THEOPHYLLINE DISTRIBUTION KINETICS ANALYZED BY REFERENCE TO SIMULTANEOUSLY INJECTED UREA AND INULIN

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Abstract
Theophylline distribution kinetics were studied after i.v. injection in five anesthetized dogs. [14C]Urea and inulin were injected simultaneously as reference compounds to measure body fluid spaces and to calculate compartmental blood flows and permeability coefficient-surface area products for transcapillary exchange. The distribution of all three compounds was modeled with three-compartment systems in which the central compartment corresponds to intravascular space. The total volume of theophylline distribution averaged 0.72 .+-. 0.09 liters/kg (.+-.S.D.), indicating net tissue binding as reflected in a tissue/intracellular water partition coefficient of 1.17 .+-. 0.10. Cardiac output measurements averaged 4.78 .+-. 0.95 liters/min and were similar to the sum of compartmental blood flows estimated from the intercompartmental clearances of urea and inulin (4.62 .+-. 1.10 liters/min) and to the sum of theophylline intercompartmental clearances (5.10 .+-. 1.29 liters/min). Theophylline intercompartmental clearance to each peripheral compartment was faster than expected from its free-water diffusion coefficient and was similar to estimated compartmental blood flow. It is possible that theophylline transcapillary exchange is carrier mediated and that its rapidity contributes to the frequency of adverse reactions after i.v. administration of this drug.