R. Masereeuw et al., RENAL EXCRETION AND ACCUMULATION KINETICS OF 2-METHYLBENZOYLGLYCINE IN THE ISOLATED-PERFUSED RAT-KIDNEY, Journal of Pharmacy and Pharmacology, 48(6), 1996, pp. 560-565
The effect of protein binding on kidney function has been studied by i
nvestigating the renal accumulation and secretion of the hippurate ana
logue 2-methylbenzoylglycine in the isolated perfused rat kidney in th
e absence and presence of bovine serum albumin (BSA). Experiments were
performed with either 2.5% pluronic or a combination of 2.2% pluronic
and 2% BSA as oncotic agents; a wide concentration range (1-190 mu g
mL(-1)) of 2-methylbenzoylglycine was studied. Tubular secretion appea
red to be a function of the amount of unbound drug in the perfusate an
d was best described by a model consisting of a high and low affinity
Michaelis-Menten term. Parameters obtained after the analysis of renal
excretion data were maximum transport velocity for the high affinity
site (T-M,T-H) = 3.0 +/- 2.8 mu g min(-1), Michaelis-Menten constant f
or tubular transport for the high affinity site (K-T,K-H) = 0.5 +/- 0.
8 mu g mL(-1), maximum transport velocity for the low affinity site (T
-M,T-I) = 250 +/- 36 mu g min(-1) and Michaelis-Menten constant for tu
bular transport for the low affinity site (K-T,K-L) = 62 +/- 17 mu g m
L(-1). The compound accumulated extensively in kidney tissue, ratios u
p to 175 times the perfusate concentration were reached. Accumulation
data were best analysed by a two-site model similar to the model used
to describe renal excretion. Calculated parameters were -1 theoretical
maximum capacity of the high affinity site (R(M,H)) = 26 +/- 23 mu g
g(-1), affinity constant for renal accumulation at the high affinity s
ite (K-A,K-H) = 0.2 +/- 0.4 mu g mL(-1), theoretical maximum capacity
of the low affinity site (R(M,L)) = 1640 +/- 1100 mu g g(-1) and affin
ity constant for renal accumulation at the low affinity site (K-A,K-L)
= 60 +/- 58 mu g mL(-1). The very high accumulation in kidney tissue
could be explained by active tubular uptake, mediated by the secretory
mechanisms involved, and dependent on the amount of free drug in the
perfusate. This study shows that anionic drugs, subject to active secr
etion, may reach high concentrations in tubular cells even at low plas
ma concentrations.