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Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in rabbits after intravenous administration

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Abstract

The pharmacokinetics of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX), a major metabolite, were investigated in rabbits after intravenous bolus injection and infusion using a specific HPLC assay. The arterial sampling (from the carotid artery) was used in all the studies since peculiar and significant arterial-venous differences in the plasma concentration of MTX and 7-OH-MTX were found following bolus administration of the drug. The disposition kinetics of MTX appeared polyexponential with a small terminal phase having a half-life of 10.2–27.5 hr. Extensive formation of 7-OH-MTX occurred at the two dose levels (15 and 50 mg/kg). Nonlinear disposition of MTX was reflected in several aspects of data analysis. A disproportionate increase in the AUC with dose was observed. An increase in dose not only reduced the mean total body clearance (7.49 vs. 4.26 ml/min/kg) and renal clearance (4.89 vs. 2.76 ml/min/kg), but also prolonged the mean residence time (26.2 vs. 43.3 min). The steady-state volume of distribution (Vss) of MTX was estimated to range from 0.16 to 0.25 L/kg. More than 90% of the dose was excreted as MTX and 7-OH-MTX within 8 hr after dosing. Renal clearances decreased with the increasing plasma levels, suggesting active tubular secretion as one of the excretion mechanisms. A similar pattern for renal clearance of 7-OH-MTX was obtained. Infusion studies of 7-OH-MTX revealed that this metabolite had a longer residence time and a larger Vss as compared with MTX, which were in accordance with its physicochemical properties. Essentially complete doses of 7-OH-MTX could be recovered in the rabbit urine.

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Authors and Affiliations

  1. Department of Pharmacodynamics, College of Pharmacy, Univeristy of Illinois, 60612, Chicago, Illinois

    Mei-Ling Chen & Win L. Chiou

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  1. Mei-Ling Chen
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  2. Win L. Chiou
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This research was in part supported by a grant from the National Cancer Institute, PHS CA 29754.

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Chen, ML., Chiou, W.L. Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in rabbits after intravenous administration. Journal of Pharmacokinetics and Biopharmaceutics 11, 499–513 (1983). https://doi.org/10.1007/BF01062208

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