Adrenoceptor influences on fluid and electrolyte transport in the rat intestine

An investigation of rat jejunal and distal colonic electrolyte transport in-vitro was undertaken using an Ussing chamber prepartion. Selective α2-adrenoceptor stimualtion in the jejunum was found to depress theo-phylline elevated anion secretion, as evidenced by decreases in short- circuit current (SCC). or α1 -Adrenoceptor stimulation, after α2 -adrenoceptor antagonism in the jejunum, evoked transient increases in basal anion secretion, as reflected by transient increases in basal SCC. The use of the neurotoxin tetrodotoxin indicated that this was a direct epithelial secretory effect. 5-hydroxytryptamine (5-HT) on the jejunum elicited transient increases in basal anion secretion, as demonstrated by transient increases in basal SCC. The use of tetrodotoxin, reserpine and α1 -adrenoceptor antagonists, indicated that a major component of this epithelial secretory effect by 5-HT, was associated with activation of intramural nervous pathways of the sympathetic nervous system, ultimately stimulating α1-adrenoceptors. This might represent an important secretory mechanism by 5-HT in the jejunum. β2-Adrenoceptor stimulation in the distal colon was found to decrease basal SCC, as evidenced by the metoprolol resistant effect of the selective β2- adrenoceptor agonist salbutamol, and lack of effect of the selective β1-adrenoceptor agonist prenalterol. An investigation of rat distal colonic fluid and electrolyte transport in-vivo was undertaken using an colonic loop technique. Although a basal colonic absorption of Na+ and Cl-, and a secretion of K+ were observed, these processes were not under tonic α-adrenergic regulation, as evidenced by the lack of effect of selective α-adrenoceptor antagonism. The secretory effects of prostaglandin-E2 were inhibited by α-adrenoceptor activation, whereas such stimulation did not evoke pro-absorptive responses upon basal transport, unlike noradrenaline.

Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution.