26 June 2007

Pharmacology bleg

I have a request for any of you who know about the pharmacology of antidepressants. I have a friend who is taking Wellbutrin (bupropion) for smoking and codeine for chronic pain. I'm curious whether the combination may be attenuating the effect of the codeine and thus whether he should talk to his doctor about changing the codeine dose or switching medications.

Here's why: Codeine itself isn't really an analgesic. It is a substrate of a polymorphic P450 enzyme CYP2D6, and is metabolized to the more potent drug morphine. Some SSRI's like fluoxetine inhibit CYP2D6 activity. Thus combining prozac with codeine can attenuate its effects (see below).

What I'd like to know is whether bupropion might have the same effect on codeine metabolism. But I can't find anything directly on the topic.

From this chart of the various enzymes involved, it looks like that might be the case. But then I found this in the Wikipedia entry on buproprion

As bupropion is metabolized to hydroxybupropion by CYP2B6, drug interactions with CYP2B6 inhibitors (paroxetine, sertraline, fluoxetine metabolite norfluoxetine, diazepam, clopidogrel, orphenadrine and others) are possible. The expected result is the increase of bupropion and decrease of hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6 inducers (carbamazepine, clotrimazole, rifampicin, ritonavir, St John's Wort and others).

Hydroxybupropion (but not bupropion) inhibits CYP2D6 and is a substrate of that enzyme. Significant increase of the concentration of some drugs metabolized by CYP2D6 (venlafaxine, desipramine and dextromethorphan, but not fluoxetine or paroxetine) when taken with bupropion has been observed.

So I need your help. Can anyone point me in the direction of studies on bupropion and codeine? Or maybe just explain this in a way I can understand?

For your enjoyment, here are a few studies of fluoxetine and codeine that I came across in looking for an answer.

Inhibition by fluoxetine of cytochrome P450 2D6 activity.
Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM
Clin Pharmacol Ther. 1993 Apr ; 53(4): 401-9

Potent inhibition of cytochrome P450 2D6 (CYP2D6) in human liver microsomes by fluoxetine and its major metabolite norfluoxetine was confirmed (apparent inhibition constant values, 0.2 mumol/L). Several other serotonergic agents were also found to be competitive inhibitors of this genetically polymorphic enzyme. The O-demethylation ratio of dextromethorphan that expressed CYP2D6 activity in 19 patients receiving fluoxetine fell in the region of the antimode separating the O-demethylation ratio values observed in 208 extensive metabolizers from 15 poor metabolizers of a control group of healthy subjects. Inhibition of CYP2D6 activity in patients undergoing treatment with fluoxetine or other serotonin uptake inhibitors could contribute to toxicity or attenuated response from concurrent medications that are substrates of this enzyme. Other in vitro studies indicated that CYP2D6 catalyzes the O-demethylation of oxycodone to form oxymorphone. This reaction was inhibited by fluoxetine and its normetabolite in liver microsomes from both extensive and poor metabolizer individuals, indicating that these compounds are not selective inhibitors of CYP2D6 activity.

Treatment of codeine dependence with inhibitors of cytochrome P450 2D6.
Fernandes LC, Kilicarslan T, Kaplan HL, Tyndale RF, Sellers EM, Romach MK
J Clin Psychopharmacol. 2002 Jun ; 22(3): 326-9

Codeine is O-demethylated by cytochrome P450 2D6 (CYP2D6) to form the more potent drug morphine, accounting for much of codeine's analgesic and dependence-producing properties. Because morphine production can be decreased by inhibition of CYP2D6, the authors hypothesized that CYP2D6 inhibition could be used to treat codeine dependence. A randomized, double-blind, placebo-controlled trial was conducted. All patients received brief behavioral therapy. Two weeks of baseline monitoring were followed by 8 weeks of daily treatment with fluoxetine or quinidine (two potent CYP2D6 inhibitors) or placebo. Thirty patients were assessed (all white, age 40 + 12 years using 127 + 79 mg/day of codeine [mean + SD]), and 17 entered treatment. Eight patients remained in the study by treatment week 8. Quinidine > fluoxetine > placebo inhibited CYP2D6 as reflected in the change of the O-demethylation of dextromethorphan, a specific CYP2D6 probe. At treatment week 8, placebo, quinidine, and fluoxetine reduced mean daily codeine intake by 57%, 56%, and 51% of baseline intake respectively; there was no difference among treatment groups. In this small sample, CYP2D6 inhibitors did not appear to have a useful role in the treatment of codeine dependence.