Effect of nutritional status on the hepatobiliary excretion of methotrexate in the rat.

The effect of induced protein-calorie malnutrition (PCM) and its subsequent nutritional repletion with chow or total parenteral alimentation (TPA) on the hepatobiliary excretion of methotrexate (MTX) was determined in the Sprague-Dawley rat. Compared with full-fed controls, PCM resulted in a decrease in body and liver weight, bile flow, and the cumulative excretion of MTX but a consistently higher plasma MTX concentration at each time-point measured. Repletion with chow and TPA resulted in a gain in body weight and an increase in liver weight. Chow repletion resulted in an increase in bile flow and biliary excretion of MTX equal to that for the controls. Repletion with chow also resulted in a consistently lower plasma MTX concentration as compared with PCM rats. Repletion of PCM via TPA did not affect biliary, or plasma, MTX concentrations although the cumulative biliary excretion of MTX was further decreased. The biliary clearance of MTX was decreased by PCM. The clearance for rats repleted with chow, however, was greater than that for the controls. The clearance for PCM rats repleted via TPA was equal to that for PCM rats but less than that for the controls. When expressed as a function of liver weight and compared with PCM rats, the clearance for rats repleted with chow was increased while that for malnourished rats repleted parenterally was decreased. These studies suggest that the biliary excretion of MTX in the rat is a carrier-mediated process that is sensitive to the nutritional status of the host and independent of the effect of nutritional status on liver weight.