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Clearance studies of methotrexate and 7-hydroxy-methotrexate in rabbits after multiple-dose infusion

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Abstract

The concentration-dependent clearance of methotrexate (MTX) and its metabolite, 7-hydroxy-methotrexate (7-OH-MTX), was demonstrated in 5 rabbits using 7 infusion rates (10.5–323 mg/hr). Mean total body clearance (from 34.3 to 13.1 ml/min) and mean renal clearance (from 25.6 to 7.6 ml/min) of MTX were found to decrease with increasing steady-state plasma concentrations (from 5.1 to 412 μg/ml), whereas nonrenal clearances remained relatively constant. An essentially steady-state plasma level of 7-OH-MTX was achieved during each MTX infusion, and its renal clearance also decreased (from 37.3 to 6.5 ml/min) with increasing metabolite levels (from 1.8 to 293 μg/ml).

Saturable renal tubular secretion appeared operative for both drug and metabolite since their renal clearance (based on the free drug) to inulin clearance ratios were much greater than unity and the ratios were markedly reduced in 2 rabbits after probenecid treatment. Plasma protein binding of MTX (56%) and 7-OH-MTX (49%) were independent of concentrations between 0.1 and 300 μg/ml. Negligible MTX metabolism was found in rabbit kidney homogenates, thus validating renal clearance measurement in the present study.

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Authors and Affiliations

  1. Department of Pharmacodynamics, College of Pharmacy, University 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. Clearance studies of methotrexate and 7-hydroxy-methotrexate in rabbits after multiple-dose infusion. Journal of Pharmacokinetics and Biopharmaceutics 11, 515–527 (1983). https://doi.org/10.1007/BF01062209

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