Blood–brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab) knock-out mice and controls

Uhr, Manfred; Grauer, M; Yassouridis, Alexander; Ebinger, Martin

doi:10.1016/j.jpsychires.2005.10.005

Cited by 79 publications

(64 citation statements)

References 39 publications

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“…In the present study, we have focused on brain and serum. This might be a limitation but on the other hand, Uhr and co-workers have shown in previous studies that administration of antidepressants (amitriptyline and citalopram) did not result in any significant differences in tissue drug levels besides the brain Uhr et al, 2007;Uhr et al, 2000). The results from these studies indicate that although transport in other tissues than the brain is also eliminated by the P-gp knockout its overall impact seems to be of limited relevance.…”

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

confidence: 77%

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

confidence: 77%

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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“…Recent studies showed that penetration of amitriptyline and its metabolites (including nortriptyline) into the brain is enhanced in mice lacking P-gp (4,5 ). Therefore, dysfunctional sequence variants of the ABCB1 gene might lead to diminished P-gp activity and higher bioavailability of P-gp substrates in the central nervous system.…”

Section: Abcb1 (P-glycoprotein/mdr1) Gene G2677t/a Sequence Variationmentioning

confidence: 99%

ABCB1 (P-Glycoprotein/MDR1) Gene G2677T/A Sequence Variation (Polymorphism): Lack of Association with Side Effects and Therapeutic Response in Depressed Inpatients Treated with Amitriptyline

Laika

Leucht

Steimer³

2006

Clinical Chemistry

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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-Purpose. Tramadol Hydrochloride is a widely-used centrally acting analgesic drug, which has some features of being a P-gp substrate. The present study evaluates the functional involvement of Pgp in CNS distribution of tramadol. Methods. The possibe involvement of P-glycoprotein in brain distribution of tramadol was evaluated using a pharmacokinetic approach in two groups of Pgp-inhibited and control rats. Six male Sprague-Dawley rats were used in each group to collect plasma and brain at 1, 5, 10, and 30 min following two tramadol doses of 1 and 10 mg/kg. Results. The brain uptake clearances of tramadol in Pgp-inhibited and control rats were 2.47±0.56 and 2.34±0.56 ml min , respectively, for 10 mg/kg dose. The brain-to-plasma concentration ratio (Kp,app) of more than 1 in all the time points following both the high and low dose cases (sometimes more than 3) indicated the brain accumulation of the drug. Linear correlation was found between tramadol dose and both corresponding plasma and brain concentrations, but the presence of a dose-dependency was not confirmed by the data obtained for brain-to-plasma concentration ratio. Conclusion. Considering the results of the previous studies and the present research, it seems that the brain accumulation of tramadol is not affected by P-gp inhibition which implies that there may be some other transport mechanisms involved in BBB transport of tramadol.

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Blood–brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab) knock-out mice and controls

Cited by 79 publications

References 39 publications

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

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

ABCB1 (P-Glycoprotein/MDR1) Gene G2677T/A Sequence Variation (Polymorphism): Lack of Association with Side Effects and Therapeutic Response in Depressed Inpatients Treated with Amitriptyline

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

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