Transport jejunal

Free folate, released by conjugase action, is absorbed by a carrier-mediated mechanism in the jejunum. However, the folate in milk is mainly bound to a specific binding protein (which has been used in radioligand binding assays for folate) the protein-folate complex is absorbed intact, mainly in the ileum, by a mechanism that is distinct from the jejunal transport system for free folate. The biological avculability of folate from milk, or of folate from diets to which milk has been added, is considerably greater than that of unbound folate, whereas that of folate from cereal foods, or of free folic acid taken with cereal foods, is lower. 

The lengthy permeability chapter (Chapter 7) recounts the study of many different artificial membrane formulations, comparing transport results of each to human jejunal permeabilities. A very promising in vitro screening system was described the double-sink sum-Pe PAMPA GIT model. It is most applicable to molecules that are classified as soluble in the BCS scheme. 

The jejunal perfusion approach generates data which may be used to predict absorption/bioavailability and to establish in vivo-in vitro correlation (IVIVC) even for extended release (ER) products. If a dmg is transported mainly by passive diffusion and has a jejunal Peff higher than metoprolol (1.5 x 10-4 cm s 1 = high-permeability compound), it can be expected to be completely absorbed throughout the small and large intestine [5, 46]. 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

The 5-HT4 receptors modulate the activities of channels and transporters by increasing cAMP levels. These include activation of L-type Ca2+ channels (326), chloride currents in human jejunal mucosa and rat distal colon (330,331), and the If pacemaker current in atrial myocytes (332) and stimulation of aldosterone release from the adrenal glands (333,334), striatal dopamine release (324), hippocampal and frontal cortex acetylcholine release (335,336), and hippocampal 5-HT release (337). 5-HT4 receptors also inhibit various channels, including a KV3.2-like delayed rectifier K+ channel (303), a voltage-activated K+ channel in colliculi neurons (320,338), a Ca2+-activated, afterhyperpolariz-ing, and K+ current in hippocampus (325). 

Sugawara M, Iseki K, Miyazaki K, Shiroto H, Kondo Y, Uchino J. Transport characteristics of ceftibuten, cefixime and cephalexin across human jejunal brush-border membrane. J Pharm Pharmacol 1991 43(12) 882-4. 

Maenz DD, Forsyth GW (1986) Cholera toxin facilitates calcium transport in jejunal brush border vesicles. In Can.J. Physiol. Pharmacol. 64 568-574. 

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