No abstract

Information on the extent to which xenobiotics interact with P-glycoprotein (PGP) during transit through the intestine is crucial in determining the influence of PGP on oral drug absorption. We have recently described a novel use of isolated ileum from PGP-deficient mdr1a(Ϫ/Ϫ) mice to resolve PGPand non-PGP-dependent drug efflux and provide a definitive measure of intrinsic drug permeability without recourse to inhibitors (Stephens et al., 2002). The present study uses this approach to investigate the impact of PGP on intestinal permeability of paclitaxel and digoxin in different regions of the mouse intestine (jejunum, ileum, and proximal and distal colon). Absorption of paclitaxel and digoxin in tissues from wild-type mice was low and showed little regional variation. In contrast, absorption of both drugs was markedly higher in mdr1a(Ϫ/Ϫ) intestine, although the increase was highly region-dependent, with the ileum and distal colon showing the greatest effect and much smaller changes in the jejunum and proximal colon. These effects were accompanied by the abolition of paclitaxel and digoxin secretion in mdr1a(Ϫ/Ϫ) mice, suggesting that regional variations in intestinal permeability are masked by differential PGP expression, confirmed by immunoblotting studies. Propranolol permeability, which is not influenced by PGP, showed similar regional variation in both wild-type and mdr1a(Ϫ/Ϫ) tissues, suggesting that differences are at the level of transcellular permeability. These data suggest that the ileum and the distal colon are regions of relatively high transcellular permeability for xenobiotics that are compensated by enhanced expression of PGP.

SUMMARY We investigated the possibility that loperamide might influence absorption and secretion in the human jejunum in vivo. Using a triple lumen tube perfusion technique in healthy normal volunteers we showed that loperamide did not affect net absorption of water or electrolytes under basal condition. When secretion was induced by prostaglandin E2, however, loperamide significantly reduced that secretion and in three out of six subjects secretion was abolished. Loperamide was effective when it was given either before or after secretion had been initiated. The results lend support to the suggestion that the antidiarrhoeal activities of loperamide may include an antisecretory effect. screening. The mixing segment was 15 cm long, the test segment 30 cm and the infusion rate 10 ml/min. In basal studies the equilibration period was 40 minutes and the test period one hour. In experiments with prostaglandin E2 (PGE2) the equilibration period was 30 minutes and the test period 40 minutes. During test periods jejunal aspirate from the proximal end of the test segment was collected by suction with a hand held syringe at a rate of 1.5 ml/min. Aspirates from the distal end of the segment were collected by continuous low grade suction. At 15 minute intervals small samples of aspirate were withdrawn and used to measure pH and pCO2 for the calculation of bicarbonate concentration.Two perfusion solutions were used, one contained bicarbonate (Na, 135; K,5; Cl, 105; HCO3, 35; mmolI1) and the other was bicarbonate-free (Na, 135; K,5; Cl, 140; mmol/l). Both perfusates contained polyethylene glycol 4000 (PEG) 2 gm/l and 14C PEG 0 5 ,uCi/l as a non-absorbable marker.Loperamide solution was administered intraluminally as a bolus of 4 mg or 8 mg followed half an hour later by perfusion with a solution containing loperamide (3 mg/l or 6 mg/l). In control periods the same volumes of a placebo solution were given. PGE2 was administered intraluminally by adding it to the perfusate in a final concentration of 5x10-6M.Transit time was assessed by noting the time taken for a 1-5 ml bolus of bromsulphthalein dye (BSP) to pass along the 30 cm segment as previously described. The infusion rate was measured at the beginning and end of the experiment.