Interaction of probenecid with the protein binding of methotrexate

The effect of probenecid on the plasma protein binding of methotrexate (MTX) has been examined in vitro. At concentrations greater than or equal to 5 x 10(-4) M, probenecid caused a significant reduction (greater than 30%) in the plasma binding of MTX. It is suggested that in vivo this would lead to a greater dispersion into the tissues and a larger volume of distribution, and may be partly responsible for the longer MTX elimination half-life observed with concurrent administration of probenecid.