Carrier-mediated absorption

A new interpretation of salicylic acid transport across the lipid bilayer implications of pH-dependent but not carrier-mediated absorption from the gastrointestinal tract. /. Pharmacol. 

Takagi, M. Taki, Y. Sakane, T. Nadai, T. Sezaki, H. Oku, N. Yamashita, S., A new interpretation of salicylic acid transport across the lipid bilayer Implication of pH-dependence but not carrier-mediated absorption from the gi tract, J. Pharmacol. Exp. Therapeut. 285, 1175-1180 (1998). 

Solute uptake can also be evaluated in isolated cell suspensions, cell mono-layers, and enterocyte membrane vesicles. In these preparations, uptake is normalized by enzyme activity and/or protein concentration. While the isolation of cells in suspension preparations is an experimentally easy procedure, disruption of cell monolayers causes dedifferentiation and mucosal-to-serosal polarity is lost. While cell monolayers from culture have become a popular drug absorption screening tool, differences in drug metabolism and carrier-mediated absorption [70], export, and paracellular transport may be cell-type- and condition-depen-dent. 

Figure 2.11 A comparison between human and rat effective intestinal permeability coefficients (Peff). The equation describes the correlation for passive diffusion. The inset shows the Peff values in the lower range ( = passive absorption A = carrier-mediated absorption) [46, 47],...

Utoguchi N, Watanabe Y, Takase Y, Suzuki T, Matsumoto M (1999) Carrier-mediated absorption of salicylic acid from hamster cheek pouch mucosa. J Pharm Sci 88 142-146... 

Certain cyclic dipeptides have the ability to be transported by additional paracellular mechanisms, thereby enhancing their transport. " Not only absorptive transport but also excretive transport are observed for certain cyclic dipeptides. The intestinal absorption of certain cyclic dipeptides consists of carrier-mediated absorptive... 

Food constituents may compete with drags for carrier-mediated absorption mechanisms. 

The lipid-aqueous partition coefficient of a drug molecule affects its absorption by passive diffusion. In general, octanol/pH 7.4 buffer partition coefficients in the 1-2 pH range are sufficient for absorption across lipoidal membranes. However, the absence of a strict relationship between the partition coefficient of a molecule and its ability to be absorbed is due to the complex nature of the absorption process. Absorption across membranes can be affected by several diverse factors that may include the ionic and/or polar characteristics of the drug and/or membrane as well as the site and capacity of carrier-mediated absorption or efflux systems. 

Single-pass intestinal perfusion studies For evaluatton of intestinal prermeability and lymphatic uptake Predict the exact mechanism of absorption, that is, passive absorption, carrier mediated absorption or active transport Evaluate the P-gp efflux and role of transporters (MRP, BCRP2) in reducing the oral bioavailability of drugs... 

Said, EI.M., 2004. Recent advances in carrier-mediated absorption of water-soluble vitamins. Annual Review of Physiology. 66 419-446. 

The mucosa of the GIT represents an interface between the external and internal environments. The expansive surface area is necessary for the efficient hydrolysis of foodstuffs and the absorption of energy and nutrients. The mucosa also influences the systemic availability of non-nutrient compounds in the diet, both beneficial and detrimental. Digestion and absorption of glucosinolates are critical determinants of health benefits (see Chapter 4) Similarly, the bioavailability and health benefits of phytoestrogens, such as genistein (see Chapters 5 and 10) are at least partly dependent on the carrier-mediated processes of absorption associated with the GIT (Oitate et al, 2001). Moreover, the metabolic activities of the mucosa can influence the systemic concentrations and forms of dietary phytochemicals, as exemplified by research with soy isoflavones (Andlauer et al., 2000). 

Historically, the absorption of lipid-soluble nutrients has been considered to be carrier-independent, with solutes diffusing into enterocytes down concentration gradients. This is true for some lipid-soluble components of plants (e.g. the hydroxytyrosol in olive oil Manna et al., 2000). However, transporters have been reported for several lipid-soluble nutrients. For example, absorption of cholesterol is partly dependent on a carrier-mediated process that is inhibited by tea polyphenols (Dawson and Rudel, 1999) and other phytochemicals (Park et al., 2002). A portion of the decreased absorption caused by tea polyphenols may be due to precipitation of the cholesterol associated with micelles (Ikeda et al., 1992). Alternatively, plant stanols and other phytochemicals may compete with cholesterol for transporter sites (Plat and Mensink, 2002). It is likely that transporters for other lipid-soluble nutrients are also affected by phytochemicals, although this has not been adequately investigated. 

The shapes of the profiles for the amount absorbed vs. time for F-PHEA with different MWDs have been reported previously (9). In general, the amount of F-PHEA absorbed increases steadily with time although polymers with smaller MWD are absorbed more rapidly. The effect is illustrated in Table I which is reproduced from a previous paper (9). Interpretation of F-PHEA s absorption kinetics can be complicated however, either by varying the administered dose or the administered molecular weight distribution. Table I shows clearly the increasing percent absorbed of a weight averaged F-PHEA of 4.68 kD as the dose was systematically reduced. This data is evidence of the existence of carrier-mediated transfer for F-PHEA in the... 

Figure 8 A peptide carrier mediated transport to improve oral absorption.

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

DI Friedman, GL Amidon. Passive and carrier-mediated intestinal absorption components of two angiotensin converting enzyme (ACE) inhibitor prodrugs in rats Enalapril and fosinopril. Pharm Res 6(12) 1043-1047, 1989. 

K Hosoya, Y Horibe, KJ Kim, VHL Lee. (1998). Carrier-mediated V°-nitro-L-argi-nine absorption across the pigmented rabbit conjunctiva. J Pharmacol Exp Therap 285 223-227. 

Thus, the fraction of dose absorbed is exponentially related to the absorption number. Equation (10) shows that the absorption number (and therefore the membrane permeability) is a fundamental parameter while other parameters such as the partition coefficient and pKa are useful guides but not fundamental parameters. For highly soluble drugs with linear absorption kinetics, dose and dissolution have no effect on the fraction of dose absorbed. In the case of drugs that are absorbed by a carrier-mediated process, a mean permeability should be used [30],... 

DM Oh, PJ Sinko, GL Amidon. Predicting oral drug absorption in humans A macroscopic mass balance approach for passive and carrier-mediated compounds. In DZ D Argenio, ed. Advanced Methods of Pharmacokinetic and Pharmacodynamic Systems Analysis. New York Plenum Press, 1990, pp 3-11. 

Molecules with a large molecular weight or size are confined to the transcellular route and its requirements related to the hydrophobicity of the molecule. The transcellular pathway has been evaluated for many years and is thought to be the main route of absorption of many drugs, both with respect to carrier-mediated transport and passive diffusion. The most well-known requirement for the passive part of this route is hydrophobicity, and a relationship between permeability coefficients across cell monolayers such as the Caco-2 versus log P and log D 7.4 or 6.5 have been established [102, 117]. However, this relationship appears to be nonlinear and reaches a plateau at around log P of 2, while higher lipophilicities result in reduced permeability [102, 117, 118]. Because of this, much more attention has recently been paid towards molecular descriptors other than lipophilicity [86, 119-125] (see section 5.5.6.). The relative contribution between the para-cellular and transcellular components has also been evaluated using Caco-2 cells, and for a variety of compounds with different charges [110, 112] and sizes [112] (see Section 5.4.5). 

Solvents used to increase solubility for compounds during screening of permeability across the cell monolayers, together with commonly used excipients for formulations, can also affect the barrier as they contain ingredients which enhance drug absorption [100, 151]. There are different mechanisms by which these compounds can modulate the barrier [4, 149, 150] for example, they may increase the tight junctional pathway inhibiting carrier-mediated transport, or cholesterol... 

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