Influence of renal insufficiency on the pharmacokinetics of cicletanine and its effects on the urinary excretion of electrolytes and prostanoids.

Abstract

1 The kinetics of a single oral dose (300 mg) of cicletanine a new antihypertensive drug with diuretic properties, and its effects on the urinary excretion of electrolytes and of the major stable metabolites of prostacyclin and thromboxane A2 were studied in patients with normal renal function (n = 6), mild (n = 9) and severe (n = 10) renal insufficiency. 2 In normotensive subjects with normal renal function, cicletanine was rapidly and regularly absorbed, its apparent elimination half-life established around 7 h, and both its renal clearance (0.4 ml min-') and its cumulative renal excretion (0.85% of the administered dose), were low. Mild renal insufficiency did not significantly alter these parameters, while severe renal impairment reduced the renal clearance and the cumulative urinary excretion of cicletanine and increased its apparent elimination half-life (31 h). However the area under the plasma curve was not changed due to reduced plasma concentrations in these patients. 3 Cicletanine induced a rapid and marked (four fold as a mean) increase in the urinary excretion of water, sodium and potassium which lasted for 6 to 10 h, in subjects with normal renal function. Renal insufficiency did not alter the slope of the calculated plasma concentration-effects curves but reduced the maximum effect observed for water, sodium and potassium. 4 A single oral dose of cicletanine did not change the urinary excretion of 6-ketoprostaglandin Fla and thromboxane B2 in the three groups of patients studied, the basal values of which being found to be closely related to the creatinine clearance. 5 It was concluded that i) from a pharmacokinetic view point, the dosage of cicletanine should only be slightly reduced in patients with a glomerular filtration rate below 30 ml min-', ii) as with most of the diuretic agents, its natriuretic properties were markedly decreased in these patients and iii) an alteration in the renal synthesis of prostacyclin or thromboxane seems unlikely to participate in the pharmacological effects of cicletanine.

Misuse of the standard error of the mean [letter]

“…In the study by Ferry et al (1988) the healthy volunteers and the group with mild renal impairment overlap in terms of creatinine clearance and GFR; the overlap in GFR is obscured by use of the s.e. mean instead of the s.d.…”