Why has the PAH transport system proven so difficult to characterize? The major problems appear to arise in three areas: species differences, differences in methodology, e.g., vesicle preparation techniques, and multiplicity of related transport systems. Species differences are certainly important in some areas, e.g., the luminal membrane where the same investigators have shown the presence of an anion exchanger capable of transporting PAH in rat and dog but not in rabbit. Since all of these species effectively secrete PAH, one must question whether or not the primary luminal component of the PAH secretory system has yet been identified. Other species differences have also been described. For example, the amphibian, Necturus, demonstrates bidirectional organic anion transport, including an uphill luminal step and the urinary bladders of certain species of crustaceans show net reabsorption, whereas the bladders of other species show net secretion of PAH. However, these differences may well prove to be important tools in assessing PAH transport, since amplification of specific pathways and the increased experimental control possible in intact tissue preparations from some of these species, e.g., flounder, snake and amphibian tubules or crustacean urinary bladder, may facilitate resolution of many of the remaining uncertainties. Species differences cannot explain the wide variety of results reported for the basolateral membrane transport step, since many of the conflicting studies were done in the same species. Difficulties inherent in vesicle techniques have been discussed above (Subsection III-A2), and emphasize the need to correlate such data with intact tissue preparations. However, the major source of confusion appears to be related to the ability of PAH to interact with several transport systems, directly or indirectly. Thus, despite the preponderance of evidence showing that the PAH transport system at the basolateral membrane is distinct from those for sulfate, mono- and dicarboxylic acids, acidic amino acids, and uric acid, there remains the real possibility that under physiological conditions: PAH may be a minor substrate for these other systems, substrates for other systems may inhibit PAH transport directly through competition for the PAH carrier or indirectly through competition for the same energy source, and entry of a substrate on one system may trans-stimulate PAH uptake on another. Furthermore, the existence of multiple systems may explain the inability of certain manipulations, e.g., Na gradient dissipation in vivo, to block PAH transport. PAH entry may simply increase via another pathway, e.g., anion exchange.(ABSTRACT TRUNCATED AT 400 WORDS)