Expansion
Folate, thymidylate, purine and ribonucleotide reductase pathways
Expansion
| Drug | Target | Notes |
|---|---|---|
| Methotrexate | Dihydrofolate reductase | Rescued by folinic acid |
| Trimethoprim | Bacterial dihydrofolate reductase | Selective for the bacterial enzyme |
| Pyrimethamine | Protozoal dihydrofolate reductase | Toxoplasmosis, malaria |
| 5-fluorouracil | Thymidylate synthase | Folinic acid potentiates it |
| 6-mercaptopurine, azathioprine | Purine synthesis | Degraded by xanthine oxidase, so allopurinol is dangerous |
| Hydroxycarbamide | Ribonucleotide reductase | Also raises HbF in sickle cell disease |
| Cytarabine | DNA polymerase | Acute myeloid leukaemia |
| Mycophenolate | Inosine monophosphate dehydrogenase | Lymphocyte-selective, since they lack salvage |
Two interactions worth committing to memory. Allopurinol with azathioprine or 6-mercaptopurine blocks their degradation and causes profound marrow suppression, so the thiopurine dose must be cut by about 75 per cent. And methotrexate should not be given with trimethoprim, since both block folate metabolism.
Mycophenolate’s selectivity illustrates the salvage pathway’s importance: lymphocytes depend almost entirely on de novo purine synthesis, whereas most other cells can salvage, which is why it is immunosuppressive with relatively little marrow toxicity.