Figure 19.

Putative energy level diagram for CYP2C9 oxidation of diclofenac. 2C9+diclofenac refers to the free energy of the separate diclofenac molecule and CYP2C9 enzyme. 5-TS/5-RC and 4′-TS/4′-RC correspond to the free energies of the transition states/reactant complexes to 5- and 4′-hydroxylation, respectively. In this hypothesis, the energy barrier to 4′-hydroxylation (Δ^⧧G_4′) is larger than that of 5-hydroxylation (Δ^⧧G₅). However, the free energy of binding is greater for 4′-hydroxylation, and the relative energy of the transition state to 4′-hydroxylation is lower than that for 5-hydroxylation; hence 4′-hydroxylation would be the preferred pathway.