Age-dependent alterations of intestinal absorption. I. Theoretical aspects

To test the absorption of orally administered d-xylose in the upper small intestine its concentration in the blood plasma must be measured. Absorption is determined as a function of time by subtraction of the blood values found after intravenous administration, which would indicate the rates of metabolism and extraction of xylose by the body. It is suggested that comparison with the behavior of a proposed four compartment model may give a biological interpretation of the results.The possible dependence of amount and rate of absorption can be determined if the same time after feeding of the same diet is used in each absorption measurement. It is suggested that the time point to be used for administration be that time at which the highest concentration of xylose in the peripheral blood is found.     

Alpha glucosidase inhibition in the treatment of non-insulin-dependent diabetes mellitus

Two studies of the new alpha-glucosidase inhibitor, miglitol, in patients with non-insulin-dependent diabetes mellitus (NIDDM) are reported. In the first, 13 patients, poorly controlled on sulphonylureas, received miglitol 50mg three times daily for 4 weeks. Post-prandial blood glucose was reduced after breakfast, lunch, and tea compared with placebo (p less than 0.05-0.01) but there was no improvement in fasting blood glucose, serum fructosamine or haemoglobin A1. In a dose-response study the effect of a single dose of miglitol (0,50,100,150 or 200mg) on post-prandial glycaemia after a test breakfast was assessed in 20 patients with mean +/- SEM fasting blood glucose 9.9 +/- 0.4 mmol/l. With 50mg miglitol, there was a significant reduction in blood glucose from 30 to 120 min post-prandially compared with placebo. Increasing doses of miglitol further depressed the post-prandial rise in blood glucose and with 200mg there was no significant change from fasting levels. Side-effects were limited to flatus and loose stools particularly with the higher doses but were not severe. Miglitol effectively reduces post-prandial blood glucose rise in NIDDM with as little as 50mg but there is considerable individual variation. Larger doses may be necessary in patients already poorly controlled on sulphonylureas.     

Motility- and blood flow-dependent absorption of amino acids in canine small intestine.

A relationship between L-phenylalanine and L-serine absorption, intestinal motility and blood flow has been studied with a canine in situ isolated jejunal loop in acute experiments and in chronic preparations in conscious dogs. During spontaneous rhythmic contractions, as well as after mechanical and pharmacological stimuli, rhythmic changes in blood flow, related to intestinal contractions, were observed. They had no bearing on mean blood flow or absorption as long as they did not occur together with tonic contractions. The tonic contractions resulted in a prolonged decrease in jejunal blood flow ano diminished amino acid absorption rate. Absorption and motility index, as well as blood flow and motility were negatively correlated. There was a positive rectlinear correlation between intestinal blood flow and absorption, regardless of whether changes in blood flow resulted from the increase in motility or were induced by intestinal artery occlusion. These correlations suggest that changes in amino acid absorption during increased motility depend on changes in blood flow. This relationship may be important in clinical syndromes with hypermotility.     

Inappropriate use of the law of corresponding areas to calculate the time course of absorption for multicompartmental systems

From the law of corresponding areas, Dost has derived a simple method for calculating the percentage absorbed of a drug during an entire period of treatment. The method utilizes a graphical procedure to determine the fraction of a dose absorbed at each time point, when data are available following oral and intravenous administration of the drug. The method has been suggested for use with drugs whose kinetics are described by single and multicompartment systems. The method is valid for single-compartment body systems and can be shown to be the graphical equivalent of the well-known Wagner-Nelson method. However, it can be proved mathematically that the graphical method will not yield correct answers for multicompartment body systems. Here, for identical plasma concentrations following oral and intravenous administration of the same dose, the amount of drug in the peripheral compartment(s) will always be greater following intravenous administration than after oral administration (during the absorption phase). Therefore, areas under the curve calculated from shifted intravenous curves will always overestimate the amount absorbed. Analog and digital computer simulations illustrate the mathematical treatments.Supported in part by Grant GM 16496 from the National Institutes of Health.Presented in part at the Sixth International Congress of Pharmacology, IUPHAR, July 20–25, 1975, Helsinki, Finland.This paper was submitted to a Consulting Editor who served as a Journal Editor during its review process.During the course of this study, Dr. Galeazzi was a Fellow of the Swiss National Science Fund.     

Comparison of intestinal absorption of cholesterol with different plant sterols in man*

Abstract. Intestinal absorption of cholesterol, campes-terol, campestanol, stigmasterol and sitosterol were measured in 10 healthy subjects by an intestinal perfusion technique over a 50 cm segment of the upper jejunum using sitostanol as non-absorbable marker. Cholesterol absorption was highest and averaged 33%, whereas the absorption rate of sitosterol averaged 4.2% and of stigmasterol 4.8%. Higher absorption rates were found for campesterol (9.6%). Canipestanol, the 5a saturated derivative of campesterol, showed the highest absorption rate (12.5%) of all plant sterols. A positive correlation between the absorption rate of cholesterol and campesterol was established. In addition, there was a negative correlation between the ratio of sitosterol to cholesterol and the mass of cholesterol absorption. These results are in agreement with previous observations in animal studies, namely, that increasing the length of the side-chain of cholesterol decreases the absorbability of the sterol. Surprisingly, campestanol, the 5α saturated derivate of campesterol, was shown to have higher absorbability compared with its unsaturated compound. This finding is in contrast to previous assumptions, that hydrogenisa-tion of the nucleus double bond of a sterol causes a decrease of absorbability, as has been demonstrated for cholesterol/cholestanol and sitosterol/sitostanol.     

Effect of Methotrexate on Drug Absorption from the Rat Small Intestine in Situ and in Vitro

Abstract The effect of methotrexate (20 mg/kg intramuscularly) on the absorption of phenobarbitone, sulphafurazole, mecamylamine, quinidine and isoniazid from the rat small intestine was studied in situ and in vitro. The disappearance of all drugs studied from the intestinal fluid in situ was retarded on the third day after methotrexate administration. The fluid transfer and the amount of drugs passed through the intestinal wall in vitro were also decreased. The absorption of phenobarbitone was reversible within six days, whereas the absorption of quinidine was still retarded on the sixth day after methotrexate administration. Methotrexate did not modify the amount of quinidine excreted into the intestinal lumen after intravenous administration. The levels of other drugs except isoniazid in the blood at the end of the experiment showed changes corresponding to their disappearance from the intestinal lumen. In situ the drug levels in the intestinal wall were much lower than in vitro. Their levels in the intestinal wall reflected drug absorption in vitro but not in situ. The methotrexate-induced reversible decrease in absorption seems to be attributable at least partly to diminished water flux through the intestinal wall, although other mechanisms may also exist.     

THE AVAILABILITY OF FOOD FOLATE IN MAN

Availability for absorption of folate in 12 foodstuffs and five folate derivatives was studied by measurement of urinary folate excretion in normal subjects who were kept in a fully saturated folate state during the period of study.     

Clinical use of a bio-assay of serum digitoxin activity

Summary In 73 patients on digitoxin maintenance medication a progressive increase of mean serum digitoxin activity was found with increasing dose. However, there were considerable variations within each group. Change of dose was followed by a new steady state level close to that predicted by zero order absorption-first order elimination kinetics of the drug. In atrial fibrillation the expected fall in ventricular rate was always observed with increasing serum concentration. No significant difference in serum level was found 24 h after identical peroral and intravenous doses had been given to different groups of patients. However, significantly higher serum values were found in normal subjects than in patients with heart disease after identical peroral treatment. This probably indicates poorer absorption by the patients. In 13 subjects, the estimated serum digitoxin half-lives were 3.7 to 11.3 days. These large differences may explain much of the variation in serum values found during steady state therapy. The elimination curves were in accordance with a first order drug kinetics. Only three patients with definite digitalis intoxication were seen, all of whom had high serum values which did not overlap patients without features of intoxication. The results showed that several patients on maintenance therapy were under-digitalized. It is hoped that this or similar methods may make it possible to adjust individual treatment to compensate for differences in absorption, distribution and elimination, and thereby to increase the benefits and decrease the risks of toxicity of digitoxin therapy.     

A novel per-oral insulin formulation: proof of concept study in non-diabetic subjects.

AIMS: The aim of our study was to examine the absorption of insulin from the gastrointestinal (GI) tract, using a novel oral formulation-adding a delivery agent SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate) in combination with insulin. METHODS: Capsules containing insulin and SNAC, in various combinations, were administered orally, as a single dose, to 12 non-diabetic subjects and four control subjects (receiving SNAC or insulin only) in order to assess its biological effect and safety. Plasma glucose levels, insulin and C-peptide concentrations, as well as SNAC levels, were determined, at timed intervals up to 4 h. RESULTS: In all cases, a glucose-lowering effect was demonstrated, preceded by an increase in plasma insulin levels. The nadir of plasma glucose levels appeared after 30-50 min, following the ingestion of the mixture. The plasma insulin levels were found to parallel the blood SNAC levels. Plasma C-peptide levels were suppressed by the lowered glucose levels achieved concurrent with the increasing amount of exogenous insulin absorbed, indicating that the secretion of endogenous hormone was partially abolished. There were no biological effects regarding blood glucose levels upon administration of SNAC or insulin when given alone. No adverse effects were detected during the trial or several weeks after the trial. CONCLUSIONS: Insulin in combination with a novel delivery agent, SNAC, given orally, is absorbed through the GI tract in a biologically active form. This was demonstrated by a glucose lowering effect of the mixture as well as a suppression of an endogenous insulin secretion.