Metabolizing tamoxifen

What an interesting time we live in. Turns out that there are specific genes that affect enzymes that metabolize drugs. And some drugs inhibit the enzymes. This is important for women taking tamoxifen, because if it’s not metabolized well then it has less protective value. For me, tamoxifen is supposed to increase my survival chances just as much as chemo did. So metabolizing it well seems pretty important.

However, if I don’t metabolize it well, there’s not much in the way of other options for those of us in the pre-menopausal state. My guess, given my oncologist’s total devotion to eradicating cancer, is that if I get tested and am found to be a poor metabolizer, that he’ll say ok, time to get you post-menopausal and use aromatase inhibitors.

He’s mentioned ovarian removal several times, and we keep dancing around it – with me saying, “Umm.. NO WAY IN HELL,” and yet he keeps pushing it. I do understand his point of view – his eye is very much on the ball of keeping his patients alive, and I’m sure that he sees way too many cancers that come back, metastasized. Which is not necessarily an immediate death sentence, but it is an eventual death sentence all the same.

So I may well ask for the test. I don’t know if it’s covered by insurance. In the meantime, I noticed that one of the medicines that I take to help fight fatigue – wellbutrin – may mess with tamoxifen metabolism. Why my oncologist didn’t catch that important little detail I don’t know. Maybe it’s not as big a deal as it seems, but given his insistence that I take tamoxifen, it seems like we should do all we can to make sure it’s working. I look forward to talking with him about it, getting his take on all this info.

Here are my notes so far in preparation for meeting with him – it’s a good thing he puts up with me being such a research nerd, though I think he secretly must appreciate it at least a little:

Pharmacogenomics of Tamoxifen in a Nutshell – And Who Broke the Nutcracker? Journal of Oncology Practice, Vol 1, No 4 (November), 2005: pp. 155-159

dnadirect.com – info. on CYP2D6 and tamoxifen

tamoxifen and some antidepressants don’t mix (helpful diagrams)

drugs to test for

“The CYP2D6 Gene: 25% of Medications

The CYP2D6 gene affects 25% of drugs in clinical use. If genetic test results indicate that a person is a 2D6 Poor Metabolizer, these drugs may not be effective due to improper or slow processing of the drug by the patient; or when several drugs are administered at once, their risk for severe adverse reactions may increase due to the slower metabolism of one of the drug’s in their regimen.

In addition, some medications (including some antidepressants), can interfere with the metabolism of other 2D6-processed drugs and result in adverse side effects or lowered therapeutic benefit. The medications below are strongly affected by 2D6 gene variations, according to current research.

Drugs Metabolized by 2D6

Beta Blockers: S-metoprolol (Lopressor, Toprol XL), propafenone (Rhythmol), timolol (Blocadren)
Antidepressants: amitriptyline (Elavil), clomipramine (Anafranil), desipramine (Norpramin), duloxetine (Cymbalta), imipramine (Tofranil), paroxetine (Paxil)
Pain Medications: codeine (Empirin, Tylenol with Codeine), tramadol (Ultram)
Others: aripiprazole (Abilify), dexfenfluramine (Adifax), dextromethorphan (Robitussin, Tryaminic), flecainide (Tambocor), metoclopromide (Reglan, Maxolon, Octamide), mexiletine (Mexitil), ondansetron (Zofran), tamoxifen (Nolvadex)

Drugs That Inhibit 2D6:
amiodarone (Cordarone), bupropion (Wellbutrin, Zyban), chlorpheniramine (Chlor-Trimeton), cimetidine (Tagamet), clomipramine (Anafranil), duloxetine (Cymbalta), fluoxetine (Prozac), haloperidol (Haldol), methadone (Dolophine), mibefradil (Posicor), paroxetine (Paxil), quinidine (Cardioquin, Quinaglute, Quinidex), ritonavir (Norvir)”

Inhibition of CYP2D6 activity by bupropion, J Clin Psychopharmacol. 2005 Jun;25(3):226-9.

“Bupropion is therefore a potent inhibitor of CYP2D6 activity, and care should be exercised when initiating or discontinuing bupropion use in patients taking drugs metabolized by CYP2D6.”

Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations. Clin Ther. 2005 Nov;27(11):1685-95.

“In addition, bupropion inhibits CYP2D6 and may reduce clearance of agents metabolized by this enzyme.”

Bupropion: pharmacology and therapeutic applications. Expert Rev Neurother. 2006 Sep;6(9):1249-65.

“Bupropion undergoes metabolic transformation to an active metabolite, 4-hydroxybupropion, through hepatic cytochrome P450-2B6 (CYP2B6) and has inhibitory effects on cytochrome P450-2D6 (CYP2D6), thus raising concern for clinically-relevant drug interactions.”

Toys R on Us & the Bad Oncologist, Cancer Bitch, Oct. 24, 2007.

“My psychiatrist, the Effusive Shrink, had told me early on that some of my anti-despair medicines would mix badly with Tamoxifen. I mentioned this to the first oncologist while I was in the middle of chemo and he waved me off, saying there was plenty of time yet. The Effusive Shrink had to call him twice before he called her back. Flash forward to the Girl Oncologist, who made me wait while she looked up drug interactions. She found one, with Cymbalta. She said she’d talk to the Effusive Shrink about substituting Effexor. I met with the Effusive Shrink today who said that another anti-nihilism drug that I take, Wellbutrin, also mixes badly with Tamoxifen.”

Pharmacogenomics in the Clinic: New Questions About Tamoxifen

“Is testing cost-effective? The CYP2D6 test is commercially available for about $250. By comparison, a 5-year course of tamoxifen costs roughly $5,000. Thus, women who would not receive tamoxifen produce a savings for the health care system even after testing for PMs prospectively, to say nothing of avoiding the suffering and salvage maneuvers of administering ineffective therapy upfront. Not least, liability pressures coming from those with relapsed disease in the adjuvant tamoxifen setting are probably indefensible, given the easy availability of CYP2D6 testing already….oncologists should embrace the new insights about tamoxifen and make CYP2D6 testing routine.”

+ interesting article about the issue of genetically impacted metabolism of antidepressants:

Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics. 2006 Jan-Feb;47(1):75-85.

“Pharmacogenetics has arrived in clinical psychiatric practice with the FDA approval of the AmpliChip CYP450 Test that genotypes for two cytochrome P450 2D6 (CYP2D6) and 2C19 (CYP2C19) genes. …..CYP2D6 is important for the metabolism of many antidepressants and antipsychotics, and CY2C19 is important for some antidepressant metabolism.”

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Filed under breast cancer, CYP2D6, tamoxifen, tests

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