DNC News

 

Tamoxifen and antidepressants, a poor combination.

 

Subject: Tamoxifen works to prevent cancer reoccurrence by interfering with the cancer promoting action of estrogen. Antidepressants may lessen the benefit of this treatment. It may be possible to predict who will get the most benefit from use.

 

Few women are happy about getting breast cancer. Nor are they happy about the increased frequency of hotflashes caused by the drug Tamoxifen which is commonly prescribed as a follow up treatment after chemotherapy and radiation treatments to lower the chance of reoccurrence of breast cancer.

 

These women are frequently prescribed anti depressants to help the depression and because some feel that these drugs also lessen the side effects of the tamoxifen. Recent research suggests that the antidepressants classified as serotonin reuptake inhibitors (SSRIs) may diminish the effectiveness of tamoxifen by limiting its conversion into the medically active chemicals that actually produce the benefit.

 

The most important of these chemicals is called endoxifen. It binds to estrogen receptors and slow cancer growth. A study published January 5, 2005 reports that taking tamoxifen along with an SSRI lowers the blood concentration of endoxifen. [i]

 

Tamoxifen is converted into endoxifen in the liver by a specific liver enzyme called CYP2D6. There are a long list of CYP enzymes that are part of the liver's P450 detoxification pathways.  You don't have to remember all these names.  Most of the various CYP liver enzymes can be induced; exposure to the chemicals which they act on stimulates increased production of the enzyme. This is why regular drinkers, smokers, or drug users build up a tolerance to their vices; with exposure they make more of the enzymes they need.  Their livers learn to make excess enzymes to detoxify the poisons. The CYP2D6 enzyme is an exception to this trait. It is considered noninducible.It doesn't respond to chemical exposure.  At this point the only thing I have found which increases CYP2D6 activity is pregnancy. [ii] Yet different people make vastly different amounts of CYP2D6.  This variation appears to be genetic.   Otherwise it would make sense to try to induce the enzyme to increase the conversion of Tamoxifen to endoxifen.

 

 

For awhile there was some thought that CYP2D6 enzymes were inhibited by St Johns Wort extracts but that theory has been disproved. [iii] Thus St Johns Wort might be considered as a possible alternative antidepressant for women taking tamoxifen. Hypericum, the active chemical in this St John's Wort, does affect some of the other CYP liver enzymes. There is a concern often raised about other drug interactions this herb may have so each situation needs to be evaluated individually.

 

There are several variations to the genes which code for the production of the CYP2D6 enzyme. Some of these variations do not work well. As a result some women are able to convert tamoxifen into endoxifen more effectively than other women. About 42% of women have the variant genes which produce an enzyme that does not convert Tamoxifen well. The women with the normal gene produce almost two to four times as much endoxifen as the ones with the variant. In women with the normal gene using SSRIs reduced endoxifen production by 58%. Paroxitine (Paxil) and sertraline (Zoloft) had the greatest effect at preventing tamoxifen conversion to endoxifen. Venlafaxine (Effexor) had less effect.

 

These results follow an earlier report by the same researchers reporting similar findings published in July, 2004. [iv]

The genetic variation in CYP2D6 production explains some of the variation in results seen in women using tamoxifen. It appears that tamoxifen will be far more effective in women who produce CYP2D6 and far less effective in the women who don't make an effective enzyme. As almost two fifths of the female population fall into the later category, we have some new information to help assess risk versus benefit before using tamoxifen.

 

The decision whether or not to use tamoxifen weighs heavily on many women being treated for breast cancer. If this research proves correct, it will make sense to determine which gene variation they have. Without the correct gene to code for CYP2D6, tamoxifen may provide little benefit. It also argues against the use of Serotonin reuptake inhibitor antidepressants while taking tamoxifen.

 

 

 

 

 

[i] J Natl Cancer Inst. 2005 Jan 5;97(1):30-9.

 

CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment.

 

Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA.

 

Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis , IN 46202 , USA .

 

BACKGROUND: The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites. METHODS: Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test. All statistical tests were two-sided. RESULTS: Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95% confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95% CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95%CI = 65.9 to 90.1 nM) (both P = .003 ). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95% CI = -86.1 to -19.5 nM, P = .0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites. CONCLUSION: Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.

 

PMID: 15632378 [PubMed - in process]

 

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[ii] Clin Pharmacol Ther. 1997 Oct;62(4):400-7.   

 

Induction of CYP2D6 in pregnancy .

 

Wadelius M, Darj E, Frenne G, Rane A.

 

Department of Clinical Pharmacology, University Hospital , Uppsala , Sweden . mia.wadelius@klinfarm.uu.se

 

Expression of the drug-metabolizing enzyme cytochrome P4502D6 (CYP2D6) is predominantly under genetic control, and enzyme-inducing drugs have little influence on its activity. We studied the activity of CYP2D6 during pregnancy. One hundred forty pregnant women were genotyped for CYP2D6. Seventeen of them (four poor metabolizers, seven heterozygous extensive metabolizers, and six extensive metabolizers) were phenotyped with dextromethorphan in late pregnancy and 7 to 11 weeks after parturition. During pregnancy the dextromethorphan/dextrorphan metabolic ratio was significantly reduced (p = 0.0015) among homozygous and heterozygous extensive metabolizers, indicating increased CYP2D6 activity. In contrast, poor metabolizers showed an increased metabolic ratio during pregnancy. These results are consistent with previous findings of a marked increase in metabolism of the CYP2D6 substrate metoprolol during pregnancy. Both studies indicate an increase in CYP2D6 activity during pregnancy, which may be caused by an induction of the CYP2D6 enzyme.

 

PMID: 9357391 [PubMed - indexed for MEDLINE]

 

[iii] Life Sci. 2000 Jan 21;66(9):PL133-9.   

Effect of St. John's wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers.

 

Markowitz JS, DeVane CL, Boulton DW, Carson SW, Nahas Z, Risch SC.

 

Department of Pharmaceutical Sciences, Medical University of South Carolina , Charleston 29425 , USA . markowij@musc.edu

 

The effects of the herb St. John's wort (Hypericum perforatum), a purported antidepressant, on the activity of cytochrome P-450 (CYP) 2D6 and 3A4 was assessed in seven normal volunteers. Probe substrates dextromethorphan (2D6 activity) and alprazolam (3A4 activity) were administered orally with and without the co-administration of St. John's wort. Urinary concentrations of dextromethorphan and dextrorphan were quantified and dextromethorphan metabolic ratios (DMRs) determined. Plasma samples were collected (0-60 hrs) for alprazolam pharmacokinetic analysis sufficient to estimate tmax, Cmax, t 1/2, and AUC. Validated HPLC methods were used to quantify all compounds of interest. No statistically significant differences were found in any estimated pharmacokinetic parameter for alprazolam or DMRs. These results suggest that St. John's wort, when taken at recommended doses for depression, is unlikely to inhibit CYP 2D6 or CYP 3A4 activity.

 

PMID: 10698361 [PubMed - indexed for MEDLINE]

 

[iv] Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition).

Vol 22, No 14S (July 15 Supplement), 2004: 508

© 2004 American Society of Clinical Oncology

 

The effect of CYP 2D6 genotype and CYP2D6 inhibitors on tamoxifen

V. Stearns, D. F. Hayes, Y. Jin, L. Ullmer, A. Nguyen, A. M. Storniolo, D. Flockhart and Z. Desta

Johns Hopkins School of Medicine, Baltimore, MD; University of Michigan, Ann Arbor, MI; Indiana University School of Medicine, Indianapolis, IN

508

Background: We have recently identified and characterized a potent active metabolite of tamoxifen, endoxifen. Co-administration of tamoxifen with the CYP 2D6 inhibitor paroxetine results in a significant reduction in plasma endoxifen concentrations (JNCI 2003;95:175864). We report preliminary data from an ongoing prospective study to confirm these findings. Methods: Wild type (Wt) or variant (Vt) genotype of CYP 2D6 (*4 & *6), 2C9 (*2 & *3), or 3A5 (*3) was determined in 80 women who were prescribed tamoxifen 20 mg/day for the adjuvant treatment of breast cancer. Plasma concentrations of tamoxifen and its metabolites N-desmethyl tamoxifen (NDM), 4-hydroxy tamoxifen (4-OH), and endoxifen, were determined 1 and 4 months after initiating tamoxifen. Results: Among subjects who carried CYP 2D6 Wt/Wt, Wt/Vt or Vt/Vt genotype, a statistically significant difference in 4-month plasma endoxifen concentrations was observed, but not in concentrations of tamoxifen or other metabolites (Table). Results were similar after 1 month of tamoxifen. Wt/Wt subjects who were not taking 2D6 inhibitors had significantly higher endoxifen concentrations than those who were Wt/Vt or Vt/Vt (P=0.007). This trend disappeared in subjects who were taking CYP 2D6 inhibitors (P=0.99). The use of CYP 2D6 inhibitors significantly decreased endoxifen concentration in Wt/Wt subjects (P=0.0001) and modestly in Wt/Vt subjects (P=0.07). The CYP 2D6 inhibitors sertraline and paroxetine, but not venlafaxine, were associated with low concentrations of endoxifen. CYP 2C9 genotype and inhibitors, and CYP 3A5 genotype did not effect plasma tamoxifen and metabolite concentrations. Conclusions: CYP 2D6 *4 and *6 genotype and the use of 2D6 inhibitors strongly influence tamoxifen conversion to endoxifen. The clinical implications of these findings are under study. Prescribing practices should not be changed at present.

 

 

 


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