Dr. Taft et al., CONCENTRATION-DEPENDENT TUBULAR SECRETION OF ACETAZOLAMIDE AND ITS INHIBITION BY SALICYLIC-ACID IN THE ISOLATED-PERFUSED RAT-KIDNEY, Drug metabolism and disposition, 24(4), 1996, pp. 456-461
An isolated perfused rat kidney (IPK) technique was used to study the
effect of salicylic acid (SA) on the excretion of acetazolamide (AZ),
Initial experiments were conducted in the absence of interactants at t
hree nominal AZ concentrations (50, 100, and 250 mu g/ml). Over the co
ncentration range studied, AZ demonstrated net tubular secretion in th
e IPK, Significant decreases in excretion ratio (4.97 +/- 0.79-2.66 +/
- 1.1) and secretory clearance (0.809 +/- 0.23-0.541 +/- 0.28) were ob
served with increasing AZ concentration, consistent with saturation of
tubular secretion, Using a facilitated model for renal secretion, val
ues of tubular transport parameters were obtained from a plot of excre
tion ratio vs. unbound AZ concentration: t(max) = 118 +/- 29.4 mu g/mi
n, K-M = 53.4 +/- 22.4 mu g/ml, and t(max(A)) = 6.31 +/- 2.82 mu g/min
, In the presence of SA (200 mu g/ml), renal secretion of AZ was inhib
ited, as demonstrated by significant decreases in renal clearance (0.7
31 +/- 0.21-0.147 +/- 0.03) and excretion ratio (3.77 +/- 0.82-0.378 /- 0.07). Although these findings were indicative of a reabsorption co
mponent to AZ excretion in the IPK that had not been previously propos
ed, the results were consistent with a previous investigation of conco
mitant administration of AZ and SA in humans (Br. J. Clin, Pharmacol.
27, 866, 1989), thereby endorsing utilization of the IPK as a screenin
g tool for renal clearance mechanisms in humans.