FOOD-INTAKE AND THE PRESYSTEMIC METABOLISM OF SINGLE DOSES OF AMITRIPTYLINE AND NORTRIPTYLINE

The influence of food on presystemic metabolism of single doses of ami triptyline (AMI) and nortriptyline (NT) was examined. In randomised or der 25 mg tablets of each drug was given to 9 healthy, female voluntee rs bath in the fasting state and together with a standardised breakfas t. Concentrations of the drugs and of their dealkylated, hydroxylated and conjugated metabolites were measured by gas chromatography - mass spectrometry (AMI experiment) or high-pressure liquid chromatography ( NT experiment). Standard pharmacokinetic parameters were calculated. F ood intake did not consistently or significantly influence the bioavai lability of either AMI or NT, nor the demethylation of AMI, nor the hy droxylation or the primary or secondary conjugation of NT. There were large interindividual changes in AUC of AMI after food (+94% to -44%). A significant negative correlation between AUC of AMI but not of NT d uring fasting conditions and per cent change in AUC after food was fou nd (r = -0.72, P = 0.029). The implication of this (negative) correlat ion for an individual patient might be to keep the intake of the drug in standardised relation to food to avoid undue heavy changes in drug concentration, which might just occur with a change in time relation b etween intake of drug and food. From a mechanistic view the results ar gue against a direct and selective influence of food on the presystemi c oxidation and conjugation of weakly basic drugs but does not exclude that food may reduce the presystemic metabolism of some such drugs in directly, by enhancing their rate of hepatic delivery. Presentation of data from food interaction studies should not be restricted to genera l descriptions. It seems equally important to present the variability of individual data to allow inspection of the extent and direction of effects. This should be of interest for patient, prescriber as well as the regulatory agency. (C) Elsevier, Paris.