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Clearance Studies of Methotrexate in Dogs after Multiple-Rate Infusion¹

Department of Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612

Plasma, renal, and nonrenal clearances of methotrexate as well as their interrelationship were studied in five conditioned male beagle-mongrel dogs using the multiple-rate infusion method. Steady-state plasma methotrexate concentrations of 1, 20, and 100 µg/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 to study the effect of acid-base imbalance on the clearances. NaCl solution (0.9%) infusion served as a control. Plasma and urine concentrations of methotrexate were quantitated by a sensitive high-performance liquid chromatographic method. Distortion of body acid-base balance did not significantly change the clearances of methotrexate. The results showed that the plasma clearance (4.02 to 4.68 ml/min/kg) of methotrexate was relatively constant over the concentration range studied. The renal and nonrenal clearances, on the other hand, were concentration dependent. As the plasma methotrexate concentration increased from 1 to 20 or 100 µg/ml, renal clearance decreased from 3.60 to 4.28 ml/min/kg to 2.62 to 2.73 ml/min/kg, and nonrenal clearance increased from 0.35 to 0.42 ml/min/kg to 1.38 to 1.74 ml/min/kg. Concentration-dependent renal clearance may be due to saturation of the process involving active tubular secretion of methotrexate.

¹ This research was supported in part by Grant CA-29754 from the National Cancer Institute.

² Abstracted from a dissertation submitted in 1984 by C. Y. Lui to the Graduate College, University of Illinois at Chicago, in partial fulfillment of Ph.D. degree requirements.

³ To whom requests for reprints should be addressed.

Received 2/27/84. Revised 7/27/84. Revised 12/28/84. Accepted 1/ 8/85.