Toxicokinetics of endogenous substances: a neglected issue.
Some specific problems related to the pharmacokinetics and toxicokinetics of endogenous substances are reviewed in this paper with specific reference to baseline and its variation, reversible dynamic pools, saturable tubular reabsorption, the stability of the parent compound, poorly absorbed substances, analytical procedures and statistical analysis. 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 variation according to specific rhythms, age, sex or simple fluctuation, active absorption and passive diffusion, saturable enzyme processes, renal threshold, the distribution of the exogenous drug in relation to that already present in the body and a possible balance between endogenous synthesis and dietary intake are the main mechanisms which allow homeostatic equilibria to be preserved and restored when impaired. The presence 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 lead to non-linear kinetics. Clearance and, for substances excreted via urine not interacting with plasma proteins, renal clearance, are important parameters to check linearity/non-linearity, and give more accurate information than the half-life of the elimination phase, which with this kind of substance varies in non-linearity and baseline fluctuation or rhythms. Appropriate statistical approaches are suggested to analyse proof of absorption, length of treatment, gender difference and the linearity/proportionality assessment of absorption. Possible discrepancies in the dose-absorption relationship when dose-linearity and dose non-proportionality are simultaneously encountered are carefully discussed and attributed to the presence of the baseline. This review is aimed at stimulating the attention of scientists and regulatory authorities to several unsolved issues in the toxicokinetics and pharmacokinetics of endogenous substances, which appear to have been overlooked in current operating guidelines.
Marzo
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Institute for Pharmacokinetic and Analytical Studies, Stabio, Switzerland.
D000818:Animals; D006801:Humans; D010599:Pharmacokinetics; D014116:Toxicology