A significant methotrexate-glutamine pharmacokinetic interaction


Charland SL, Bartlett DL, Torosian MH






Previous studies indicate that glutamine-supplemented diets decrease the enterocolitis associated with methotrexate administration. The influence of glutamine on the pharmacokinetics of methotrexate and the formation of its major hepatic metabolite, 7-hydroxy-methotrexate was examined in 36 adult, female Lewis rats. Animals were randomly assigned to receive either a 3% glycine-supplemented solid diet (GLY; 25.0% protein; 17.6 kJ/g, or 4.2 kcal/g) or a 3% glutamine- supplemented solid diet (GLN; 25.0% protein; 17.6 kJ/g, or 4.2 kcal/g) ad libitum for 35 days. Animals were separated into two groups (serum methotrexate pharmacokinetics, n = 20; or methotrexate renal elimination, n = 16) and given a 10 mg/kg dose of methotrexate. There was a 25% decrease in mean methotrexate total serum clearance in the GLN group compared with the control 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 was decreased by 65%. There was no significant difference in methotrexate volume of distribution or half- life between the two groups. Glutamine decreases methotrexate systemic clearance, thus exposing the host as well as the tumor to greater methotrexate concentrations.