Reabsorption, as highlighted previously, is the most important factor controlling renal handling of drugs. The degree of reabsorption depends on the physicochemical properties of the drug, principally its degree of ionization and intrinsic lipophilicity (log D). The membranes of the cells that form the tubule are lipoidal (as expected) and do not represent a barrier to lipophilic molecules. Reabsorption occurs all along the nephron. Reabsorption re-establishes the equilibrium between the unbound drug in the urine (largely the case) and the unbound drug in plasma. As the kidney reabsorbs water so the drug is concentrated and hence if lipophilic, reabsorbed by passive diffusion. The majority (80-90 %) of filtered water is reabsorbed in the proximal tubule. Most of the remainder is reabsorbed in the distal tubule and collecting ducts. From initial filtration the urine is concentrated approximately 100-fold. We can thus expect that for neutral compounds renal clearance (unbound values) will range between GFR, for compounds that are not reabsorbed, and a value some 100fold below this for compounds that are completely reabsorbed to an equilibrium with free drug in plasma. Figure 6.1 illustrates this relationship between lipophilicity and renal clearance for a series of neutral compounds.
Clearly, the ability to cross membranes, as represented by octanol partitioning, correlates with the extent of reabsorption, with reabsorption only occurring at log D7.4 values above 0.
6.4 Plasma Protein Binding and Renal Clearance | 69
Was this article helpful?