusing in particular on metabolism issues, without forgetting the clinically relevant sources of pharmacokinetics variability (mainly the genetic sources) and aiming on the identification of phenotypic and/or genetic biomarkers for therapy optimization.

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

Cited by 24 publications

References 59 publications

Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice

Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice

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

Venlafaxine pharmacokinetics focused on drug metabolism and potential biomarkers

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