EFFECT OF PROTEIN-CALORIE MALNUTRITION ON METHOTREXATE PHARMACOKINETICS

Methotrexate toxicity is increased in protein-calorie malnutrition. Th e influence of protein-calorie malnutrition on the pharmacokinetics an d binding of methotrexate (MTX) and the formation of its major hepatic metabolite, 7-hydroxy-methotrexate was examined in 30 adult, female L ewis rats. Animals were randomized to receive either a standard diet ( 22.0% protein; 4.20 kcal/g) or a protein-depleted diet (PD) (0.03% pro tein; 4.27 kcal/g) ad libitum for 35 days. Animals were then separated into two groups for either methotrexate pharmacokinetics (n = 20) or serum protein binding (n = 10) studies. The mean weight loss in the PD group was 26% of their initial body weight, as compared with a 29% we ight gain in the control group. In the protein binding study, a signif icant decrease in serum albumin (19%), uncorrected creatinine clearanc e (38%), and free fraction of MTX (15%) was found in the PD group. All animals in the pharmacokinetic study received a single intraperitonea l injection of MTX (10 mg/kg), and serum MTX and 7-hydroxy-methotrexat e concentrations were determined using a specific, reversed phase, hig h-performance liquid chromatography assay. The mean AUC0-3 in the PD g roup was 43.6 +/- 3.9 mug/mL per hour compared with 15.8 +/- 1.1 mug/m L per hour in the control group (p < .001). The time to peak and the p eak serum concentrations were significantly greater in the PD animals, which indicated delayed absorption and clearance. These results sugge st that the increase in MTX toxicity observed in protein-calorie malnu trition is associated with a decrease in MTX clearance, and is not rel ated to changes in protein binding or formation of 7-hydroxy-methotrex ate.