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Inhibition of Renal Tubular Transport of Methotrexate by Probenecid¹

Division of Neurosurgery, Albany Medical College, Albany, New York 12208 [R. S. B.]; Department of Neurosurgery [A. B., O. W.] and General Clinical Research Center [G. C.], Roswell Park Memorial Institute, Buffalo, New York 14203; and Laboratory of Neurochemistry, National Institute of Neurological Diseases and Stroke, NIH Bethesda, Maryland 20014 [D. B. T.]

The mechanism of excretion of methotrexate (MTX) has been investigated in the monkey. Under steady-state conditions of varied plasma levels of MTX, it was determined that MTX was excreted by renal tubular transport as well as by glomerular filtration. The maximum rate of renal tubular transport of MTX (81 µg/min) was attained at plasma levels of MTX from 6 to 8 µg/ml. Correspondingly, the rate of clearance of MTX from plasma was shown to diminish from a value that was 3-fold greater than the glomerular filtration rate at plasma levels of MTX of 0.04 to 1.7 µg/ml to values approximating glomerular filtration rate at plasma levels of MTX from 6 to 32 µg/ml.

Pretreatment of animals with probenecid (700 mg/sq m) totally inhibited renal tubular transport of MTX when MTX was administered in doses from 1.8 to 621 mg/sq m. Following inhibition of renal tubular transport of MTX by probenecid, steady-state plasma levels of MTX were seen to be double corresponding levels determined in non-probenecid-pretreated controls given comparable doses of MTX. The total urinary excretion of MTX in animals pretreated with probenecid (700 mg/sq m) was reduced by a factor of 2.6 from values determined in non-probenecid-pretreated control animals receiving similar varied doses of MTX (1.8 to >600 mg/sq m).

The mode of i.v. injection of MTX was seen to effect the concentration of MTX in plasma. Initial loading followed by continuous sustaining infusion of MTX provided stable and higher levels of MTX in plasma than was determined in controls or in experimental animals pretreated with probenecid and receiving identical doses of MTX by single bolus injection.

¹ Supported by NIH Contract NINDS-72-2328, NIH Grant CA15980, and a Billjo Foundation Grant.

² To whom reprint requests should be addressed.

Received 7/12/74. Accepted 9/25/74.

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