Transport of drugs carrier-mediated

Drug absorption from the oral cavity occurs through the passive diffusion of the nonionized form from an aqueous phase to one that is lipid in nature. In addition, there is also evidence for the carrier-mediated transport of drugs, whereby the levo isomers, but not the dextro isomers, of many drugs are absorbed. 

Ogihara, T. Tamai, I. Tsuji, A. Application of fractal kinetics for carrier-mediated transport of drugs across intestinal epithelial membrane. Pharm. Res. 1998, 15 (4), 620-625. 

ROLE OF TRANSPORT PROCESSES AT THE BLOOD-BRAIN BARRIER CARRIER-MEDIATED TRANSPORT OF DRUGS... 

Carrier-mediated transport of drugs and their metabolites has recently been recognized as an important issue in pharmaceutical research. There is a wealth of information that suggests that transporters are responsible both for the uptake and efflux of drugs and other xenobiotics, and may be key determinants of the disposition of a drug [91,92]. Transporter proteins are divided into two categories (1) the adenosine triphosphate (ATP) binding cassette (ABC) transporter superfamily and (2) the solute carrier (SLC) family of proteins. 

Y Horibe, KJ Kim, VHL Lee. (1998). Carrier-mediated transport of monocarboxy-late drugs in the pigmented rabbit conjunctiva. Invest Ophthalmol Vis Sci 39 1436-1443. 

Yuasa H, Hirobe M, Tomei S, Watanabe J (2000) Carrier-mediated transport of riboflavin in the rat colon. Biopharm Drug Dispos 21 77-82... 

Quantitative measurement of diffusional uptake and carrier-mediated transport of nutrients and drugs in experimental animals was greatly facilitated with the introduction of Olden dorfs brain uptake index (BUI) [42].Test and reference tracers are injected as an intraarterial bolus into the carotid artery of the anaesthetized animal. After 5 s the animal is killed and the brain is removed for radioactivity counting. This method measures the ratio of the unidirectional brain extraction, E, of the test substance and of the reference ([ H]-water, [ " C]-butanol), which are labelled with different isotopes, during a single passage through the brain capillary bed ... 

From these results it can be concluded that liver slices are a powerful tool for studying the mechanisms and specificity of carrier-mediated uptake of drugs and drug interactions which occur at the transport level. 

Russell-Jones, G.J. Carrier-mediated transport, oral drug delivery. In Encyclopedia of Controlled Drug Delivery Mathiowitz, E., Ed. John Wiley Sons, Inc. New York, 1999 1, 173-184. 

The second method in this group is the intestinal rings or slices. This method for studying drug absorption has been used extensively for kinetic analysis of carrier-mediated transport of glucose, amino acids and peptides (Kararli 1989 Osiecka et al. 1985 Porter et al. 1985 Kim et al. 1994 Leppert and Fix 1994). The method is easy to use the intestine of the animal is cut... 

Fig. 9 Schematic representation depicting the movement of molecules from the absorbing (mucosal or apical) surface of the GIT to the basolateral membrane and from there to blood. (A) transcellular movement through the epithelial cell. (B) Paracellular transport via movement between epithelial cells. (Q Specialized carrier-mediated transport into the epithelial cell. (D) Carrier-mediated efflux transport of drug out of the epithelial cell. (Copyright 2000 Saguaro Technical Press, Inc., used with permission.)...

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. 

Several attempts have been made to estimate the dose required in humans in relation to a drug s potency, and to put this into the context of solubility and permeability for an optimal oral drug [2, 3]. A relatively simple example of this is where a 1.0 mg kg-1 dose is required in humans, then 52 pg mL"1 solubility is needed if the permeability is intermediate (20-80%) [3]. This solubility corresponds approximately to 100 pM of a compound with a MW of 400 g mol-1. Most screening activities for permeability determinations in, e.g., Caco-2, are made at a concentration of 10 pM or lower due to solubility restrictions. The first implication of this is that the required potency for these compounds needs to correspond to a dose of <0.1 mg kg-1 in humans if the drug should be considered orally active. Another implication would be the influence of carrier-mediated transport (uptake or efflux), which is more evident at low concentrations. This could result in low permeability coefficients for compounds interacting with efflux transporters at the intestinal membrane and which could either be saturated or of no clinical relevance at higher concentrations or doses. 

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... 

Tsuji, A., Tamai, I., Carrier-mediated intestinal transport of drugs, Pharm. Res. 1996, 33, 963-977. 

Tamai, I. [Molecular characterization of intestinal absorption of drugs by carrier-mediated transport mechanisms]. Yakugaku Zasshi 1997, 117, 415-434. 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

Lastly, pharmacogenomics could provide new tools for the design of more specific and active CNS pharmaceuticals. The efficacy of a broad spectrum of neuro-pharmaceutical drugs is often complicated by their inability to reach their site of action because of the BBB. One way to overcome this is to use carrier-mediated transport at the luminal and/or abluminal membranes of the endothelial cells of the BBB. This will provide a physiologically based drug delivery strategy for the brain by designing new chemical entities or fused proteins that can cross the BBB via these transporters. 

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