Absorption, drug across intestinal epithelium

Figure 2 Apically directed P-gp-mediated efflux of drugs across intestinal epithelium and synergistic interactions of P-gp with CYP3A4 in attenuating the absorptive transport. Heavy arrows versus light arrows indicate relative magnitudes of the flux. This exemplifies an elimination mechanism that a dual substrate of P-gp and CYP3A4 may encounter in the enterocyte. Conceivably, the metabolite may or may not be a substrate for P-gp (as drawn, it is a substrate). Abbreviation P-gp, P-glycoprotein.

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.)... 

Wetting agents can also affect the absorption of drugs. For example, the common pharmaceutical wetting agent, sodium dodecyl sulfate, has been shown to increase the absorption of drugs and peptides across the human intestinal epithelium. Studies have confirmed that such agents enhance absorption via the paracellular pathway. 

Systemic bioavailability is the product of fraction of dose absorbed (/a), fraction of dose escaping gut metabolism (/g), and fraction of dose escaping first-pass metabolism (F ). Permeability class is based upon /a, which may be estimated either in vivo or in vitro by direct measurement of mass transfer across human intestinal epithelium. In vivo methods include (i) mass balance studies using unlabeled, stable-isotope labeled, or a radiolabeled drug substance (ii) oral bioavailability using a reference intravenous dose or (iii) intestinal perfusion studies either in humans or an acceptable animal model. Suitable in vitro methods involve the use of either excised human/animal intestinal tissues or cultured epithelial monolayers. All of these methods are deemed appropriate for drugs whose absorption is controlled by passive mechanisms. 

Drugs are transported in the aqueous phase of blood plasma. To have an effect, drugs must enter cells or reach cell membrane receptors. All aspects of the absorption, distribution, biotransformation and elimination of drugs involve transfer across cell membranes. Other barriers, including multiple layers of cells (e.g. the intestinal epithelium or epidermis), also exist. 

Figure 9.14 The effective permeabilities (Pefr, different clinically relevant concentrations to mean SD) of cimetidine in human jejunum at investigate saturation in any carrier-mediated two clinically relevant luminal concentrations. transport across the intestinal epithelium. No The rate and extent of intestinal absorption of difference in Pefr values between the two cimetidine have been widely discussed, and Fa concentrations was noted, and, togetherwith the for this drug has been estimated at around observation that human permeability in vivo is 75% [90, 91], It has been reported that cimetidine similar to permeability in the Caco-2 model (with is a substrate for both P-gp and/or organic cation low expression of carrier proteins), this suggests transporters (OCNT1 and OCNT2) [82, 92], We that passive diffusion is the dominant determined the human jejunal in vivo Pe - at two mechanism even for cimetidine [82],...

Drugs can cross the intestinal epithelial barrier in a number of ways. They may permeate either through the cell (transcellular) or between adjacent cells (para-cellular). Enterocytes have tight intercellular junctions that restrict paracellular transport to small hydrophilic molecules.7 These cells possess active and facilita-tive transporters for nutrients, as well as an array of efflux transporters [e.g., P-glycoprotein (P-gp) and related transporters] and enzymes (e.g., cytochrome P450 type 3A4) that restrict transcellular absorption. Transcytotic transport of macromolecules is possible, but compounds are often destroyed in lysosomes. With the exception of M-cells, transcytosis is not considered a major mechanism of the transcellular pathway for absorption of macromolecules across gastrointestinal epithelium.6... 

It is apparent that no single method is sufficient for studying or predicting drug absorption across the intestinal epithelium.6 Consequently, simple algorithms based on physicochemical values are only marginally successful in predicting permeability, but the use of Caco-2 data increases predictive capabilities.20 Thus, Caco-2... 

Drug distribution in such sites or compartments is a complex process that depends on the systemic circulation concentration and subsequent passage across single cell endothelial or epithelial membranes with specialized physical and molecular barrier functionality. For certain orally administered AIDS medications (e.g., zidovudine and didanosine), oral absorption is limited because of poor absorption from the G1 tract, enzymatic biotransformation in the intestinal epithelium, or first-pass effects (Sinko et al., 1995, 1997). For other AIDS drugs (e.g., protease inhibitors), oral absorption may be complete however, drug distribution into the brain is limited by drug efflux proteins, which promiscuously interact and translocate lipophilic substrates back into blood as they diffuse into the BBB endothelium (Edwards et al., 2005 Kim et al., 1998). 

Quatemized derivatives of chitosan, obtained by introducing various alkyl groups to the amino groups of chitosan molecule structure, were extensively studied for oral insulin delivery [135]. These derivatives are drastically more soluble in neutral and alkaline environments of the intestine and, hence, are more efficient than chitosan for drug delivery and absorption across the intestinal epithelium of the jejunum and ileum. TMC is prepared by reacting chitosan with trimethyliodide... 

Oral delivery is desirable due to the ease of administration, lower cost, and increased patient compliance. Despite these advantages, oral delivery of macromolecules is challenging due to low penetration across the intestinal epithelial barrier. To circumvent these barriers, drugs have been attached to mac-romolecular carriers such as dendrimers that can potentially aid in absorption across the intestinal epithelium. PAMAM dendrimers are effectively transported across epithelial barriers (Wiwattanapatapee et al. 2000 El-Sayed et al. 2002 Kitchens et al. 2006). SN-38, a potent anticancer drug, when complexed with PAMAM dendrimers showed increased solubility and uptake by Caco-2 cells (Kolhatkar et al. 2008). Orally administered anti-inflammatory drug ketoprofen in the form of PAMAM complexes (Man et al. 2006) prolonged activity and increased bio availability with a sustained release profile. 

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