A NEW SIMPLE APPROACH TO STUDY THE EFFECT OF CHANGES IN URINE FLOW AND OR URINE PH ON RENAL CLEARANCE AND ITS APPLICATIONS

  • 1 October 1986
    • journal article
    • research article
    • Vol. 24  (10) , 519-527
Abstract
After entering the renal tubular lumen either through glomerular filtration or tubular secretion, drug molecules are considered to be removed from there by two competing processes: tubular fluid flow for urinary excretion and tubular reabsorption into blood circulation. The relative overall magnitude of the "force" or "efficiency" of these two processes will determine the fraction of drug molecules to be either excreted or reabsorbed, and hence their renal clearance (CLr). Urine flow rate (Q) is assumed to be proportional to the mean flow rate of tubular fluid at reabsorption sites (mainly in distal tubules), and used as an index to indirectly estimate the relative reabsorption "force" or "efficiency" (this may also be called apparent intrinsic reabsorption clearance). With the above assumptions, a plot of 1/CLr vs. 1/Q should yield a straight line under apparent first-order conditions. This has been confirmed for urea, theophylline, ethanol, chloramphenicol, amobarbital, riboflavin and fluoride based on human and dog (riboflavin only) data reported in the literature. Assuming that tubular reabsorption occurs only through the diffusion of unionized molecules, a plot of 1/CLr vs. fn/Q should also yield a straight line for weak acids and weak bases under linear conditions; the fn is the mean fraction of drug present in the unionized form at reabsorption sites whose mean pH is approximated or reflected by the urinary pH. The above straight line plot has been confirmed with human data for phenobarbital as well as human and rat data for salicylic acid. The effect of urine pH on biological half-life of pseudoephedrine in humans has also been successfully characterized. In addition to the simplicity in the CLr correlation or prediction (one or two sets of CLr data may be sufficient), useful information such as the extent of tubular reabsorption and secretion may also be obtained from the slope and intercept of the plot. This simple "dynamic" approach has also been used to study the hepatic and pulmonary clearance as well as to predict the effect of changes in perfusion rate on intestinal absorption clearance of drugs. Thus, it presents a universal approach to study organ clearance without the need to know details of their physiology, anatomy and kinetics of drug distribution in and removal from the entire organ.