Analysis of methadone disposition in the pregnant rat by means of a physiological flow model

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Abstract
A physiological flow model simulating the pregnant rat is constructed for methadone. The model includes brain, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. Since methadone kinetics may provide valuable information for optimal therapy, an attempt is made to describe methadone kinetics in brain and other tissues simultaneously. The concentration-time profiles of methadone in various tissues after an i.v. bolus dose of 2 rng/kg are reasonably described by the model. The role of the different organs in the disposition of methadone is further explored by simulations. It is found that methadone is initially sequestered in lung tissues immediately after intravenous administration. Therefore, both venous and arterial blood pools are included in the model. Rapid uptake then takes place into vascular-rich organs, including kidneys, liver, and muscle, followed by redistribution into less penetrable organs, such as brain, fetal, and intestinal tissues. Data indicate that diffusional resistance governs the transfer of drug into brain, fetal, and intestinal tissues. Simulations suggest that muscular tissues play an important role in the rat and in man, becoming the major methadone reservoir. The tissue-to-blood partition coefficients derived from equilibrium conditions in this study are generally higher than those reported hitherto. The model is scaled up to a human to investigate whether it can be used to predict the concentration of methadone in different organs after a certain dose. Volume of distribution (Vdss) and biological half-life are consistent with earlier findings in man. The study is done by means of the GC-MS method with selected ion-monitoring where deuterated methadone is used as an internal standard.