Variability of methotrexate pharmacokinetics and pharmacodynamics.

It is apparent that MTX is a useful agent in the treatment of rheumatoid arthritis resistant to first and second line therapies. However, despite its long term use in this disease, considerable uncertainty exists about the basic pharmacokinetics of low dose oral MTX and therefore about its pharmacodynamics. It is probable that when MTX is re-examined with the help of modern analytical technology in a rheumatoid setting that pharmacological insights to the variability in dose-response relationships for efficacy and certain toxicities may emerge. There is still considerable uncertainty of the hepatotoxic potential of MTX. Further investigation of the accumulation of active polyglutamated MTX in liver may throw light on the likelihood of promoting iatrogen disease and perhaps the contribution of oral administration to this problem. Finally, examination of dose-response relationship utilising accurate pharmacokinetics may help to establish guidelines for the safe and effective usage of MTX in rheumatoid arthritis.