This proposal is directed to the elucidation of mechanisms for transport of pharmacologically active weak electrolytes across the epithelia lining the gastro-intestinal tract. It is suggested that the currently accepted model for these transport processes (the pH partition hypothesis) is an overly simplistic representation of mechanism, and that a more complex, three compartment system is required to fully delineate the characteristics of the transport processes. The proposal includes three types of experiments (1) In vivo studies on the absorption, and secretion of drugs will allow examination of the utility of the three compartment model as a broadly applicable, and fully quantitative description of drug transport mechanisms. (2) In vitro studies on synthetic membranes, and on epithelia will be used to identify, and evaluate the determinants of weak electrolyte permeation. (3) Biophysical, and biochemical approaches will be used to characterize the processes responsible for the establishment of the intra-epithelial pH gradients which are the driving forces for net transport of weak electrolytes across epithelia. The project will focus on the development of physiological, and pharmacological approaches to the regulation of drug transport, and on the roles of the alimentary epithelia as loci of drug interactions. Particular attention will be paid to the significance of the alimentary epithelia in the pharmacokinetics of common drugs of abuse, including the barbiturates, narcotics, and the narcotic antagonists, and to the possibility that modification of the alimentary transport processes may facilitate recovery from intoxication with these substances.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM022369-11
Application #
3271114
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1976-06-01
Project End
1987-08-31
Budget Start
1986-07-01
Budget End
1987-08-31
Support Year
11
Fiscal Year
1986
Total Cost
Indirect Cost
Name
George Washington University
Department
Type
Schools of Medicine
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20052
Moe, A J; Hollywood, J A; Jackson, M J (1989) Proton efflux from rat intestinal basal-lateral membrane vesicles is stimulated by ATP and Na+. Comp Biochem Physiol A Comp Physiol 93:845-50
Moe, A J; Mallet, R T; Jackson, M J et al. (1988) Effect of Na+ on intestinal succinate transport and metabolism in vitro. Am J Physiol 255:C95-101
Moe, A J; Hollywood, J A; Jackson, M J (1988) Weak base binding and transport in pig brush border membrane vesicles. J Pharmacol Exp Ther 246:1012-7
Moe, A J; Jackson, M J (1987) Isolation and characterization of brush border membrane vesicles from pig small intestine. Comp Biochem Physiol A Comp Physiol 88:511-7
Mallet, R T; Jackson, M J; Kelleher, J K (1986) Jejunal epithelial glucose metabolism: effects of Na+ replacement. Am J Physiol 251:C803-9
Mallet, R T; Kelleher, J K; Jackson, M J (1986) Substrate metabolism of isolated jejunal epithelium: conservation of three-carbon units. Am J Physiol 250:C191-8
Shiau, Y F; Fernandez, P; Jackson, M J et al. (1985) Mechanisms maintaining a low-pH microclimate in the intestine. Am J Physiol 248:G608-17
Jackson, M J; Norris, S H (1985) Transport of sodium and chloride across rat gastric mucosa in vitro. J Physiol 360:293-310