Concentration andpH dependent steady-state volume of distribution of methotrexate estimated by a simple physiologically based method

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Abstract
The effects of plasma concentration and pH on the steady-state volume of distribution, Vss,of methotrexate (MTX) were studied in five conditioned male beagle-mongrel dogs. Steady-state plasma MTX concentrations of approximately 1, 20, and 100μg/ml were targeted for by i.v. bolus doses followed by i.v. infusions. An isotonic solution of sodium bicarbonate or ammonium chloride was simultaneously infused for the purpose of inducing plasma pH change, while the infusion of an isotonic solution of sodium chloride served as a control. Plasma and urine concentrations of MTX were quantitated by a sensitive high-performance liquid chromatographic method, and the Vssof MTX was estimated by a recently reported physiologically based method of Chiou and Lam. Statistically significant (p pHdependent Vssof MTX were observed. Concentration dependence of Vsswas noted in sodium chloride and ammonium chloride infused dogs, but not in bicarbonate treated dogs. There was an average 50.0 and 44.8% increase in Vssat 1 μg/ ml relative to the two higher concentrations (20 and 100 μg/ ml) for dogs treated with ammonium and sodium chloride, respectively. However, Vssof MTX at the targeted concentrations of 20 and 100 μg/ml was relatively constant. Plasma pHdependence of Vsswas observed only at the plasma concentration of 1 μg/ml, and on the average, ammonium chloride and sodium chloride treatments resulted in 50.0 and 31.3% higher Vss,respectively, when compared with the bicarbonate treatment. These phenomena appear to be adequately explained by the reported tissue uptake kinetics of MTX.