Activation of prodrugs affected by CYP induction/inhibition
- February 26, 2021
Prodrugs are inactive precursors designed to be converted to an active form after administration. This is to overcome poor physio-chemical or pharmacokinetic properties of the active drug.
Prodrugs – methods of activation
Prodrugs are activated by a variety of mechanisms including:
|Most prodrugs are unaffected by concomitant administration with other medicines, however significant interactions may occur for prodrugs activated by cytochrome CYP450 enzymes.
Activation by cytochrome P450 enzymes may be affected by other medicines taken concomitantly or by genetic differences. The significance of the interaction will depend on:
(Increase activity, usually not clinically significant)
|Incidence of genetic polymorphisms1
||Tamoxifen converted to endoxifen which is 30-100x more potent as an antagonist of estrogen receptors.
Codeine has minimal analgesic efficacy until converted to morphine.
Tramadol is converted to O-desmethyl-tramadol (M1) active metabolite by CYP2D6 (inhibition may decrease analgesia and produce symptoms of opiate withdrawal).
CYP2D6 is not subject to induction
|CYP2C19||Clopidogrel is converted to active thiol metabolite.||Strong
Caucasians <5%Increased activation
|CYP2C9||Losartan, 14% converted by CYP2C9 to active metabolite E3174, remainder converted by CYP3A to inactive metabolites||Strong
1 See Pink Book, Cytochrome P450 Enzymes