Search results for "ATP binding"
showing 10 items of 155 documents
Pharmacodynamic effects of aripiprazole and ziprasidone with respect to p-glycoprotein substrate properties.
2013
Introduction Aripiprazole, an atypical antipsychotic drug with mixed antagonism and agonism on dopamine D2 and serotonin receptors, is a substrate of the efflux transporter P-glycoprotein (P-gp). Here we tested the pharmacodynamic consequences of these properties in a P-gp deficient mouse model by studying the effects of aripiprazole and of ziprasidone on motor coordination. Methods The motor behaviour of wild-type (WT) and P-gp deficient [abcb1ab(-/-)] mice was investigated on a RotaRod. Mice received acute injections of either aripirazole or ziprasidone. For comparison, the dopamine receptor antagonist haloperidol and serotonin receptor ligands buspirone and ketanserin were also applied. …
Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein
2010
According 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,…
Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment
2013
Background: 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 Senantiomer, 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. Methods: 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 escitalop…
Dehydroepiandrosterone up-regulates the Adrenoleukodystrophy-related gene (ABCD2) independently of PPAR alpha in rodents
2007
International audience; X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease caused by mutations in the ABCD1 gene, which encodes a peroxisomal ABC transporter, ALDP, supposed to participate in the transport of very long chain fatty acids (VLCFA). The adrenoleukodystrophyrelated protein (ALDRP), which is encoded by the ABCD2 gene, is the closest homolog of ALDP and is considered as a potential therapeutic target since functional redundancy has been demonstrated between the two proteins. Pharmacological induction of Abcd2 by fibrates through the activation of PPARa has been demonstrated in rodent liver. DHEA, the most abundant steroid in human, is described as a PPARa activat…
DNA-Ploidy, Morphometric-Stereological and P-Glycoprotein Study of Superficial Bladder Carcinomas
1992
We carried out a DNA-ploidy, morphometric-stereologic and P-glycoprotein study on 40 newly diagnosed superficial bladder cancer patients (G1-G2), correlating the results with histological grade and clinical outcome. Variations in the number of patients who present recurrences, progression or remain tumor-free during the whole follow-up period (at least 5 years) were not significant when related to nuclear size, proliferative diploid index, presence of aneuploidy and expression of P-glycoprotein. It is striking how the majority of disease-free subjects showed a proliferative diploid index higher than 10%. Moreover, 3 of them presented an aneuploid cell population. In our study, only histolog…
Incidence of Abcd1 level on the induction of cell death and organelle dysfunctions triggered by very long chain fatty acids and TNF-alpha on oligoden…
2012
X-linked adrenoleukodystrophy (X-ALD) is characterized by ABCD1 deficiency. This disease is associated with elevated concentrations of very long chain fatty acids (C24:0 and C26:0) in the plasma and tissues of patients. Under its severe form, brain demyelination and inflammation are observed. Therefore, we determined the effects of C24:0 and C26:0 on glial cells:oligodendrocytes, which synthesize myelin, and astrocytes, which participate in immune response. So, 158N murine oligodendrocytes, rat C6 glioma cells, rat primary cultures of neuronal-glial cells, and of oligodendrocytes were treated for various periods of time in the absence or presence of C24:0 and C26:0 used at plasmatic concent…
Fibrate induction of the adrenoleukodystrophy-related gene (ABCD2)
2001
X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease due to a defect in the ABCD1 (ALD) gene. ABCD1, and the two close homologues ABCD2 (ALDR) and ABCD3 (PMP70), are genes encoding ATP-binding cassette half-transporters of the peroxisomal membrane. As overexpression of the ABCD2 or ABCD3 gene can reverse the biochemical phenotype of X-ALD (reduced beta-oxidation of very-long-chain fatty acids), pharmacological induction of these partially redundant genes may represent a therapeutic approach to X-ALD. We previously reported that the ABCD2 and ABCD3 genes could be strongly induced by fibrates, which are hypolipidaemic drugs and peroxisome-proliferators in rodents. We provide e…
Expression and differential localization of xenobiotic transporters in the rat olfactory neuro-epithelium.
2011
International audience; Transporters, such as multidrug resistance P-glycoproteins (MDR), multidrug resistance-related proteins (MRP) and organic anion transporters (OATs), are involved in xenobiotic metabolism, particularly the cellular uptake or efflux of xenobiotics (and endobiotics) or their metabolites. The olfactory epithelium is exposed to both inhaled xenobiotics and those coming from systemic circulation. This tissue has been described as a pathway for xenobiotics to the brain via olfactory perineural space. Thereby, olfactory transporters and xenobiotic metabolizing enzymes, dedicated to the inactivation and the elimination of xenobiotics, have been involved in the toxicological p…
Modelling intestinal absorption of salbutamol sulphate in rats
2005
The objective was to develop a semiphysiological population pharmacokinetic model that describes the complex salbutamol sulphate absorption in rat small intestine. In situ techniques were used to characterize the salbutamol sulphate absorption at different concentrations (range: 0.15-18 mM). Salbutamol sulphate at concentration of 0.29 mM was administered in presence of verapamil (10 and 20 mM), grapefruit juice and sodium azide (NaN3) (0.3, 3 and 6 mM). Different pharmacokinetic models were fitted to the dataset using NONMEM. Parametric and non-parametric bootstrap analyses were employed as internal model evaluation techniques. The validated model suggested instantaneous equilibrium betwee…
Genetic Polymorphisms and Individualized Tacrolimus Dosing
2010
Background. Genetic polymorphisms of metabolism enzymes or intestinal drug transporters may affect pharmacokinetic responses to immunosuppressive drugs in renal transplant recipients. We sought to identify the frequency of genetic polymorphisms and their importance for individualization of tacrolimus doses. Patients and Methods. We performed an observational study in 35 renal transplant recipients treated with tacrolimus, mycophenolate mofetil, and corticosteroids. Tacrolimus concentrations were determined by immunoanalysis (IMx method; Abbott Diagnostics, Abbott Park, Ill), on 11 blood samples per patient during the first 6 weeks after renal transplantation. For each patient, we calculated…