AJP - Renal Physiology, Vol 251, Issue 1 103-F114, Copyright © 1986 by American Physiological Society
Kinetic analysis of rat renal tubular transport based on multiple-indicator dilution method
N. Itoh, Y. Sawada, Y. Sugiyama, T. Iga and M. Hanano
New methods, based on the multiple-indicator dilution (MID) technique, to
study the kinetic relations between the renal tubular cell entry process
and the secretory process of drugs are proposed. [3H]Cimetidine was used as
a model drug. T-1824-labeled albumin (a vascular reference),
[14C]creatinine (an extracellular reference), and [3H]cimetidine were
rapidly injected into the renal artery of isolated perfused rat kidney, and
normalized outflow-time patterns were secured from rapidly sampled renal
venous perfusate. A distributed two-compartment model was fitted to the
dilution data by nonlinear least-squares regression, and the influx,
efflux, and sequestration rate constants were estimated. Both the influx
and the sequestration process (based on the unbound cimetidine
concentration) had two transport systems (i.e., Michaelis-Menten-type
saturable transport and linear-type passive transport), whereas the efflux
process was independent of the intracellular cimetidine concentration. At
the low dose of cimetidine the influx clearance was larger than those of
the efflux and sequestration, whereas at the high dose no remarkable
difference was observed among these three clearances due to the large
decrease in the influx clearance. Thus the MID technique is a sensitive new
method to study the rate-limited process of renal tubular transport in
rats.
