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Effect of Protein‐Calorie Malnutrition on Methotrexate Pharmacokinetics
Author(s) -
Charland Scott L.,
Bartlett David,
Torosian Michael H.
Publication year - 1994
Publication title -
journal of parenteral and enteral nutrition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.935
H-Index - 98
eISSN - 1941-2444
pISSN - 0148-6071
DOI - 10.1177/014860719401800145
Subject(s) - pharmacokinetics , methotrexate , toxicity , serum albumin , protein calorie malnutrition , metabolite , medicine , blood proteins , free fraction , pharmacology , albumin , endocrinology , chemistry , malnutrition , protein–energy malnutrition
Methotrexate toxicity is increased in protein‐calorie malnutrition. The influence of protein‐calorie malnutrition on the pharmacokinetics and binding of methotrexate (MTX) and the formation of its major hepatic metabolite, 7‐hydroxy‐methotrexate was examined in 30 adult, female Lewis 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% protein; 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% weight gain in the control group. In the protein binding study, a significant decrease in serum albumin (19%), uncorrected creatinine clearance (38%), and free fraction of MTX (15%) was found in the PD group. All animals in the pharmacokinetic study received a single intraperitoneal injection of MTX (10 mg/kg), and serum MTX and 7‐hydroxy‐methotrexate concentrations were determined using a specific, reversed phase, high‐performance liquid chromatography assay. The mean AUC 0–3 in the PD group was 43.6 ± 3.9 μg/mL per hour compared with 15.8 ± 1.1 μg/mL per hour in the control group ( p <.001). The time to peak and the peak serum concentrations were significantly greater in the PD animals, which indicated delayed absorption and clearance. These results suggest that the increase in MTX toxicity observed in protein‐calorie malnutrition is associated with a decrease in MTX clearance, and is not related to changes in protein binding or formation of 7‐hydroxy‐methotrexate. ( Journal of Parenteral and Enteral Nutrition 18: 45–49, 1994)