Bioavailability of oral vs. subcutaneous low-dose methotrexate in patients with Crohn's disease

Background: Oral methotrexate and folic acid are partly absorbed by a common intestinal transporter. Aim: To determine the relative bioavailability of oral low-dose methotrexate administered with and without concomitant folic acid vs. subcutaneous administration in patients with stable Crohn's disease. Methods: Ten patients were randomized to receive their regular maintenance dose of methotrexate (15-25 mg) for three consecutive weeks: orally, orally with 5 mg folic acid or subcutaneously. Blood samples were drawn at specified intervals during 24 h, and methotrexate levels were determined by fluorescence immunoassay. Areas under the curve extrapolated to infinity (AUC(infinity)) were compared between the three routes. Results: The geometric mean AUC(infinity) values (95% confidence intervals) were 360 nmol.h/L (301-430 nmol.h/L), 261 nmol.h/L (214-318 nmol.h/L) and 281 nmol.h/L (209-377 nmol.h/L) per milligram of methotrexate administered for subcutaneous, oral and oral with folic acid administration, respectively (P < 0.05 and P < 0.01 for oral with folic acid and oral vs. subcutaneous administration, respectively). The geometric mean relative bioavailabilities (95% confidence intervals) were 0.73 (0.62-0.86) and 0.77 (0.60-0.99) for oral and oral with folic acid administration, respectively (difference not significant). Conclusions: In patients with stable Crohn's disease, the oral bioavailability of methotrexate is highly variable and averages 73% of that of subcutaneous administration. Concomitant folic acid has no significant effect on the bioavailability. Dose adjustments based on individual pharmacokinetic assessment should be considered when switching patients from parenteral to oral therapy.