描述
Trimethoprim and methotrexate both inhibit dihydrofolate reductase (DHFR), producing additive antifolate toxicity with potentially life-threatening pancytopenia and mucositis.
机制
Trimethoprim inhibits bacterial DHFR but also has measurable affinity for human DHFR; combined with methotrexate's DHFR inhibition and shared renal OCT2/OAT elimination pathways, both pharmacodynamic and pharmacokinetic synergism contribute to toxicity.
临床意义
Multiple case reports and cohort studies document severe pancytopenia, megaloblastic anaemia, and fatal outcomes when trimethoprim is added to methotrexate therapy.
处理措施
Avoid the combination whenever possible, especially with high-dose or weekly low-dose methotrexate regimens; if unavoidable, closely monitor CBC, renal function, and provide folinic acid rescue.