A SIGNIFICANT METHOTREXATE-GLUTAMINE PHARMACOKINETIC INTERACTION

Previous studies indicate that glutamine-supplemented diets decrease t he enterocolitis associated with methotrexate administration. The infl uence of glutamine on the pharmacokinetics of methotrexate and the for mation of its major hepatic metabolite, 7-hydroxy-methotrexate was exa mined in 36 adult, female Lewis rats. Animals were randomly assigned t o receive either a 3% glycine-supplemented solid diet (GLY; 25.0% prot ein; 17.,6 kJ/g, of 4.2 kcal/g) or a 3% glutamine-supplemented solid d iet (GLN; 25.0% protein; 17.6 kJ/g, or 4.2 kcal/g) ad libitum for 35 d ays. Animals were separated into two groups (serum methotrexate pharma cokinetics, n = 20; or methotrexate renal elimination, n = 16) and giv en a 10 mg/kg dose of methotrexate. There was a 25% decrease in mean m ethotrexate total serum clearance in the GLN group compared with the c ontrol group (0.63 +/- 0.09 L . h(-1). kg(-1) and 0.47 +/- 0.13 L . h( -1). kg(-1), respectively, p = 0.01). Renal methotrexate elimination w as decreased by 65%. There was no significant difference in methotrexa te volume of distribution or half-life between the two groups. Glutami ne decreases methotrexate systemic clearance, thus exposing the host a s well as the tumor to greater methotrexate concentrations.