Absorption potentiation mechanisms

The Evolving Role of the Caco-2 Cell Model to Estimate Intestinal Absorption Potential and Elucidate Transport Mechanisms... 

Caco-2 cells have been valuable in the estimation of drug absorption potential, transport mechanisms, and effect of permeation enhancers on transepithelial transport.35,39,53,67-69,78-81 Owing to the sensitivity of the cells and the limited solubility of new molecular entities, Caco-2 permeability studies are routinely done with relatively low concentration of compounds. One way to increase the solubility of these compounds is to use organic solvents. The low tolerability of Caco-2 cells to organic solvents limits the use of this approach in permeability studies. 

Complementary use of PAMPA and Caco-2 cells for evaluation of absorption potential. PAMPA measurements are used to discard compounds with clear absorption problems whereas Caco-2 cells would be used to evaluate mechanisms of permeation or reasons for low permeation. It is highly unlikely that PAMPA measurements would be used to select compounds to be tested in vivo. 

Compounds can cross biological membranes by two passive processes, transcellu-lar and paracellular mechanisms. For transcellular diffusion two potential mechanisms exist. The compound can distribute into the lipid core of the membrane and diffuse within the membrane to the basolateral side. Alternatively, the solute may diffuse across the apical cell membrane and enter the cytoplasm before exiting across the basolateral membrane. Because both processes involve diffusion through the lipid core of the membrane the physicochemistry of the compound is important. Paracellular absorption involves the passage of the compound through the aqueous-filled pores. Clearly in principle many compounds can be absorbed by this route but the process is invariably slower than the transcellular route (surface area of pores versus surface area of the membrane) and is very dependent on molecular size due to the finite dimensions of the aqueous pores. 

A negative imaginary potential in the time-independent Schrodinger equation absorbs the particle flux, thus violating the law of conservation of flux, which is satisfied for real potentials [12,13]. Then, the quantum electrodynamical phenomenon of pair annihilation can be represented by particle loss due to an effective absorption potential H = —zVabs since the exact mechanism of positron loss is totally irrelevant to the study of the atomic processes in consideration [9,10,14-16]. The only important aspect of pair annihilation for the present purpose is the correct description of the loss rate. The absorption potential H is proportional to the delta function 5 (r) of the e+-e distance vector r (Section 4.2). 

Pair annihilation of a positron e+ and an electron e by y-ray emission was briefly explained in Section 1.3. There, the hydrogen-like system ePe, or positronium Ps, was described quantum mechanically as a QBS having a finite lifetime r because of an absorption potential —z Vabs- This potential also causes positron flux loss, or positron absorption, in collisions with atoms. 

A number of kinetic models are available to attempt to explain the potential mechanisms of hydrogen absorption and desorption from MgH2 (Barkhordarian et al., 2006 Mintz and Zeiri, 1995). The equations for the models are ... 

Medicinal chemists have tended to avoid the aromatic nitro group as a structural component of potential drugs because of the well-known ability of compounds such as trinitrotoluene (TNT), used in munitions, to cause a high incidence of methemoglobinemia following skin absorption. The mechanism involved is presumably in vivo reduction to nitroso and phenyl-hydroxylamine intermediates. However, many nonbenzenoid nitro compounds have been utilized in clinical practice since the introduction of the nitrofuran drugs in 1944. 

At a fundamental level, a determination must be made whether a biological mechanism for an interaction exists. The most common pharmacokinetic mechanisms include metabolic inhibition or induction, protein binding displacement, and interference with absorption. Potential pharmacodynamic synergy or antagonism must also be considered. Interactions must be considered from the perspective of... 

Not fully understood. Changes in gastric pH caused by the antacid, and retarded gastric motility have been suggested as potential mechanisms. An in vitro study showed no absorption interaction occurred between cimetidine and antacids. ... 

The potential mechanisms of anthocyanin glycosides absorption in the small intestine may involve a specific glucose transporter, such as SGLTl, as previously suggested for the flavonoids [74]. 

---