Transport mechanisms protein

Care should be exercised when attempting to interpret in vivo pharmacological data in terms of specific chemical—biological interactions for a series of asymmetric compounds, particularly when this interaction is the only parameter considered in the analysis (10). It is important to recognize that the observed difference in activity between optical antipodes is not simply a result of the association of the compound with an enzyme or receptor target. Enantiomers differ in absorption rates across membranes, especially where active transport mechanisms are involved (11). They bind with different affinities to plasma proteins (12) and undergo alternative metaboHc and detoxification processes (13). This ultimately leads to one enantiomer being more available to produce a therapeutic effect. 

Because bretylium is poody absorbed from the GI tract (- 10%), it is adrninistered iv or im. Very litde dmg is protein bound in plasma. Bretylium is taken up by an active transport mechanism into and concentrated in postganglionic nerve terminals of adrenergicahy innervated organs. Peak plasma concentrations after im injections occur in about 30 min. Therapeutic plasma concentrations are 0.5—1.0 p.g/mL. Bretylium is not metabolized and >90% of the dose is excreted by the kidneys as unchanged dmg. The plasma half-life is 4—17 h (1,2). 

Protein trafficking is the transport of proteins to their correct subcellular compartments or to the extracellular space ( secretory pathway ). Endo- and exocytosis describe vesicle budding and fusion at the plasma membrane and are by most authors not included in the term protein trafficking. Protein quality control comprize all cellular mechanisms, monitoring protein folding and detecting aberrant forms. 

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. 

Taken together, these results indicate that similar to other proton-translocating membrane proteins, both types of Na /H exchangers contain critical sulfhydryl groups that are involved in the transport mechanism. These sulfhydryl groups do not appear to be present at the external transport site but may be involved in switching from an inactive to an activated state. 

Studies of the effect of permeant s size on the translational diffusion in membranes suggest that a free-volume model is appropriate for the description of diffusion processes in the bilayers [93]. The dynamic motion of the chains of the membrane lipids and proteins may result in the formation of transient pockets of free volume or cavities into which a permeant molecule can enter. Diffusion occurs when a permeant jumps from a donor to an acceptor cavity. Results from recent molecular dynamics simulations suggest that the free volume transport mechanism is more likely to be operative in the core of the bilayer [84]. In the more ordered region of the bilayer, a kink shift diffusion mechanism is more likely to occur [84,94]. Kinks may be pictured as dynamic structural defects representing small, mobile free volumes in the hydrocarbon phase of the membrane, i.e., conformational kink g tg ) isomers of the hydrocarbon chains resulting from thermal motion [52] (Fig. 8). Small molecules can enter the small free volumes of the kinks and migrate across the membrane together with the kinks. 

The study of active transport mechanisms has grown substantially in recent years, with transport proteins such as P-gp, BCRP, and MRP-2 among the most studied [59]. Several types of in vitro assays to assess substrates of transporters have been established these include assays directed toward intestinal and biliary efflux [60]. Assays that measure passive and active transport are also used to assess penetration of the blood-brain barrier. In addition to the assays described above, transfected cell lines that overexpress transporters present in the blood-brain barrier are also employed [61]. 

Levodopa, a dopamine precursor, is the most effective agent for PD. Patients experience a 40% to 50% improvement in motor function. It is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa requires active transport by a large, neutral amino acid transporter protein from the small intestine into the plasma and from the plasma across the blood-brain barrier into the brain (Fig. 29-2). Levodopa competes with other amino acids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements and administration of these should be spaced by at least 2 hours from the levodopa dose.1,8,16,25... 

Fig. 7.1. The intestinal permeability of drugs in vivo is the total transport parameter that may be affected by several parallel transport mechanisms in both absorptive and secretory directions. Some of the most important transport proteins that may be involved in the intestinal transport of drugs and their metabolites across intestinal epithelial membrane barriers in humans are displayed.

Lee, V. H., et al. Biopharmaceutics of transmucosal peptide and protein drug administration role of transport mechanisms with a focus on the involvement of PepTl. J. Control. Release 1999, 62, 129-140. 

Pinocytosis is a type of endocytosis that is responsible for the transport of large molecules such as proteins and colloids. Some cell types (e.g., endothelial cells) employ this transport mechanism extensively, but its importance in drug action is uncertain. 

The copper transport function of ceruloplasmin has been documented in several reviews (e.g. see refs. 15, 42, 43) and a transport function established. The turnover of ceruloplasmin allows copper ions to move from the major sites of ceruloplasmin synthesis in liver cells [44,45] to peripheral tissues for incorporation into copper-dependent enzymes [46,47], but transport mechanisms may also be active which involve copper atoms in the intact protein. However, the complexity of the protein has made it difficult to determine which, if any, of the six integral copper atoms are involved in copper delivery or whether there exist additional... 

On the other hand, highly purified preparations (180-fold) obtained by Huennekens and his co-workers (H22) have been shown to be a hemo-protein with a molecular weight of approximately 185,000. With regard to these different results it is interesting that in RBC of individuals suffering from hereditary methemoglobinemia a complete lack of NAD diaphorase has been reported (S10, Sll) this would indicate the importance of an enzyme which contains FAD. The reasons for the discrepancies between the preparations obtained by two teams of investigators are not understood as yet. Perhaps they are implicated in the electron transport mechanisms or in the nature of a certain cofactor which is to be discussed now. 

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