THE INFLUENCE OF FOOD-INTAKE ON THE EFFECT OF 2 CONTROLLED-RELEASE FORMULATIONS OF FUROSEMIDE

Differences in the urinary excretion rate of furosemide may explain di screpancies observed between the bioavailability and the total diureti c effect of different formulations of this drug. Furosemide was given at a dose of 60 mg as two oral controlled release (CR) formulations (F R and LR), with and without breakfast, in a randomized, four-treatment , four-period, crossover design to 28 healthy volunteers. Urinary volu me, and contents of furosemide and sodium, were measured in samples ta ken over 24h. The extent and rate of absorption of furosemide from FR were decreased after breakfast as compared to fasting: the mean (SD) o f total furosemide excreted decreased from 11.38 (3.12) to 7.73 (1.67) mg, p<0.0001, and the median range) mean residence time increased from 6.3 (4.1-9.3) to 9.5 (5.9-11.8)h, p<0.001. On the other hand, the ext ent of absorption of LR was increased after breakfast, from 8.04 (3.22 ) to 9.45 (1.83) mg, p<0.05, without a significant change in MRT. FR h ad a higher extent and rate of absorption than LR during fasting, but its extent of absorption was lower than that of LR in the postprandial state. Interestingly, the total fraction of furosemide absorbed, as e stimated from total furosemide excretion, was not correlated with the total diuresis (r(2)=0.079) and the differences in drug response compa red among the four periods were much smaller than would be expected fr om the differences in amount absorbed. This discrepancy may be explain ed by differences in urinary excretion rate of furosemide and, related to this, differences in efficiency profiles between the four treatmen ts. Therefore, the urinary excretion profile of a formulation of furos emide may be more important for the cumulated drug effect than the amo unt absorbed.