Effect of indomethacin on the metabolic and hormonal response to a standardized breakfast in normal subjects.

We have investigated the influence of a single oral administration of indomethacin on blood glucose, plasma free fatty acids (FFA), alpha-amino-nitrogen, insulin and glucagon concentrations in young healthy subjects. Two groups of 6 subjects were studied, the first received a standardized 500 kcal mixed meal without any previous drug administration (controls) whereas the second group received 50 mg indomethacin 2 h before ingesting an identical meal. Plasma indomethacin concentration reached its maximum (2.36 +/- 0.36 micro g/ml) 15 min after administration and declined to 0.45 +/- 0.04 micro g/ml after 2 h. Indomethacin ingestion was followed by a significant increase in blood glucose and plasma FFA reaching their maximum value at 45 min and returning to basal levels at 120 min. No simultaneous changes in plasma alpha-amino-nitrogen, insulin or glucagon levels were detected during this period. The meal was followed by a rise in blood glucose and plasma insulin as well as by a decrease in plasma FFA concentration. No significant differences were detected between the controls and the subjects receiving indomethacin. In controls, the meal was followed by a rise in plasma alpha-amino-nitrogen and a modest although significant increase in glucagon levels. In indomethacin-treated subjects, the increment of alpha-amino-nitrogen was less marked and the increase in plasma glucagon was not observed. Thus, indomethacin by itself can exert several metabolic effects; however, it does not deteriorate the blood glucose or insulin profile after a regular meal. The present work is the first to demonstrate that an inhibitor of prostaglandin synthesis inhibits the plasma glucagon rise occurring after a physiological stimulus such as a normal meal. On the basis of previous in vitro experiments, we suggest that this effect results from an inhibition of glucagon secretion by the PG synthesis inhibitor.

Micellar solubilisation of corticoids by nonionic surfactants.

Summary The availaibility of a drug in the presence of surfactants depends on the amount of free drug in solution. In previous work (1), we tried to measure the amount of free corticoïds (Dexamethasone, Fluprednylidene 21 - acetate and Betamethasone 17 - valerate) in topical preparations containing various amounts of non-ionic surfactants (ethers of polyoxyethyleneglycol. With this aim, experiments have been carried out to characterise the nature of the interaction between these drugs and the surfactants. We have studied the micellar solubilisation of the three steroïds by means of solubility measurements. From the results obtained, we have calculated the solubilising capacities of surfactants expressed on molar basis and we can assume that solubilisation probably takes place in the inner part of micelles. Calculations of solubility ratios (R) as a function of the percentage of surfactant enable determination of a binding capacity of the surfactants for the drugs. This value is a constant independent of the concentration of the surfactants. If the distribution law is obeyed, the interaction can also be expressed by a partition coefficient calculated from the results of the solubility measurements. To verify whether the distribution law really applies and if the interaction is independent of the amount of free drug in solution, we have employed, for Dexamethasone, the methods of equilibrium and differential dialysis.