The objective of the proposed research is to determine the extent to which coadministered glucose and calcium affect the intestinal absorption of the orally administered anticonvulsant, phenytoin, from solution. Phenytoin possesses a narrow therapeutic range and minor blood level fluctuations can result in dramatic clincial effects with respect to insufficient activity or effective overdosage. While the drug is well absorbed from solution, its poor dissolution and interactions with coadministered substances in the gastrointestinal (GI) tract can significantly affect its absorption. Two of these substances (glucose and calcium) apear to affect interactions at the intestinal membrane from phenytoin solution. Several reports in the literature and preliminary data obtained for this proposal indicate that these interactions are other than effects on solubility. Phenytoin's long-range side effects include changes in glucose and calcium homeostasis. Its mechanism of action in excitable cells appears to involve the drug's binding to membrane protein channels controlling cellular ion transport (specifically sodium and calcium). This binding is enhanced in depolarized cells including those in epileptic foci. The existence of similar membrane proteins involved in nutrient- ion cotransport in the leaky epithelia of the small intestine and ion transport in the tight epithelia of the large intestine suggests phenytoin binding in the GI tract. The extent of this binding will be affected by nutrient and ion transport-induced depolarization of enterocytes. Thus the presentation in the intestinal lumen of certain coadministered nutrients and ions are suspected of altering phenytoin's binding to these intestinal transport proteins resulting in drug absorption effects through a parallel pathway. Isolation of this phenomenon will be done experimentally through rat intestinal perfusion studies since this degree of isolation could most directly link the interaction to clinical significance. However, more isolated in vitro studies including intestinal ring uptake, voltage clamping, and possbily brush-border and inside-out basolateral membrane vesicles as well as isolated cell suspensions may be required to uncouple those ion trnasport processes effecting phenytoin membrane transport. In vivo dog experiments will be used to separate solubility effects from solution- membrane interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS024616-02
Application #
3476718
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1987-04-01
Project End
1992-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Pharmacy
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Stevenson, C M; Kim, J; Fleisher, D (1997) Colonic absorption of antiepileptic agents. Epilepsia 38:63-7
Lu, H H; Thomas, J; Fleisher, D (1992) Influence of D-glucose-induced water absorption on rat jejunal uptake of two passively absorbed drugs. J Pharm Sci 81:21-5
Lu, H H; Thomas, J D; Tukker, J J et al. (1992) Intestinal water and solute absorption studies: comparison of in situ perfusion with chronic isolated loops in rats. Pharm Res 9:894-900
Kou, J H; Fleisher, D; Amidon, G L (1991) Calculation of the aqueous diffusion layer resistance for absorption in a tube: application to intestinal membrane permeability determination. Pharm Res 8:298-305
Fleisher, D; Sheth, N; Kou, J H (1990) Phenytoin interaction with enteral feedings administered through nasogastric tubes. JPEN J Parenter Enteral Nutr 14:513-6
Fleisher, D; Sheth, N; Griffin, H et al. (1989) Nutrient influences on rat intestinal phenytoin uptake. Pharm Res 6:332-7