MICRODIALYSIS A NEW TOOL TO OBTAIN INSIGHT INTO PERIPHERAL KINETICS OF COMPOUNDS

Introduction: Computerized mathematical biokinetic and biodynamic models are used in risk assessment for describing the behavior of xenobiotics in the human body and predicting effects after exposure. These models are developed on the basis of plasma and urine concentrations and lack information about peripheral tissues, while these tissue concentrations generally determine the clinical effects. Microdialysis is a sampling technique, useful for measuring substances in vivo in peripheral tissue. To evaluate the suitability of microdialysis for measuring peripheral kinetics a kinetic theophylline model was studied. Methods: Microdialysis catheters were inserted in adipose tissue, muscle tissue and the vena femoralis of 12 anaesthetized rats. Theophylline 20 mg/kg IV was administered and concentrations were determined every 10 minutes. Unbound blood-concentrations, measured using microdialysis, were fitted in a one- and a two-compartment model, using kinetic software ph Edsim[R]. Thereafter, using the fitted models, a prediction was made of a concentration-time curve in peripheral tissues. A comparison was made between the predicted kinetics by the model and the actually measured peripheral kinetics using microdialysis. Results: The blood curve fitted well in a one-compartment model, with a correlation coefficient of 0.922. However, the use of a two-compartment model is defensible as well since the correlation coefficient in a bi-exponential curve is 0.937. Using a two-compartment model, the amount of theophylline in the peripheral compartment after the same IV dose was simulated. In a two-compartment model, distribution can be seen as an `absorption'-phase in the peripheral compartment, since theophylline has to be distributed towards the peripheral tissues. Consequently, the predicted curve showed a gradual increase in tissue concentrations. On the contrary, the measured theophylline concentrations in adipose and muscle tissue followed the plasma-curve. Discussion: In a one-compartment model the compound of interest is distributed fast and equally throughout the body. Therefore concentration-time-profiles in adipose and muscle tissue should follow the plasma-profile, as in this experiment. No proof was found that adipose or muscle tissue acts as a second compartment, although other tissues in the body (intracellular, intracerebral) can still form a second compartment. Although the blood curve fitted a two-compartment model slightly better than a one-compartment model, the concentrations at the side of interest appeared to follow the plasma concentrations. Therefore, in this rat study the effects of theophylline can be predicted using plasma concentrations and one-compartment kinetics. Microdialysis proved to be a useful tool to gain more insight into peripheral kinetics of theophylline. A human study has been planned to study the peripheral kinetics of theophylline under normal and in particular circumstances in shock. Spaans E(1,2), Kuil A van de(1), Boereboom FTJ(1,2), Vries I de(1,2), Joore JCA(1,2), Vleeming W(1), Meulenbelt J(1,2) (1) National Institute of Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands (2) University Medical Center Utrecht, Utrecht, The Netherlands