Abstract
A lumped compartmental model has been derived to predict methotrexate concentration as a function of time for L1210 cells in BD2F 1 female mice at doses ranging from 3 mg/kg to 400 mg/kg. Using standard methods of parameter estimation as well as experimental determinations, an integrated approach was derived to account for the differences between the subcutaneous (s.c.) and intraperitoneal (i.p.) modes of injection. It was found that a single generalized forcing function can be used to fit plasma concentration after s.c. injection for all doses. Adequate fits (average error<20% while the standard deviation of experimental determinations was±22%) of L1210 cell data after s.c. injection were obtained. The best results were for a maximum facilitated influx constant Vmax of 0.424 Μg/min/ml, a Michaelis influx constant Km of 1,42 Μg/ml, and a first-order efflux constant α of 0.047 min−1.The model simulations were not sensitive to Vmax, Km,and αso long as the ratio Vmax/αwas approximately 9Μg/ml. The values of V max ,K m ,and α which were obtained from our analysis of the in vivodata can be explained on the basis of previously performed in vitroexperiments. The parameters obtained from modeling the s.c. data were then applied for i.p. injection data. The resulting fits were adequate (average error<20% while the standard deviation of experimental determinations was±22%). A single generalized forcing function for drug concentration in the peritoneal cavity after i.p. injection for all doses was derived. The application of these results enables the prediction of methotrexate concentration in neoplastic cells at other doses after either s.c. or i.p. injection.
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Weissbrod, J.M., Jain, R.K. & Sirotnak, F.M. Pharmacokinetics of methotrexate in leukemia cells: Effect of dose and mode of injection. Journal of Pharmacokinetics and Biopharmaceutics 6, 487–503 (1978). https://doi.org/10.1007/BF01062105
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DOI: https://doi.org/10.1007/BF01062105