Antihistamines as P450 2D6 inhibititors (decreased codeine effect)

[Ethyl]

Swie has been using hydroxyzine along with his heroin/opium use, and last night he tried using it with codeine too.
He noticed the typical sedation that one gets from antihistamines/opiates combined but he noticed that the codeine appear less potent. He took 300mg and it felt more like 120/150mgs.
Swie then google about hydroxyzine and p4 2d6 and he came with this info:

Classic antihistamines, namely diphenhydramine, chlorpheniramine, clemastine, perphenazine, hydroxyzine, and tripelennamine, share structural features with substrates and inhibitors of the polymorphic cytochrome P450 (CYP) isozyme CYP2D6. Therefore, the current study was undertaken to characterize the in vitro inhibition of CYP2D6 by these commonly used, histamine H1 receptor antagonists. Microsomal incubations were performed using bufuralol as a specific CYP2D6 substrate and microsomes derived from human cells transfected with CYP2D6 cDNA. Reaction velocities were assessed in the absence and presence of antihistamines (20 microM) at 11 substrate concentrations (1, 2.5, 5, 7.5, 10, 15, 20, 25, 50, 75, and 100 microM), as well as at three nonsaturating substrate concentrations (2.5, 5, and 20 microM) and three inhibitor concentrations (5, 20, and 50 microM). In the presence of all antihistamines, the Vmax and KM of bufuralol 1'-hydroxylation were significantly altered, compared with the uninhibited reaction (p < 0.05). Lineweaver-Burke plots suggested competitive inhibition of the reaction by diphenhydramine and mixed inhibition by all other antihistamines tested. Diphenhydramine and chlorpheniramine, with estimated Ki values of approximately 11 microM, were the weakest inhibitors of CYP2D6 in vitro. Whereas tripelennamine, promethazine, and hydroxyzine were similar in their inhibitory capacities (Ki approximately 4-6 microM), clemastine appeared to be significantly more potent, with a Ki of approximately 2 microM. These data demonstrate that classic histamine H1 receptor antagonists, available in over-the-counter preparations, inhibit CYP2D6 in vitro. Furthermore, the CYP2D6-inhibitory concentrations of these antihistamines are in the range of their expected hepatic blood concentrations, suggesting that, under specific circumstances, clinically relevant interactions between classic antihistamines and CYP2D6 substrates might occur.

Source: hxxp://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=9616188&do pt=Citation

So those of you taking antihistamines with codeine, you are really decreasing the conversion of codeine -> morphine by inhibiting CYP2D6.
It may be a good ideia for swimmers who like this combo to take first the codeine and then allmost before the peak of codeine take the your antihistamine of choice.

Reputation Comments on this post:

Very informative and easy to read

[Tortoise]

Some guy named Moonface experienced the very same thing yesterday when he took 320mg of codeine.

Moonface has used codeine many times and thought that he'd try to improve it with a little dimenhydinate (25mg) and grapefruit juice. Both were taken just as the effects of codeine were becomng apparent and very soon thereafter the buzz plateaued well short of the expected mark. It ended up feeling more like about 150mg and he was very dissapointed.

Unfortunately, he doesn't know wether it was the grapefruit juice, antihistamine or both that ruined it for him. He has informed me that from now on he will only consider taking these things towards the end of the peak, if at all.