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  • 1
    Electronic Resource
    Electronic Resource
    P-Glycoprotein-Dependent Disposition Kinetics of Tacrolimus: Studies in mdr la Knockout Mice (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1213-1218 
    Details
    ISSN: 1573-904X
    Keywords: tacrolimus ; disposition kinetics ; P-glycoprotein ; mdr la knockout mice ; brain distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study was performed to evaluate the involvement of P-glycoprotein in disposition kinetics of tacrolimus (FK506), a substrate of P-glycoprotein, in the body. Methods. The blood and tissue concentrations of FK506 after i.v. or p.o. administration (2 mg/kg) to normal andmdrla knockout mice were measured by competitive enzyme immunoassay. Results. The blood concentrations in knockout mice were significantly higher than those in normal mice. The value of the total clearance (CLtot) for knockout mice (19.3 mL/min/kg) was about 1/3 of that for normal mice (55.8 mL/min/kg)(P 〈 0.001), although there was no significant difference in the distribution volume at the steady-state (Vdss) (about 4.6 L/kg) between both types of mice. FK506 rapidly penetrated the blood-brain barrier and the brain concentration reached a maximum, which was about 10 times higher in knockout mice than in normal mice, 1 hr after administration. The brain concentration in normal mice thereafter decreased slowly, whereas in knockout mice, an extremely high concentration was maintained for 24 hr. Conclusions. The pharmacokinetic behavior of FK506 in the tissue distribution is related with the function of P-glycoprotein encoded by themdr la gene. The brain distribution of FK506 is dominated by the P-glycoprotein-mediated drug efflux and presumably also by the binding to FK-binding proteins (immunophilins) in the brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018993312773
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  • 2
    Electronic Resource
    Electronic Resource
    Absorptive-Mediated Endocytosis of an Adrenocorticotropic Hormone (ACTH) Analogue, Ebiratide, into the Blood–Brain Barrier: Studies with Monolayers of Primary Cultured Bovine Brain Capillary Endothelial Cells (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 529-534 
    Details
    ISSN: 1573-904X
    Keywords: ebiratide ; adrenocorticotropic hormone analogue ; adsorptive endocytosis ; absorptive-mediated endocytosis ; blood–brain barrier (BBB) transport ; internalization ; primary cultured brain capillary endothelial cells ; peptide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The internalization of a neuromodulatory adrenocorticotropic hormone (ACTH) analogue, [125I]ebiratide (H-Met(O2)-Glu[125I]His-Phe-D-Lys-Phe-NH(CH2)8NH2), was examined in cultured mono-layers of bovine brain capillary endothelial cells (BCEC). HPLC analysis of the incubation solution showed that [125I]ebiratide was not metabolized during the incubation with BCEC. The acid-resistant binding of [125I]ebiratide to BCEC increased with time for 120 min and showed a significant dependence on temperature and medium osmolarity. Pretreatment of BCEC with dansylcadaverine or phenylarsine oxide, endocytosis inhibitors, and 2,4-dinitrophenol, a metabolic inhibitor, decreased significantly the acid-resistant binding of [125I]ebiratide. The acid-resistant binding of [125I]ebiratide was saturable in the presence of unlabeled ebiratide (100 nM–1 mM). The maximal internalization capacity (B max) at 30 min was 7.96 ± 3.27 µmol/mg of protein with a half-saturation constant (K d) of 15.9 ± 6.4 µM. The acid-resistant binding was inhibited by basic peptides such as poly-L-lysine, protamine, histone, and ACTH but was not inhibited by poly-L-glutamic acid, insulin, or transferrin. These results confirmed that ebiratide is transported through the blood-brain barrier via an absorptive-mediated endocytosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015848531603
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