LETTER TO THE EDITORS
Cytochrome P450 2D6 Poor Metabolism, Curvilinearity, and Response An Intriguing Observation Requiring Integration of Psychopharmacology Into Pharmacogenetics To the Editors: e read with interest the guest editorial in which Drs Macaluso and Preskorn1 refer to a recent pharmacogenetic report.2 In that report, data from 4 placebocontrolled, double-blind, efficacy trials of venlafaxine (VEN) were analyzed. The analyses suggest that cytochrome P450 2D6 (CYP2D6) poor metabolizers (PMs) exhibit significantly lower antidepressant response and remission rates when compared with extensive metabolizers (EMs), despite similar average dose, blood levels, and tolerability profile. Macaluso and Preskorn1 hypothesize that PMs are inherently resistant to certain antidepressants and that this resistance may be responsible for the curvilinear concentration-effect relationship observed with nortriptyline. In this letter, we like to elaborate on this point because we think that the proposed hypothesis may have significant clinical implications and because PMs are considered to be generally more sensitive to the pharmacologic effects of the drugs involved. For the sake of simplicity, we focus on VEN. After its absorption, VEN undergoes extensive first pass metabolism (Fig. 1). The main, pharmacologically active, metabolite of VEN is O-desmethylvenlafaxine (ODV).3 However, VEN is also metabolized to N-desmethylvenlafaxine (NDV), N2Odidesmethylvenlafaxine (NDDV), and other minor metabolites. The pharmacological activities of NDV and NDDV are currently unknown. The formation of ODV and NDV is catalyzed by CYP2D6 and CYP3A4, respectively (Lessard et al3 and VEN summary of product characteristics). Considering the VEN study,2 discussed in the editorial mentioned before, one should note that although the total concentration (VEN + ODV) was similar in both groups, PMs and EMs differed from each other in their ratios of VEN to ODV. Expectably, PMs had lower ODV levels and higher VEN levels (and vice versa for EMs).
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FIGURE 1. A simplified scheme of VEN metabolism.
This difference is likely to be relevant, because VEN and ODV differ pharmacologically. For example, the in vitro activities of VEN are expected to be 80% higher and 10% lower than ODV in terms of central noradrenalin and serotonin reuptake inhibition, respectively.4 Furthermore, the extent of blood-brain barrier penetration may differ substantially between VEN and ODV. The brain-to-plasma ratio of VEN in mice is 3.5 times higher than that of ODV.4 The elimination half-lives of VEN and of ODV are also different (4 hours vs 10 hours, respectively).5 In our opinion, the aforementioned differences limit the utility of the sum of VEN and ODV concentrations as a comparison parameter between PMs and EMs. In fact, we believe that that the observed difference in clinical efficacy between PMs and EMs may possibly be due to differences in the concentration of the metabolites produced. Because PMs may exhibit significantly higher VEN but lower ODV concentrations in their brains when compared with ultrarapid metabolizers and EMs, we expect that the pharmacological effects in these patients will be predominantly mediated through noradrenergic stimulation. Probably, more potent serotonin reuptake inhibition is required for an adequate pharmacological effect. There is additional evidence to suggest that PMs may intrinsically have a lower cerebral serotonergic activity. Cytochrome P450 2D6, mostly known for its hepatic involvement in the metabolism of many of the drugs prescribed today, is also expressed in the human brain tissue where it takes part in the wake-sleep cycle and in serotonin regeneration from melatonin.6 One trace amine, 5-methoxytryptamine, is substrate to CYP2D6, which catalyzes its conversion to
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serotonin.6 If the activity of CYP2D6 is reduced, then it might be possible that carriers of such phenotype intrinsically have reduced serotonin levels. Furthermore, and as could be predicted from Figure 1, reduced or absent CYP2D6 activity leads to preferential overproduction of NDV and underproduction of ODV and NDDV. Such metabolic shunting (up to 22-fold higher NDV concentrations in PMs vs EMs) has been observed in clinical samples previously.7 It is currently unknown what actions these metabolites may exert in the brain of humans. In conclusion, we believe that in patients treated with VEN, variability in CYP2D6 metabolic status may result in significant differences in the cerebral levels of the various metabolites, even if the total sum of the concentrations is not significantly affected by differences in the enzyme activity. We furthermore believe that differences in the levels of the various metabolites may contribute to differences in clinical response. Thorough knowledge of psychopharmacology may aid the appropriate interpretation of pharmacogenetic data in the future. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Asmar F. Al Hadithy, PharmD, PhD Parnassia Psychiatric Institute Hospital Pharmacy The Hague, the Netherlands
[email protected]
Tom K. Birkenhager, MD, PhD Department of Psychiatry Erasmus Medical Center Rotterdam, the Netherlands www.psychopharmacology.com
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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Letter to the Editors
Birgit C. Koch, PharmD, PhD Department of Hospital Pharmacy Erasmus Medical Center Rotterdam, the Netherlands
REFERENCES 1. Macaluso M, Preskorn SH. CYP 2D6 PM status and antidepressant response to nortriptyline and venlafaxine: is it more than just drug metabolism? J Clin Psychopharmacol. 2011;31:143Y145. 2. Lobello KW, Preskorn SH, Guico-Pabia CJ. Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: a
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secondary analysis of 4 studies in major depressive disorder. J Clin Psychiatry. 2010;71(11):1482Y1487.
pharmacokinetics of venlafaxine and its active O-desmethyl metabolite. J Clin Pharmacol. 1992;32:716Y724.
3. Lessard E, Yessine MA, Hamelin BA, et al. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol. 2001;21(2):175Y184.
6. Schyman P, Usharani D, Wang Y, et al. Brain chemistry: how does P450 catalyze the O-demethylation reaction of 5-methoxytryptamine to yield serotonin? J Phys Chem B. 2010;114(20):7078Y7089.
4. Hendset M, Haslemo T, Rudberg I, et al. The complexity of active metabolites in therapeutic drug monitoring of psychotropic drugs. Pharmacopsychiatry. 2006;39(4):121Y127. 5. Klamerus KJ, Maloney K, Rudolph RL, et al. Introduction of a composite parameter to the
7. Hermann M, Hendset M, Fosaas K, et al. Serum concentrations of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in heterozygous carriers of the CYP2D6*3, *4 or *5 allele. Eur J Clin Pharmacol. 2008;64(5): 483Y487.
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Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
