Prediction of the residue levels of drugs in eggs, using physicochemical properties and their influence on passive diffusion processes.

Based on a physiologically based pharmacokinetic model, describing the relationship between the plasma concentration of a drug and its deposition into eggs, general transport constants into yolk and albumen were derived, for a number of compounds, using experimental data from literature. Using only generally accepted concepts in passive diffusion theory, these transport constants were used to derive and calibrate general equations, describing the transport into yolk and albumen, in terms of the physicochemical properties of a drug. It is shown that, in theory, it is possible to calculate/predict the transport constants, using the physicochemical parameters: pKa and plasma protein binding. For a number of sulfonamides, the model was used to predict their distribution between egg yolk and albumen; the outcome was compared to data found in literature. Within this dataset, the lipophilic nature of a drug does not seem to play a major role in explaining the distribution ratio of a drug between albumen and yolk.

Kinetic modelling and residue depletion of drugs in eggs.

1. A physiologically-based pharmacokinetic model was developed for the purpose of describing the relationship between plasma concentration of drugs and their deposition into eggs. 2. By incorporating the physiology of egg formation into the model, the transfer of drugs into the egg albumen and yolk could be described using rate constants. 3. The model was used to describe concentrations in albumen and yolk of sulphanilamide, sulphaquinoxaline and pyrimethamine as a function of time using datasets from the literature. 4. The model could be used as a tool to obtain an insight into those properties of a drug which are responsible for the amount of residue in eggs, and could help in the design of critical studies for determining withdrawal periods for eggs.

Effects on thyroid hormone metabolism and depletion of lung vitamin A in rats by airborne particulate matter.

Thyroxine (T4) and vitamin A are important regulators of normal epithelial differentiation and proliferation and might act in the promotion phase of carcinogenesis. Thyroid hormone and vitamin A metabolism are linked by a common plasma carrier protein, transthyretin (TTR). Polychlorinated biphenyls (PCBs) and related organochlorine compounds deplete vitamin A and thyroxine by interaction with TTR and alteration of their metabolism in hepatic and other organs. In the present report an outdoor airborne particulate matter (APM) extract was tested for both interaction with thyroid hormone and vitamin A metabolism, in order to address the question of whether APM has the potency to deplete vitamin A and thyroid hormones. Furthermore, studies were performed to characterize compounds present in APM that interact with TTR. A third aim was to compare the interaction of APM extracts with TTR and thyroxine-binding globulin (TBG), the major carrier protein for thyroxine in humans. Results showed that a single treatment of rats with an outdoor APM extract depleted plasma thyroxine and triiodothyronine levels and increased plasma retinol levels gradually over the time period studied, while liver retinol, lung retinol, and retinyl palmitate levels were depleted by 30-50%. As outdoor APM was able to inhibit T4-TTR binding in vitro, this suggests that the reduction in thyroxine levels in vivo is caused by the same phenomenon. Experiments showed that the neutral fraction of the APM extract accounted for most of the inhibitory activity on T4-TTR binding. Polycyclic aromatic hydrocarbons and nitrated derivatives are not likely to be responsible for the activity of the neutral fraction, because several representatives of these compounds showed no or very little interaction with TTR. Pentachlorophenol, a compound with known inhibitory activity on T4-TTR binding, was detected in the organic acid fraction of both a cigarette smoke sample and an outdoor APM sample. Finally, it was shown that several indoor and outdoor APM extracts only interact with TTR, but not with TBG. As APM has the potency to deplete lung vitamin A in vivo and vitamin A might have a protective effect in the process of lung carcinogenesis, APM might increase the susceptibility for the development of lung cancer.