Christos Reppas

Effect of hydroxypropylmethylcellulose on gastrointestinal transit and luminal viscosity in dogs

The effects of hydroxypropylmethylcellulose on upper gastrointestinal transit, viscosity, and water flux were studied in six dogs fistulated at the proximal duodenum and/or mid-jejunum. Combinations of different grades of hydroxypropylmethylcellulose were prepared as 2% or 3.3% solutions to yield input viscosities of low (approximately 5000 cp at 37 degrees C and 1 s-1), medium (15,000 cp), or high (30,000 cp) viscosity. Hydroxypropylmethylcellulose modified intralumenal viscosity, with a linear relationship existing between input and lumenal viscosity. With regard to transit, the lag time before the onset of chyme recovery increased linearly as a function of luminal viscosity. There was also a pronounced decrease in the first-order emptying rate constant as lumenal viscosity increased from water to low-viscosity hydroxypropylmethylcellulose, but as viscosity was further increased there was little additional change. These results indicate that water-soluble fibers can exert a significant influence on both the lumenal viscosity and the transit profile in the upper gastrointestinal tract.

Viscosity modulates blood glucose response to nutrient solutions in dogs

The relationship between postprandial blood glucose levels and meal viscosity was studied by adding various combinations of hydroxypropylmethylcellulose to glucose solutions and administering them to female mongrel dogs. Glucose was administered as 5% or 20% solutions in water. Hydroxypropyl-methylcellulose was dissolved in the glucose solutions to yield low (5000 cP measured at 37 degrees C and 1 s-1), medium (15,000 cP) or high (30,000 cP) viscosities. High viscosity hydroxypropylmethylcellulose significantly reduced the maximum blood glucose concentration, Cmax, by 60% (5% glucose meal) and 40% (20% glucose meal) while reducing the area under the blood level vs. time curve (AUC0-3 h) by 40-50%. Medium viscosity hydroxypropylmethylcellulose reduced the Cmax at both glucose levels, but reduced the AUC only for the 5% glucose meal. Low viscosity HPMC lowered the Cmax only after the 5% glucose meal, and had no significant effect on the AUC at either glucose level. The average time to reach maximum concentration, Tmax, was prolonged two- to three-fold at all viscosity levels for the 5% glucose solutions, but was not affected when 20% glucose solutions were administered. It was concluded that hydroxypropylmethylcellulose can effectively retard the absorption of glucose from the gastrointestinal tract, and that the extent of this effect is related to the viscosity of the solution administered.

Longitudinal versus radial effects of hydroxypropylmethylcellulose on gastrointestinal glucose absorption in dogs

Many water soluble fibers have been shown to favorably affect the postprandial glucose profile in humans. Hydroxypropylmethylcellulose (HPMC), a fiber which has been shown to increase glucose tolerance in dogs and noninsulin dependent diabetics, was chosen to study the luminal interactions which mediate this effect. The ability of HPMC to influence upper gastrointestinal (GI) viscosity, transit, and water flux of 5% and 20% glucose solutions was studied in five female dogs fistulated at the proximal duodenum and/or midjejunum. HPMC elevated intraluminal viscosity, with a linear relationship existing between input and luminal viscosity. The ability to modify intraluminal viscosity was greater for isoosmotic (5%) glucose solutions than for hyperosmotic (20%) glucose solutions. HPMC also modified the transit profile of isoosmotic (5%) glucose solutions at midgut by both increasing the lag times before the onset of chyme recovery from 5.5+/-3.1 min to 9-55 min (depending on the viscosity of the administered solution) and decreasing the first-order transit rate constants from 0.115+/-0.07 min-1 to 0.014-0.035 min-1. By contrast, the transit profile of hyperosmotic (20%) glucose solutions was not significantly affected. Net cumulative water flux across the gut wall was not significantly affected in either case by the presence of HPMC. These results, in combination with the amount of glucose recovered from midgut fistula, suggest that following the administration of glucose solutions, HPMC effects on blood glucose levels are mediated by mechanisms which relate to the increased intraluminal viscosity but vary according to the input glucose load. For isoosmotic glucose loads, both the decreased upper GI transit rate and hindered radial movement play a role. Although HPMC modifies glucose absorption from hyperosmotic solutions, this study shows that luminal effects occurring before midgut are modest.

Nutrient effects on intestinal drug absorption.

Abstract The effect of oral co-administration of nutrients on intestinal drug absorption is a function of drug dissolution, gastrointestinal (GI) residence time and intestinal membrane transport. Nutrient effects on GI residence time may influence the availability of the drug for absorption when dissolution is rate controlling; alternatively, nutrient effects on membrane transport pathways may dictate variability in drug absorption when these pathways are rate limiting. This report describes nutrient effects on the absorption variability of the anticonvulsant-antiarrhythmic drug, phenytoin (PHT). Numerous reports, detailing clinical failure to maintain drug plasma levels within the narrow therapeutic index of PHT, haue implicated phenytoin-nutrient interactions as (possibly) causative. Absorption variability due to limited time for drug dissolution during GI transit was studied by measuring PHT plasma concentrations with time following oral dosage in dogs. Variability in intestinal uptake from PHT solutions as a function of nutrient inclusion was studied by measuring steady-state membrane permeabilities from intestinal perfusions and initial-rate uptakes by intestinal rings in rats.