Absorption active transport mechanism

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. 

FIGURE 29-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase, and catechol-O-methyltransferase. Carbidopa does not cross the blood-brain barrier. Large, neutral amino acids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain (plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals. 

Drugs absorbed by active transport mechanisms appear to have a delayed rate, but not extent of absorption, in the neonatal period [20]. The absorption of vitamin K depends, to some extent, on the development of intestinal flora. 

In this book we will focus on physicochemical profiling in support of improved prediction methods for absorption, the A in ADME. Metabolism and other components of ADME will be beyond the scope of this book. Furthermore, we will focus on properties related to passive absorption, and not directly consider active transport mechanisms. The most important physicochemical parameters associated with passive absorption are acid-base character (which determines the charge state of a molecule in a solution of a particular pH), lipophilicity (which determines distribution of a molecule between the aqueous and the lipid environments), solubility (which limits the concentration that a dosage form of a molecule can present to the solution and the rate at which the molecule dissolves from... 

Less direct evidence for active transport mechanisms includes the high degree of absorption of the P-gp substrate losartan in the isolated perfused rat lung, which indicated an absence of any absorption-retarding effect of P-gp [139], Evidence to the contrary includes an increase in the uptake of idaru-bicin when administered to the IPL via the perfusate in the presence of P-gp inhibitors [70],... 

In distal convoluted tubules, calcium is transported by an active transport mechanism through rather than between cells. Moreover, in distal convoluted tubules there is a reciprocal relation between the direction and magnitude of calcium on Na+ transport. As Na+ absorption increases, calcium decreases, and conversely, reductions of Na+ absorption are accompanied by elevated calcium reabsorption. This interaction has important implications for diuretics acting in the distal convoluted tubule. 

Plain water crosses the walls of the intestine by osmotic action alone. However, if sodium and sugars are also present then the active transport mechanisms described earlier operate and water absorption can be enhanced. The effect is dependant on concentrations the maximum rate of water uptake occurs when the concentrations give a slightly hypotonic solution (200-250 mOsm/kg, cf. 287 mOsm/kg for isotonicity) (Wapnir and Lifshitz, 1985). Conversely, when the lumen contents are significantly hypertonic, water is secreted from plasma into the intestine by osmotic action this is a dehydrating effect. 

The small intestine contains a wide variety of transporters (amino acid transporters, oligopeptide transporters, glucose transporters, lactic acid transporters etc.) on the apical membrane of the epithelial cells, which serve as carriers to facilitate nutrient absorption by the intestine. On the basolateral membrane, the presence of amino acid and oligopeptide transporters has been demonstrated. Active transport mechanisms for di- and tri-peptides have also been demonstrated in the nasal and buccal epithelia. 

Active transport mechanisms exist in the gastrointestinal tract and other epithelial sites, for the absorption of di- and tri-peptides. As described above, a greater understanding of the molecular specificity of this carrier could provide important leads for the delivery of peptides. Proteins and large peptides may be transported across cells via endocytic processes. Transcytosis is achieved if the endocytic vesicles can reach the basal membrane without fusion with lysosomes. However, various studies have shown that in the majority of cases the internalized protein is degraded, indicating that the transcytotic pathway is a minor one and most of the endocytosed protein is subject to lysosomal degradation. 

Drugs absorbed by active transport mechanisms appear to have a delayed rate, but not extent of absorption, in the neonatal period (17). Drug absorption is highly variable and unpredictable in neonates and infants (19,20). Older children appear to have absorption patterns similar to adults unless chronic illness or surgical procedures alter absorption. Differences in bile excretion, bowel length, and surface area probably contribute to the reduced bioavailability of cyclosporine seen in pediatric liver transplant patients (21). Impaired absorption has also been observed in severely malnourished children (22). A rapid GI transit time may contribute to the malabsorption of carbamazepine tablets, which has been reported in a child (23). 

The Ro5 is intended to filter out molecules with potential absorption problems and it does so very well using simple terms that are easily implemented and used by medicinal chemists. This rule should not be expected, however, to discriminate well between drugs and non-drugs. Neither can it provide a quantitative estimate of compound absorption or take into account active transport mechanisms. 

Active transport mechanisms for the intestinal absorption of amino acids, oligopeptides, monosaccharides, monocarboxylic acids, phosphate, bile acids, and a number of vitamins have been identified and the review by Tsuji and Tamai provides an excellent summary of those mechanisms. The potential use of intestinal peptide and hepatic bile acid carriers to enhance drug absorption also has been reviewed. Structural and molecular modeling studies have postulated molecular structural features necessary for substrate recognition by the intestinal peptide carrier and the bile acid carrier. ... 

Little is known about the specific biochemical mechanism(s) by which selenium and selenium compounds exert their acute toxic effects. Long-term effects on the hair, skin, nails, liver, and nervous system are also well documented, and a general theory has been developed to explain the toxicity of exposure to excess selenium, as discussed below. Generally, water-soluble forms are more easily absorbed and are generally of greater acute toxicity. Mechanisms of absorption and distribution for dermal and pulmonary uptake are unknown and subject to speculation, but an active transport mechanism for selenomethionine absorption in the intestine has been described (Spencer and Blau 1962). The mechanisms by which selenium exerts positive effects as a component of glutathione peroxidase, thioredoxin reductase, and the iodothyronine 5 -deiodinases are better understood, but the roles of other selenium-containing proteins in mammalian metabolism have not been clarified. 

The thiamin (vitamin BO molecule contains a quaternary ammonium functionality and is thus badly absorbed. In healthy patients the necessary amounts of thiamin are absorbed thanks to an active transport mechanism coupled with ATP consumption. However, these mechanisms are rapidly saturable and easily inhibited, especially by chronic alcoholic consumption. As a consequence of the insufficient absorption of thiamin, alcoholism often entails Wernicke s encephalopathy (neurological disorders such as nystagmus, ocular motor nerve paralysis, memory losses, disorientation). The design of lipophilic prodrugs, able to reach the CNS by passive diffusion was then undertaken compounds like (a) and (b) result from lipophilic disulphide derivation of the open ring thiolate anion corresponding to thiamine (Fig. 33.39). 

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