Effects of nutritional depletion and repletion on plasma methotrexate pharmacokinetics

Clinically, a relationship exists among nutritional status, drug responsiveness, and host toxicity, but the effects of nutrition on chemotherapy drug metabolism are relatively unknown. This article evaluates the effect of malnutrition and nutritional repletion on plasma methotrexate (MTX) pharmacokinetics. In Study I, 55 non-tumor-bearing rats were fed regular diet (RD) (N = 27) or protein-free diet (PFD) (N = 28) for 10 days. On day 10, MTX 20 mg/kg was injected intraperitoneally and four to six animals in each group were killed at 30 minutes, 1, 2, 6, 24, and 48 hours following MTX administration. Plasma MTX was measured by dihydrofolate reductase enzyme inhibition assay and was found to be significantly elevated (P less than 0.01) in PFD animals as compared with RD animals at 1 and 2 hours following MTX injection. In Study II, 87 tumor-bearing rats were fed RD (N = 29) or PFD (N = 58) for 10 days. At this time, 27 PFD rats were switched to RD (PFD----RD), while 31 rats remained on PFD. MTX 20 mg/kg was injected intraperitoneally and six to eight rats in each group were killed at 1, 2, 6, and 24 hours post-MTX injection. Mean levels were found to be significantly elevated at 2, 6, and 24 hours in PFD (P less than 0.01) and PFD----RD (P less than 0.05) compared with RD rats. Several investigators have shown that increased plasma MTX levels at 24 and 48 hours after drug administration correlates with host toxicity in patients receiving chemotherapy. In this experimental study, malnutrition delayed plasma MTX clearance, and nutritional repletion for 2 days was insufficient to return MTX pharmacokinetics to normal. These results in experimental animals suggest an explanation for increased MTX toxicity in malnourished individuals.