UGT2B7 Enzyme inhibition

[4DQSAR]

Decades ago we were taught that codeine produces what was termed a 'depot effect' in that if you take codeine for analgesia, there is a dose-dependent lockout period when conssumption of more codeine won't add to the analgesia. Now it's unclear to me if new data has shown that to be untrue but I suggest that at the time it was considered that codeine itself was a CYP2D6 inhibitor.

The enzyme in the title is responsible for the gluconation of morphine - the active metabolite of codeine. So again, that could explain the 'depot effect' theory. One larger dose working much better than two smaller doses.

But I have looked and been unable to find a satisfactory explaination. Do we now know better or is this just a theory and nobody has really studied it?

 

[4DQSAR]

https://www.sciencedirect.com/science/article/pii/S0928098723003172

Hydrocodone, Oxycodone, and Morphine Metabolism and Drug–Drug Interactions - PMC

Awareness of drug interactions involving opioids is critical for patient treatment as they are common therapeutics used in numerous care settings, including both chronic and disease-related pain. Not only do opioids have narrow therapeutic indexes ...

pmc.ncbi.nlm.nih.gov

Note that morphine is the active metabolite of codeine, oxymorphone is a (far more active) metabolite of oxycodone, hydromorphone is a (far mor active) metabolite of hydrocodone. I could not find specific data on dihydrocodeine but presume the same enzymes are involved. It's important to point out that unlike codeine, DHC is active in it's own right. So while the majority of the analgesic activity is mediated by the (far more active) metabolite dihydromorphine, unlike codeine, their isn't a ceiling dose for DHC imposed by enzymatic O-demethylation. But I presume it will describe a 2-phase dose-response curve and about 300-400mg/day, I do not think taking more would increase activity very much.