The time course of delivery of furosemide into urine: An independent determinant of overall response

Abstract

After an oral or intravenous dose of furosemide, there is considerable interindividual variability in the amount of unchanged drug delivered into the urine. On average, approximately half as much reaches the intraluminal site of action with an oral compared to an intravenous dose. However, the natriuretic response to the same dose administered by either route is virtually the same. Similarly, after pretreatment with probenecid, the same total amount of furosemide in urine causes a greater overall response. It has been presumed that this paradox is accounted for by differences in rate of delivery of furosemide to the active site such that after an oral dose, or after pretreatment with probenecid, amounts of drug are for longer periods of time at the "steep" portion of the dose-response curve. Our analysis shows this not to be the case. For furosemide, the "slope factor" of the dose-response curve is such that the amount of diuretic delivered into the urine which is maximally efficient (21.5 micrograms/min) is considerably less than the amount causing half-maximal response (69.8 micrograms/min). Oral administration or pretreatment with probenecid maintains drug close to this maximally efficient amount more persistently than does intravenous administration. By so doing, total response to an oral dose approaches that of intravenous dosing despite delivering half the amount of drug to the active site, and after probenecid an intravenous dose causes a greater response than intravenous dosing alone despite delivering the same amount of drug to the active site. These data emphasize the importance of the time course of delivery of drug to the active site as an independent determinant of overall response.

Analysis of the natriuretic action of a loop diuretic, piretanide, in man.

“…In order to explain some of the unexpected observations seen by various groups (Branch, 1983;Chennavasin et al, 1979;Dixey et al, 1988;Homeida et al, 1977;Honari et al, 1977), terms such as 'time course of delivery' of drug and the concept of 'maximally efficient dose' have been introduced as important determinants of the overall diuretic response (Kaojarern et al, 1982). Using these terms it was possible to explain why there was a biphasic response, with an initially reduced sodium excretion followed by a subsequent increase; the result was a greater overall natriuretic response to intravenous frusemide, in the presence of probenecid.…”

Use of Emax model in diuretic studies [letter; comment]

“…A similar observation has also been reported when comparing bolus vs steady state infusion of the same dose of frusemide over 8 h (Lee et al, 1986) but without resorting to the Em. model or the concept of 'maximally efficient' dose (Kaojarern et al, 1982) employed by Alvan et al (1990) in their report. The model has however often been used without fully understanding the function of the parameters employed especially the exponential factor, s. The shape of the curve will determine the value of the exponential factor (s) such that a steeper response curve at low doses and a shallower curve at higher doses will generate an exponential factor whose value is low.…”

“…(1990) and Kaojarern et al (1982). The value of the logistic Ems,, may approach the sigmoid Em., but only if Eo (the basal response) approaches or equals zero.…”

The validity of the sigmoid Emax model and efficiency concept in diuretic studies [letter]

“…Alvan etal., 1990;H et al, 1985;Kaojarern et al, 1982). M arguments partly incorrect and sometimes obvious.…”

“…The maximally efficient concentration mathematically found at [C0o% (s-i)] /s as Kaojarern et al (1982) The clinical efficacy of oral sustained release nitroglycerin (GTN) in the prophylactic management of stable angina is recognised (Davidov & Mroczek, 1977;Winsor & Berger, 1975), although there is little correlation between systemic GTN concentration and effect.…”