Barriers, absorption

Aungst, B. J. and H. Saitoh. Intestinal absorption barriers and transport mechanisms, including secretory transport, for a cyclic peptide, fibrinogen antagonist. Pharm. Res. 1996, 33, 114-119. 

Terao, T., Hisanaga, E., Sai, Y., Tamai, I., Tsuji, A., Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier,... 

Lennernas s group at Uppsala has performed extensive studies to confirm the validity of this in vivo experimental set-up at assessing the rate and the extent of drug absorption. Recovery of PEG 4000 (a non-absorbable marker) is more than 95%, which indicates that the absorption barrier is intact. In addition, maintenance of functional viability of the mucosa during perfusion has been demonstrated by the rapid transmucosal transport of D-glucose and L-leucine. Estimation of absorption half-lives from the measured Pefr agree well with half-lives derived from oral dose studies in humans (i.e. physiologically realistic half-lives). Human Peff estimates are well correlated with the fraction absorbed in humans, and served as the basis for BCS development, and hence the technique is ultimately the benchmark by which other in situ intestinal perfusion techniques are compared. The model has been extensively used to... 

II. Nutritargeting as a Way of Bypassing Absorption Barriers A. Digestion and intestinal absorption of fat-soluble 202... 

Energy barriers for internal rotation have been derived, especially during the 1950s, by analyzing (68M12 68M13) microwave spectra of molecules. The method works with molecules with a permanent dipole moment and in the gas phase. Limitations are dictated by the molecular size. The barriers are obtained from rotational energy levels of the molecule as a whole, perturbed by the internal rotor. When different conformers are present in the sample and their interconversion is slower than microwave absorption (barriers smaller than 20 kJ mol can be measured), the spectrum is just a superposition of the lines of the separate species which can be qualitatively and quantitatively determined. 

FIGURE 1.11 A scheme of the various absorption routes across the intestinal epithelium and cellular barriers to xenobiotics absorption. A, Transcellular absorption (plain diffusion) B, paracellular absorption C, carrier-mediated transcellular absorption D, facilitated diffusion E, the MDR and P-gp absorption barrier and F, endocytosis. (From Hunter, J. and Hirst, B.H., Adv. Drug Deliv. Rev., 25, 129, 1997. With permission.)... 

To enhance absorption, it is important to identify the rate-limiting step in this process and to counter the relevant barrier in each case. The possible solutions for the absorption barriers facing lipophilic drug absorption are presented according to their physiological order, i.e., issues concerning the GI lumen (preenterocyte), followed by issues associated with the enterocyte and onward. However, it should be noted that a few concepts affect more than one step of the absorption process. 

Route of Exposure Surface Area (m2) Thickness of Absorption Barrier (pm)b Blood Flow (L/min)... 

The large internal surface area of the small intestine is attributable to its length, folding, and the presence of villi and microvilli within its lumen. The villi contain capillaries and protrude into the lumen of the small intestine. There are approximately four to five million villi in the small intestine. Each villus has many microvilli as its outer surface (Figure 11.3). The microvilli represent the absorptive barrier of the small intestine. The stomach and large intestine do not contain villi and, therefore, have a small absorptive surface area compared with the small intestine. 

The primary purpose of the skin is to serve as a covering that protects the body from the external environment. Compared with the lung and gastrointestinal tract, the skin has much lower surface area and blood flow, as well as a considerably thicker absorption barrier (Table 11.1). Nonetheless, the skin can represent a significant pathway for exposure and absorption. 

For a substance to be absorbed into the body following dermal exposure, it must initially dissolve in the stratum corneum sublayer, then diffuse through the remaining sublayers of the epidermis and into the dermis, where it will eventually diffuse into the blood capillaries. This absorption barrier ranges in thickness from 100 to 1000 pm, depending on area of the body (Klaassen and Rozman, 1991). 

In summary it can be said that there are a lot of possibilities available to overcome the efflux pump-mediated absorption barrier in the intestinal tract. Further, more selective or more potent inhibitors will follow but it has to be carefully decided for each drug or therapy which type or class of inhibitor or efflux pump modulator might be best suited. Also drug delivery systems combining different efflux pump modulating properties have to be investigated in the future. 

Strategies to overcome the absorption barrier focus on the other hand on low molecular mass permeation enhancers (Chapter 5) such as medium chain fatty acids, which can still be regarded as a kind of gold standard. As low molecular mass permeation enhancers are per se rapidly uptaken from the gastrointestinal mucosa, however, the macromolecular drug is to a considerable high extent left alone behind in the gastrointestinal tract. In addition, local and systemic toxic side effects of low molecular mass permeation enhancers cannot be excluded. In contrast, polymeric permeation enhancers (Chapter 6) are simply too big to be absorbed from the GI tract. Consequently, systemic toxic side effects can be excluded. More recently various excipients could be identified as potent efflux pump inhibitors which can be subdivided into low molecular mass efflux pump inhibitors and polymeric efflux pump inhibitors (Chapter 7). Certain polymeric... 

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