Absorption transporter-mediated

The transporter-mediated uptake of drugs into epithelial cells is emerging as a new trend in biopharmaceutics [6]. Utilization of the intestinal epithelial transporters to facilitate the absorption of drugs or prodrugs appears to be an attractive delivery approach. The purpose of this chapter is to describe the pharmaceutical and medicinal relevances of intestinal transporters. This will provide new knowledge for strategies to enhance intestinal absorption of drugs. 

Characteristically, within certain concentration limits, if a chemical is absorbed by passive diffusion, then the concentration of toxicant in the gut and the rate of absorption are linearly related. However, if absorption is mediated by active transport, the relationship between concentration and rate of absorption conforms to Michaelis-Menten kinetics and a Lineweaver-Burk plot (i.e., reciprocal of rate of absorption plotted against reciprocal of concentration), which graphs as a straight line. 

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... 

Drug absorption occurs from the site(s) of drug absorption (e.g., gut, lung, nasal epithelium) by either active (e.g., transport mediated) or passive mechanisms. The bioavailability (F) of a drug is the fraction that reaches the systemic circulation and is ultimately avail-... 

Peng, J. B., Chen, X. Z., Berger, U. V., Vassilev, P. M., Tsukaguchi, H., Brown, E. M. and Hediger, M. A., 1999, Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J Biol Chem 274, 22739—46. 

Kikuchi A, Nozawa T, Wakasawa T, et al. Transporter-mediated intestinal absorption of fexofenadine in rats. Drug Metab Pharmacokinet 2006 21 308-314. 

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.

Troutman MD, Thakker DR. Efflux ratio cannot assess P-glycoprotein-mediated attenuation of absorptive transport asymmetric effect of P-glycoprotein on absorptive and secretory transport across Caco-2 cell monolayers. Pharm Res 2003 20(8) 1200-1209. 

When the absorption is mediated by active transporters that are capacity limited, sustained presentation of the drug to the transporting enzymes may increase the efficacy of the transport and thus improves bioavailability. 

Intestinal absorption of dietary iron. Ferrous iron is absorbed by the duodenal villus tip enterocytes mediated by divalent metal transporter-1 (DMTI). Iron transport mediated by DMTl of the apical surface and the basolateral tran.sporter at the basolateral surface are coupled to ferric reductase and ferroxidase that change the iron oxidation state, respectively. The degree of iron entry is determined by the level of DMTl and its level of expression is programmed in the crypt cells. The programming of the crypt cells is coupled to the body iron stores via transferrin-mediated and HFE protein-modulated iron transport. [Modified and reprinted with permission from B. R. Bacon, L. W. Powell,... 

Increasing its oral absorption this could occur if the perpetrator slowed intestinal metabolism of the victim or blocked transporter-mediated efflux of the victim back from intestinal epithelial cells into the lumen of the intestine... 

The SLC transporters mediate either drug uptake or efflux, whereas ABC transporters mediate only unidirectional efflux. Asymmetrical transport across a monolayer of polarized ceUs, such as the epithelial and endothelial cells of brain capillaries, is called vectorial transport (Figure 2-5). Vectorial transport is important in the efficient transfer of solutes across epithelial or endothelial barriers it plays a major role in hepatobiliary and urinary excretion of drugs from the blood to the lumen and in the intestinal absorption of drugs and nutrients. In addition, efflux of drugs from the brain via brain endothelial cells and brain choroid plexus epithelial cells involves vectorial transport. 

There are many possible reasons for the non-appearance to date of successors to cromoglycate and it could be that there is a different reason or set of reasons for each individual compound. Problems of absorption, transport, distribution or metabolism may play more or less important roles in different cases. It may be that inhibition of mediator release is not the most important factor in the clinical effectiveness of cromoglycate. Most of the effort devoted to antiallergic research has assumed that inhibition of mediator release was the sole requirement of an effective prophylactic drug for allergic asthma. Only the next... 

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... 

Dimethyl sulfoxide (DMSO) may be harmful by inhalation or skin absorption. Wear appropriate gloves and safety glasses. Use in a chemical fume hood. DMSO is also combustible. Store in a tightly closed container. Keep away from heat, sparks, and open flame. DMSO easily penetrates the skin and is added as a transport mediator in some creams. This property makes it a carrier for other substances thus potentiating their risks. 

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