Carriers uptake

Florence AT. Issues in oral nanoparticle drug carrier uptake and targeting. J Drug Target 2004 12 65-70. 

To increase the residence time of drug carriers in the blood, the carriers are modified with hydrophilic synthetic polymers, such as PEG [62-64]. Coating nanoparticles with PEG sterically disrupts the interactions of blood components with the carrier surface and subsequently decreases the binding of plasma proteins. This minimizes opsonin adsorption onto the carrier and carrier uptake rates by the reticuloendothelial system (RES) [65-67]. Repulsive interactions [68] and poor permeability of proteins through PEG coating [69] may contribute to this observation. 

In addition to natural biopolymers, recent attention has also focused on biocompatible peptides as dehvery vectors. By condensing pDNA in a simple complexation fashion similar to polycations, protein transduction domain peptides demonstrate carrier uptake of 80 to 90% within 30 min, significantly more rapid than PEI or commercial liposomes [28]. These vectors are able to bypass traditional endo-cytic pathways to reach the nucleus within 1 h. Similarly, nuclear localization sequence (NLS) peptides allow superior transfection over synthetic polyplexes, and may be incorporated in traditional liposome complexes to assist in plasmid nuclear penetration [29,30]. 

The transfer efficiencies for ultrasonic nebulizers (USN) are about 20% at a sample uptake of about 1 ml/min. Almost 100% transfer efficiency can be attained at lower sample uptakes of about 5-20 pl/min. With ultrasonic nebulizers, carrier gas flows to the plasma flame can be lower than for pneumatic nebulizers because they transfer sample at a much higher rate. Furthermore, reduction in the carrier-gas flow means that the sample remains in the mass measurement system for a longer period of time which provides much better detection limits. 

Compartmentation of these reactions to prevent photorespiration involves the interaction of two cell types, mescrphyll cells and bundle sheath cells. The meso-phyll cells take up COg at the leaf surface, where Og is abundant, and use it to carboxylate phosphoenolpyruvate to yield OAA in a reaction catalyzed by PEP carboxylase (Figure 22.30). This four-carbon dicarboxylic acid is then either reduced to malate by an NADPH-specific malate dehydrogenase or transaminated to give aspartate in the mesophyll cells. The 4-C COg carrier (malate or aspartate) then is transported to the bundle sheath cells, where it is decarboxylated to yield COg and a 3-C product. The COg is then fixed into organic carbon by the Calvin cycle localized within the bundle sheath cells, and the 3-C product is returned to the mesophyll cells, where it is reconverted to PEP in preparation to accept another COg (Figure 22.30). Plants that use the C-4 pathway are termed C4 plants, in contrast to those plants with the conventional pathway of COg uptake (C3 plants). 

FIGURE 22.30 Essential features of the coinpartinenCation and biochemistry of die Hatch-Slack padiway of carbon dioxide uptake in C4 plants. Carbon dioxide is fixed into organic linkage by PEP carboxylase of meso-phyll cells, forming OAA. Eidier malate (die reduced form of OAA) or aspartate (the ami-iiated form) serves as die carrier transpordiig CO9 to the bundle slieadi cells. Within die bundle slieadi cells, CO9 is liberated by decar-boxyladon of malate or aspartate die C-3 product is returned to die mesophyll cell. 

Tricyclic antodepressants are an important group of antidepressants. They block the uptake of monoamines by nerve terminals by competing for the binding site of the reuptake carrier protein. 

Note These are examples of important transporters involved in substrate and ADP uptake into the matrix compartment as indicated, and most are reversible. These transporters are proteins and several have been isolated and sequenced. Other specific carriers occur in mitochondria from other tissues. The inner membrane does not allow rapid exchange of NAD or CoA but there are mechanisms for the slow uniport of cofactors synthesized extramitochondrially. 

Weiner, N., and Chia-Ming Chiang (1988). Gastrointestinal uptake of liposomes, in Liposomes as Drug Carriers Recent Trends and Progress (G. Gregoriadis, ed.), John Wiley and Sons, Chichester, pp. 599-607. 

Adamantane derivatives can be employed as carriers for drug delivery and targeting systems. Due to their high lipophUicity, attachment of such groups to drugs with low hydrophobicity could lead to a substantial increase of drug solubihty in lipidic membranes and thus increases of its uptake. 

Several other conditions can provoke this reverse pump type of release. One is when the transmembrane ionic gradient is reversed. Experimentally this is achieved by reducing extracellular Na+. Because the neuronal uptake of monoamines from the synapse by the transporter requires co-transport of Na+ and Cl , reversing the ionic gradient (so that the Na+ concentration is lower outside, than inside, the terminals) will drive the transporter in the wrong direction. Such carrier-mediated release could explain the massive Ca +-independent release of noradrenaline during ischaemia which increases intracellular Na+ concentration and reduces intracellular K+. 

Figure 4.13 GABA release by reversed uptake ( retrotransport ). Depolarization of a neuronal, or glial cell process by glutamate, with a concomitant rise in [Na+]i reverses the operation of the GABA uptake carrier, raising [GABA]o. (Modified from Attwell, Barbour and Szatkowski 1993, with permission from the publisher Cell Press)...

The history of observations of efflux associated with PTS carriers is nearly as old as PTS itself. Gachelin [82] reported that A -ethylmaleimide inactivation of a-methyl-glucoside transport and phosphorylation in E. coli was accompanied by the appearance of a facilitated diffusion movement of both a-methylglucoside and glucose in both directions, uptake and efflux. His results could not discriminate, however, between one carrier operating in two different modes, active transport for the native carrier and facilitated diffusion for the alkylated carrier, or two distinct carriers. Haguenauer and Kepes [83] went on to show that alkylation of the carrier was not even necessary to achieve efflux NaF treatment which inhibits P-enolpyruvate synthesis was sufficient but this study did not address the question of one carrier or two. 

Further progress may derive from a more accurate definition of the chemical and physical properties of the humic substances present at the rhizosphere and how they interact with the root-cell apoplast and the plasma membrane. An interaction with the plasma membrane H -ATPase has already been observed however this master enzyme may not be the sole molecular target of humic compounds. Both lipids and proteins (e.g., carriers) could be involved in the regulation of ion uptake. It therefore seems necessary to investigate the action of humic compounds with molecular approaches in order to understand the regulatory aspects of the process and therefore estimate the importance of these molecules as modulators of the root-soil interaction. 

T. Jahns, A. Zobel, D. Keiner, and H. Kaltwasser, Evidence for carrier mediated, energy-dependent uptake of urea in some bacteria. Arch. Microbial. 149 311 (1988). 

The above conclusion is supported by the results shown in figure 4. Just as inhibitors of the 5-HT uptake carrier can antagonize MDMA-induced [ H]5-HT release in vitro, coadministration of MDMA with an uptake inhibitor such as citalopram can completely block the acute depletion of 5-HT. Although citalopram also antagonized the MDMA-induced decrease in TPH activity, there was still a significant loss of enzyme activity when compared to control. This implies that if MDMA requires access to the interior of the nerve terminals to affect TPH activity, it does not require the activity of the uptake carrier to gain entrance. Hence, these results are consistent with the outcome of synaptosomal uptake experiments with [ HJMDMA (Schmidt et al. 1987), which show that MDMA is not actively concentrated by a carrier system. Furthermore, it is apparent that the loss of enzyme activity alone is not sufficient to reduce 5-HT concentrations, but that release via the carrier must occur simultaneously, to deplete the terminal once synthetic capacity is reduced. 

FIGURE 4. Effect of inhibition of the 5-HT uptake carrier by citalopram... 

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

Since the neurotoxic effects of drugs such as parachloroamphetamine on serotonin neurons can be prevented by serotonin uptake blockers (Ross 1976 Sanders-Bush and Steranka 1978). the possibility that serotonin uptake carrier protein was likewise involved in the neurotoxic effects of MDMA was investigated. As shown in figure 4, pretreatment of rats with the seleetive serotonin uptake blocker citalopram (10 ml/kg), prior to each injection of 10 mg/kg MDMA, resulted in nearly complete protection against the neurotoxic effects of MDMA. Citalopram-pretreated rats exhibited only a 15 pereent decrease in serotonin uptake sites. No significant alterations in the eontent of serotonin and 5-HIAA were observed following MDMA treatment, in eomparison with 60 to 80 percent reductions in the serotonergie parameters observed in rats treated with an identical dose of MDMA alone. 

The data deseribed above demonstrate that destruction of serotonin axons by MDMA involves the serotonin aetive uptake carrier and that administration of citalopram, a selective serotonin uptake blocker, prior to administration of MDMA, ean prevent the decreases in serotonin markers elicited by MDMA alone. These data are eonsistent with previous reports for other potent serotonin neurotoxins, demonstrating that pretreatment with serotonin uptake blockers can prevent the neurotoxic effects of parachloroamphetamine (Ross 1976 Sanders-Bush and Steranka 1978). Furthermore, it has been shown that MDMA-induced neurotoxicity can be prevented or reversed if a serotonin uptake blocker such as fluoxetine is administered no later than 12 hours after MDMA treatment (Schmidt 1986). 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

MPTP, into dopamine neurons seems to be essential, and blockade of that aeeumulation prevents the neurotoxieity. MPP+ also ean be transported into norepinephrine neurons (Javitch et al. 1985), leading to neurotoxicity toward cortical norepinephrine neurons, an effect blocked by inhibitors of the norepinephrine uptake carrier (Sundstrom and Jonsson 1985). 

Drug Membrane Uptake Carrier Involved in Neurotoxicity Drug Metabolite Involved in Neurotoxicity... 

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