TOXICOKINETICS OF ENDOGENOUS SUBSTANCES - A NEGLECTED ISSUE

Some specific problems related to the pharmacokinetics and toxicokinet ics of endogenous substances are reviewed in this paper with specific reference to baseline and its variation, reversible dynamic pools, sat urable tubular reabsorption, the stability of the parent compound, poo rly absorbed substances, analytical procedures and statistical analysi s. Compared to xenobiotics, endogenous substances require special care in planning pharmacokinetic and toxicokinetic investigations as they possess homeostatic equilibria. The presence of a baseline, its variat ion according to specific rhythms, age, sex or simple fluctuation, act ive absorption and passive diffusion, saturable enzyme processes, rena l threshold, the distribution of the exogenous drug in relation to tha t already present in the body and a possible balance between endogenou s synthesis and dietary intake are the main mechanisms which allow hom eostatic equilibria to be preserved and restored when impaired. The pr esence of multicomponent dynamic pools requires not only the substance administered but also the entire pool to be assayed, to determine the components that can be originated from the drug administered. Various analytical approaches are discussed and some specific examples given. The above mechanisms frequently involve saturable processes which lea d to non-linear kinetics. Clearance and, for substances excreted via u rine not interacting with plasma proteins, renal clearance, are import ant parameters to check linearity/non-linearity, and give more accurat e information than the half-life of the elimination phase, which with this kind of substance varies in non-linearity and baseline fluctuatio n or rhythms. Appropriate statistical approaches are suggested to anal yse proof of absorption, length of treatment, gender difference and th e linearity/proportionality assessment of absorption. Possible discrep ancies in the dose-absorption relationship when dose-linearity and dos e non-proportionality are simultaneously encountered are carefully dis cussed and attributed to the presence of the baseline. This review is aimed at stimulating the attention of scientists and regulatory author ities to several unsolved issues in the toxicokinetics and pharmacokin etics of endogenous substances, which appear to have been overlooked i n current operating guidelines.