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  • 1
    Electronic Resource
    Electronic Resource
    Functional relevance of carnitine transporter OCTN2 to brain distribution of l-carnitine and acetyl-l-carnitine across the blood–brain barrier (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 79 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Transport of l-[3H]carnitine and acetyl-l-[3H]carnitine at the blood–brain barrier (BBB) was examined by using in vivo and in vitro models. In vivo brain uptake of acetyl-l-[3H]carnitine, determined by a rat brain perfusion technique, was decreased in the presence of unlabeled acetyl-l-carnitine and in the absence of sodium ions. Similar transport properties for l-[3H]carnitine and/or acetyl-l-[3H]carnitine were observed in primary cultured brain capillary endothelial cells (BCECs) of rat, mouse, human, porcine and bovine, and immortalized rat BCECs, RBEC1. Uptakes of l-[3H]carnitine and acetyl-l-[3H]carnitine by RBEC1 were sodium ion-dependent, saturable with Km values of 33.1 ± 11.4 µm and 31.3 ± 11.6 µm, respectively, and inhibited by carnitine analogs. These transport properties are consistent with those of carnitine transport by OCTN2. OCTN2 was confirmed to be expressed in rat and human BCECs by an RT-PCR method. Furthermore, the uptake of acetyl-l-[3H]carnitine by the BCECs of juvenile visceral steatosis (jvs) mouse, in which OCTN2 is functionally defective owing to a genetical missense mutation of one amino acid residue, was reduced. The brain distributions of l-[3H]carnitine and acetyl-l-[3H]carnitine in jvs mice were slightly lower than those of wild-type mice at 4 h after intravenous administration. These results suggest that OCTN2 is involved in transport of l-carnitine and acetyl-l-carnitine from the circulating blood to the brain across the BBB.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00621.x
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  • 2
    Electronic Resource
    Electronic Resource
    Sodium and Chloride Ion-Dependent Transport of β-Alanine Across the Blood-Brain Barrier (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 67 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The characteristics of β-alanine transport at the blood-brain barrier were studied by using primary cultured bovine brain capillary endothelial cells. Kinetic analysis of the β-[3H]alanine transport indicated that the transporter for β-alanine functions with Kt of 25.3 ± 2.5 µM and Jmax of 6.90 ± 0.48 nmol/30 min/mg of protein in the brain capillary endothelial cells. β-[3H]Alanine uptake is mediated by an active transporter, because metabolic inhibitors (2,4-dinitrophenol and NaN3) and low temperature reduced the uptake significantly. Furthermore, the uptake of β-[3H]alanine required Na+ and Cl− in the external medium. Stoichiometric analysis of the transport demonstrated that two sodium ions and one chloride ion are associated with one β-alanine molecule. The Na+ and Cl−-dependent uptake of β-[3H]alanine was stimulated by a valinomycin-induced inside-negative K+-diffusion potential. β-Amino acids (β-alanine, taurine, and hypotaurine) inhibited strongly the uptake of β-[3H]alanine, whereas α- and γ-amino acids had little or no inhibitory effect. In ATP-depleted cells, the uptake of β-[3H]alanine was stimulated by preloading of β-alanine or taurine but not l-leucine. These results show that β-alanine is taken up by brain capillary endothelial cells, via the secondary active transport mechanism that is common to β-amino acids.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.67010330.x
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  • 3
    Electronic Resource
    Electronic Resource
    N-(p-azido-3-[125I]iodophenethyl)spiperone binds to specific regions of P-glycoprotein and another multidrug binding protein, spiperophilin, in human neuroblastoma cells (1994)
    s.l. : American Chemical Society
    Biochemistry 33 (1994), S. 256-265 
    Details
    ISSN: 1520-4995
    Source: ACS Legacy Archives
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/bi00167a034
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  • 4
    Electronic Resource
    Electronic Resource
    Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter (1999)
    [s.l.] : Nature America Inc.
    Nature genetics 21 (1999), S. 91-94 
    Details
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Primary systemic carnitine deficiency (SCD; OMIM 212140) is an autosomal recessive disorder characterized by progressive cardiomyopathy, skeletal myopathy, hypoglycaemia and hyperammonaemia. SCD has also been linked to sudden infant death syndrome. Membrane-physiological studies have suggested ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/5030
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  • 5
    Electronic Resource
    Electronic Resource
    In Vivo and in Vitro Blood–Brain Barrier Transport of 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 305-311 
    Details
    ISSN: 1573-904X
    Keywords: pravastatin ; lovastatin ; simvastatin ; 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ; blood–brain barrier (BBB) transport ; brain perfusion ; cultured brain capillary endothelial cell ; central nervous system (CNS) side effect ; lipophilicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Among the HMG-CoA reductase inhibitors, lovastatin and simvastatin have central nervous system (CNS) side effects, such as sleep disturbance, whereas pravastatin does not. This difference in CNS side effects may be due to a difference in blood–brain barrier (BBB) permeability among these inhibitors. To test this hypothesis, we compared the BBB transport ability of HMG-CoA reductase inhibitors by using an in vivo brain perfusion technique in rats and an in vitro culture system of bovine brain capillary endothelial cells. The in vivo BBB permeability coefficients of the lipophilic inhibitors, [14C]lovastatin and [14C]simvastatin, were high. In contrast, that of the hydrophilic inhibitor, [14C]pravastatin, was low and not significantly different from that of [14C]sucrose, an extracellular space marker. Similarly, the in vitro BBB permeability coefficients of [14C]lovastatin and [1C]simvastatin were high, while that of [14C]-pravastatin was low. The in vivo and in vitro transcellular permeabilities obtained for HMG-CoA reductase inhibitors were comparable. This study shows that the BBB permeability correlates with the CNS side effects of the HMG-CoA reductase inhibitors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018975928974
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  • 6
    Electronic Resource
    Electronic Resource
    Transcellular Transport of Benzole Acid Across Caco-2 Cells by a pH-Dependent and Carrier-Mediated Transport Mechanism (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 30-37 
    Details
    ISSN: 1573-904X
    Keywords: benzoic acid ; Caco-2 cell ; Monocarboxylic acid ; pH-dependent carrier-mediated transport ; pH-partition theory ; proton-coupled transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pH-dependent transcellular transport of [14 C]benzoic acid across a Caco-2 cell monolayer is shown to be mediated by a monocarboxylic acid-specific carrier-mediated transport system, localized on the apical membrane. Evidence for the carrier-mediated transport of benzoic acid includes (a) the significant temperature and concentration dependence, (b) the metabolic energy dependence, (c) the inhibition by unlabeled benzoic acid and other monocarboxylic acids, (d) countertransport effects on the uptake of [14C]benzoic acid, and (e) effects of a proteinase (papain) and amino acid-modifying reagents. Furthermore, since carbonylcyanide p-trifluoromethoxyphenylhydrazone and nigericin significantly inhibited the transport of [14C] benzoic acid, the direct driving force for benzoic acid transport is suggested to be the inwardly directed proton gradient. From these results, together with previous observations using intestinal brush border membrane vesicles, the pH dependence of the transcellular transport of certain organic weak acids across Caco-2 cells is considered to result mainly from a proton gradient-dependent, carrier-mediated transport mechanism, rather than passive diffusion according to the pH-partition theory.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018933324914
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  • 7
    Electronic Resource
    Electronic Resource
    Stereoselective and Carrier-Mediated Transport of Monocarboxylic Acids Across Caco-2 Cells (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1828-1832 
    Details
    ISSN: 1573-904X
    Keywords: carrier-mediated transport ; lactic acid ; stereoselectivity ; Caco-2 cells ; monocarboxylic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the transport mechanism of monocarboxylic acids across intestinal epithelial cells by examining the stereoselectivity of the transcellular transport of several chiral monocarboxylic acids. Methods. The transport of monocarboxylic acids was examined using monolayers of human adenocarcinoma cell line, Caco-2 cells. Results. The permeability of L-[14C]lactic acid at a tracer concentration (1 µM) exhibited pH- and concentration-dependencies and was significantly greater than that of the D-isomer. The permeabilities of both L-/ D-[14C]lactic acids involve saturable and nonsaturable processes; the saturable process showed a higher affinity and a lower capacity for L-lactic acid compared with the D-isomer, while no difference between the isomers was seen for the nonsaturable process. The transport of L-lactic acid was inhibited by chiral monocarboxylic acids such as (R)/(S)-mandelic acids and (R)/(S)-ibuprofen in a stereoselective manner. Mutually competitive inhibition was observed between L-lactic acid and (S)-mandelic acid. Conclusions. Some chiral monocarboxylic acids are transported across the intestinal epithelial cells in a stereoselective manner by the specific carrier-mediated transport mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016081007981
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  • 8
    Electronic Resource
    Electronic Resource
    Proton-Cotransport of Pravastatin Across Intestinal Brush-Border Membrane (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1727-1732 
    Details
    ISSN: 1573-904X
    Keywords: pravastatin ; intestinal absorption ; active transport ; pH-dependent transport ; HMG-CoA reductase inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study is to clarify the intestinal brush-border transport mechanism of a weak organic acid, pravastatin, an HMG-CoA reductase inhibitor. Methods. The transport of pravastatin was studied by using intestinal brush-border membrane vesicles prepared from rabbit jejunum, and uptake by the membrane vesicles was measured using rapid filtration technique. Results. The initial uptake of [14C]pravastatin was markedly increased with decreases in extravesicular pH and showed a clear overshoot phenomenon in the presence of a proton gradient (pHin/out = 7.5/5.5). A protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, significantly reduced the uptake of [14C]pravastatin. In addition, an ionophore for sodium, potassium and proton, nigericin, stimulated the uptake of [14C]pravastatin in the presence of a potassium gradient ([K + ]in/[K+ ]out = 0/145 mM). On the other hand, neither the imposition of an inwardly directed sodium gradient nor an outwardly directed bicarbonate gradient stimulated the uptake of [14C]pravastatin. In the presence of a proton gradient (pHin/out = 7.5/5.5), the initial uptake of pravastatin was saturable with the apparent Kt of 15.2 ± 3.2 mM and Jmax of 10.6 ± 1.21 nmol/mg protein/10 sec. The uptake of pravastatin was significantly inhibited by monocarboxylic acid compounds such as acetic acid and nicotinic acid in a competitive manner but not by di- or tri-carboxylic acids, or acidic amino acid. Conclusions. It was concluded that a pH-dependent transport of pravastatin across the brush-border membrane occurs by a proton-gradient dependent carrier-mediated mechanism rather than by simple diffusion of its unionized form.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016269806840
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  • 9
    Electronic Resource
    Electronic Resource
    Functional Clarification of MCT1-Mediated Transport of Monocarboxylic Acids at the Blood-Brain Barrier Using In Vitro Cultured Cells and In Vivo BUI Studies (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 55-62 
    Details
    ISSN: 1573-904X
    Keywords: blood-brain barrier ; monocarboxylic acid ; MCT1 ; immortalized cell ; benzoic acid ; membrane transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To prove the functional significance of monocarboxylic acidtransporter, MCT1 at the blood-brain barrier (BBB) for the passage ofboth endogenous and exogenous monocarboxylic acids into the centralnervous system. Methods. Monocarboxylic acid transport at the BBB was studied inrats by using a newly established immortalized brain capillaryendothelial cell (BCEC) line, RBEC1, and the results were compared withthose obtained by using primary cultured BCECs, cells stably expressedwith rat MCT1, and the in vivo brain uptake index (BUI) method. Results. The cell line, RBEC1 meets various morphological andenzymatic criteria of BCECs and appears to be suitable for the studyof BBB transport of monocarboxylic acids. The presence ofMCT1-transcript in RBEC1 was confirmed by the RT-PCR method, aspreviously observed in isolated brain capillaries. A typical substrate ofMCT1, lactic acid, was taken up by RBEC1 in a stereospecific andsaturable manner. The value of the kinetic parameter Km showed goodagreement with values previously obtained in studies using an in vivoBUI and in vitro MCT1-transfected cells. An organic weak acid,benzoic acid, which has been considered to cross biological membranesby passive diffusion, exhibited carrier-mediated transport properties,such as saturation, pH dependence, and stereospecific inhibition inRBEC1, similar to those we observed in primary cultured rat BCECs.The Km values in RBEC1, in primary cultured BCECs and in thein vivo BUI method were comparable and well agreed with that obtainedin MCT1-transfected cells, suggesting that the transport features ofbenzoic acid observed by in vitro methods well reflect thein vivo transport activity. Furthermore, hybrid depletion of MCT1 in RBEC1using an antisense oligonucleotide against rat MCT1 abolished thesaturable transport of benzoic acid. Conclusions. These observations show that MCT1 plays a significantrole in the transport of monocarboxylic acids, including the exogenousorganic weak acid benzoic acid, as well as native lactic acid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007518525161
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  • 10
    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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