Potent Cytochrome P450 2D6 Inhibitors Research Articles

Cardiac safety of ophthalmic timolol

ABSTRACTIntroduction: It is generally believed that topical administration of eye drops safeguards against harmful systemic effects. However, about 80% of the drug in the ophthalmic products is systemically absorbed and the first-pass metabolism is avoided. Ophthalmic timolol is widely prescribed in the treatment of glaucoma either alone or in the combination eye drop products, many of which have been launched fairly recently. Ophthalmic timolol may cause serious adverse effects such as symptomatic bradycardia, various conduction disorders in the heart, orthostatic hypotension, syncope and falls.Areas covered: In this review we document a number of factors associated with the properties of ophthalmic timolol and specific features of a patient, which may jeopardize patient’s cardiac safety even after topical treatment.Expert opinion: Plasma timolol levels are correlated with cardiovascular adverse effects in patients, since timolol is mainly metabolized by cytochrome P450 2D6 (CYP2D6) enzyme in the liver. Patients who are lacking the functional CYP2D6 or who are concomitantly using potent CYP2D6 inhibitor drugs (e.g. paroxetine or fluoxetine) or verapamil or other beta-blockers are at risk of getting serious cardiac adverse effects. Prior to treatment initiation, ECG should be always performed and CYP2D6 genotyping should be considered, if routinely available.

Serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity

The aims of this study were to clarify whether the ratio of S- to R-flecainide (S/R ratio) in the serum flecainide concentration was associated with the stereoselectivity of flecainide metabolism, and to investigate the effects of the cytochrome P450 (CYP) 2D6 (CYP2D6) genotype and CYP2D6 inhibitor on the serum flecainide S/R ratio. In vitro studies using human liver microsomes and cDNA-expressed CYP isoforms suggested that variability in the serum flecainide S/R ratio was associated with the stereoselectivity of CYP2D6-mediated flecainide metabolism. We examined the serum flecainide S/R ratio in 143 patients with supraventricular tachyarrhythmia. The S/R ratio was significantly lower in intermediate metabolizers and poor metabolizers (IMs/PMs) than in extensive metabolizers (EMs) identified by the CYP2D6 genotype. The cut-off value for the S/R ratio to allow the discrimination between CYP2D6 EMs and IMs/PMs was 0.99. The S/R ratio in patients with co-administration of bepridil, a potent CYP2D6 inhibitor, was lower than 0.99, regardless of the CYP2D6 genotype status. Other factors, including age, sex, body weight, and renal function, did not affect the serum flecainide S/R ratio. This study suggests that the serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity on co-administration of a CYP2D6 inhibitor.

Response to CYP2D6 substrate antidepressants is predicted by a CYP2D6 composite phenotype based on genotype and comedications with CYP2D6 inhibitors.

The cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of most antidepressants. Comedication with a potent CYP2D6 inhibitor can convert patients with extensive metabolizer (EM) or ultra-rapid metabolizer (UM) genotypes into poor metabolizer (PM) phenotypes. Since comedication is frequent in depressed patients treated with antidepressants, we investigated the effect of the CYP2D6 composite phenotype on antidepressant efficacy, taking into account both the CYP2D6 genotype and comedication with CYP2D6 inhibitors. 87 Caucasian in patients with a major depressive episode were prospectively treated with flexible doses of antidepressant monotherapy as well as comedications and genotyped for the major CYP2D6 alleles (CYP2D6*3 rs35742686, *4 rs3892097, *5 del, *6 rs5030655, and *2xN). They were classified for CYP2D6 composite phenotype and assessed for antidepressant response after 4weeks. In terms of genotypes (g), 6 subjects were UMg, 6 PMg, and 75 EMg. Ten patients were coprescribed a CYP2D6 inhibitor, resulting in the following composite phenotypes (cp): 5 UMcp, 16 PMcp, and 66 EMcp. Whereas none of the CYP2D6 genotypes were significantly associated with antidepressant response, UMcp had a lower antidepressant response than PMcp or EMcp (respectively: 39.0±17.9, 50.0±26.0, and 61.6±23.4, p=0.02). Despite small sample size, this study suggests that a CYP2D6 composite phenotype, taking into account both genotype and comedications with CYP2D6 inhibitors, could predict CYP2D6 substrate antidepressants response. Thus, to optimize antidepressant response, CYP2D6 genotype could be performed and comedications with CYP2D6 inhibitors should be avoided, when prescribing CYP2D6 substrate antidepressants.

Serotonin Syndrome

Background: There is a warning associated with all serotonergic antidepressants and its concomitant use with tramadol due to the concern for a drug–drug interaction resulting in serotonin syndrome (SS). The prescribing of antidepressants with tramadol may be unnecessarily restricted due to fear of causing this syndrome. Objectives: There are 3 objectives of this review. To (1) review case reports of SS associated with the combination of tramadol and antidepressant drugs in recommended doses, (2) describe the mechanisms of the drug interaction, and (3) identify the potential risk factors for SS. Methods: Case reports of SS associated with tramadol and antidepressants were identified via Cochrane Library, PubMed, and Ovid (through October 2012) using search terms SS, tramadol, antidepressants, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, milnacipran, trazodone, vilazodone, and bupropion. Cases involving monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were excluded. Results: Nine articles were identified describing 10 cases of suspected SS associated with therapeutic doses of tramadol combined with an antidepressant. Mechanisms of the drug–drug interactions involve pharmacodynamic, pharmacokinetic, and possible pharmacogenetic factors. Conclusions: Review of the available case reports of tramadol combined with antidepressant drugs in therapeutic doses indicates caution in regard to the potential for SS but does not constitute a contraindication to their use. Tramadol is only contraindicated in combination with MAOIs but not other antidepressants in common use today. These case reports do suggest several factors associated with a greater risk of SS, including increased age, higher dosages, and use of concomitant potent cytochrome P450 2D6 inhibitors. Tramadol can be safely combined with antidepressants; however, monitoring and counseling patients are prudent when starting a new serotonergic agent or when doses are increased.

Effects of Selective Serotonin Reuptake Inhibitors on Timolol Metabolism in Human Liver Microsomes and Cryo‐Preserved Hepatocytes

Timolol has been widely used in the treatment of glaucoma. Topically applied, timolol may cause adverse cardiovascular effects due to systemic absorption through the nasolacrimal duct. Timolol is mainly metabolized by cytochrome P450 2D6 (CYP2D6) in the liver. The aim of the present study was to characterize further the metabolism of timolol in vitro. Especially the effect of several drugs such as selective serotonin reuptake inhibitors on the metabolism of timolol was evaluated. In human liver microsomes, four timolol metabolites were identified, in cryo-preserved hepatocytes nine. In both in vitro experiments, the hydroxy metabolite M1 was the main metabolite. The in vivo half-life predicted for timolol was 3.7 hr. in cryo-preserved hepatocytes, corresponding to the half-life of timolol in humans in vivo. Fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine inhibited the formation of M1 in microsomes with IC(50) values of 1.4, 2.0, 3.5, 21 and 20 microM, respectively. In human cryo-preserved hepatocytes, the IC(50) values for fluoxetine, paroxetine and fluvoxamine were 0.7, 0.5 and 5.9 microM, respectively. In conclusion, compounds known to be potent CYP2D6 inhibitors inhibited timolol metabolism in in vitro experiments. The present results strongly suggest that fluoxetine and paroxetine may significantly affect the metabolism of timolol also in vivo and may thus potentiate the adverse cardiovascular effects of topically administered timolol.

Use of Antidepressants in Patients with Breast Cancer Taking Tamoxifen

Tamoxifen, a selective estrogen modulator has been used for more than three decades to treat all stages of estrogen receptor (ER)-positive breast cancer and to prevent the disease. Tamoxifen is a pro-drug that requires metabolic activation to 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen) to elicit its pharmacological activity. Endoxifen has identical properties and potency with 4hydroxytamoxifen, but is present in concentrations up to 10-fold higher than 4-hydroxytamoxifen. The cytochrome P450 2D6 (CYP2D6) enzyme plays a key role in converting tamoxifen into its active metabolites with significantly greater affinity for the ER and greater ability to inhibit cell proliferation. Genetic variants in the CYP2D6 gene may result in CYP2D6 enzymes with reduced or null activity, thereby decreasing the anti-cancer effect. In addition to genetic inactivation of CYP2D6, inhibitors of CYP2D6, including some antidepressants to treat hot flashes or depression in patients with breast cancer, may also alter enzyme activity and negatively affect the outcomes of patients receiving adjuvant tamoxifen. This article reviews and discusses the following issues: tamoxifen metabolism, antiproliferative effects of tamoxifen and its metabolites, CYP2D6 genetic polymorphisms, treatment for hot flashes and depression in breast cancer, and the pharmacological interactions between tamoxifen and antidepressants via CYP2D6. Although routine CYP2D6 testing is not recommended yet, coadministration of potent or intermediate CYP2D6 inhibitors in women taking tamoxifen should be avoided.

Adjuvant Tamoxifen Treatment Outcome According to Cytochrome P450 2D6 (CYP2D6) Phenotype in Early Stage Breast Cancer: Findings from the International Tamoxifen Pharmacogenomics Consortium.

Abstract Background: An estimated 1.3 million women worldwide will be diagnosed this year with early stage breast cancer. The majority of women have estrogen receptor (ER) positive breast cancer and are candidates for endocrine therapy. Tamoxifen remains the most commonly employed agent worldwide and substantially reduces recurrence and mortality. Tamoxifen is a pro-drug. CYP2D6 converts tamoxifen to endoxifen, which is primarily responsible for inhibition of estrogen-stimulated breast cancer growth in vitro. There have been conflicting reports regarding the relationship between CYP2D6 genotype/phenotype and tamoxifen clinical outcome. The ITPC was established to collect the worldwide experience relating to genetic variation in CYP2D6 and the outcomes of women with ER positive breast cancer treated with adjuvant tamoxifen. Establishment of the predictive value of CYP2D6 would enable the a priori identification of patients that could be spared ineffective therapy.Methods: Individual patient data including tumor characteristics, genotype, medication data, and recurrence information were requested from all published and non-published reports of clinical outcomes related to CYP2D6 and deposited at PharmGKB. CYP2D6 genotype was available for the following null (*3, 4, 5 and 6) and IM (*10, 17 and 41) alleles. CYP2D6 inhibiting medication data was requested for weak and potent CYP2D6 inhibitors. The primary analysis was to determine the association of CYP2D6 phenotype (combined genotype and medication) with breast cancer recurrence in tamoxifen treated early stage, ER positive invasive breast cancer.Results: At this time, the ITPC has received patient data on 3432 patients from the U.S., Sweden, UK, Germany, Belgium, and Japan. Median age at diagnosis was 62 years. CYP2D6 genotype was available in 3,392 (99%). The allele frequency for CYP2D6*4, the most common allele associated with the CYP2D6 poor metabolizer phenotype, was q=0.23. A total of 1152 recurrences representing first events (either local, regional, distant, or contralateral breast cancer) were recorded. At the time of abstract submission, patient and genotype data from an additional 1300 tamoxifen treated patients were pending submission.Conclusions: The ITPC represents the largest collection of individual patient data in regard to the potential importance of CYP2D6 phenotype in adjuvant tamoxifen therapy. The findings from this consortium are expected to substantially improve the global understanding of CYP2D6 and tamoxifen clinical outcome. Final results will be presented at the meeting Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 33.

Pharmacokinetic Variability of Aripiprazole and the Active Metabolite Dehydroaripiprazole in Psychiatric Patients

Aripiprazole is a new atypical antipsychotic drug with a partial agonist activity at dopamine 2 and serotonin 1A receptors. The metabolism of aripiprazole involves both cytochrome P450 2D6 (CYP2D6) and CYP3A4. This study investigated the pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole on the basis of 155 drug monitoring samples from psychiatric patients treated with therapeutic doses of aripiprazole (10-30 mg/day). Serum concentrations of drug and metabolite were determined by liquid chromatographic and tandem mass spectrometric detection. Pharmacokinetic variability was expressed as the range in concentration/dose (C/D) ratios, and the effect of sex and occasionally coprescribed CYP2D6 or CYP3A4 inhibitors/inducers was studied. In addition, the dose-concentration relationship and combined interquartile range of concentrations obtained at low dose (10-15 mg/day) and high dose (20-30 mg/day) were described. Individual C/D ratios ranged 37-fold for aripiprazole, 78-fold for dehydroaripiprazole, and 27-fold for the active sum of aripiprazole + dehydroaripiprazole. Median C/D ratios in male and female patients differed by less than 15%, and none of the differences were significant (P > 0.14). Cases of concurrent CYP3A4 inducers/inhibitors were not found, but three patients were coprescribed the potent CYP2D6 inhibitors paroxetine or fluoxetine. No consistent difference in C/D ratio was observed in these three patients compared with the rest of the patients. There was a proportional dose-concentration relationship in the population, and the combined interquartile ranges were 230 to 960 nmol/L for aripiprazole and 330 to 1210 nmol/L for aripiprazole + dehydroaripiprazole. In conclusion, pharmacokinetic variability of aripiprazole is extensive in psychiatric patients but apparently not dependent on dose or sex. The variability of the pharmacologic active sum of aripiprazole + dehydroaripiprazole is 25% to 30% less than aripiprazole, suggesting that variability of aripiprazole is partly determined by metabolism to dehydroaripiprazole.

The effect of selective serotonin re‐uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes

Inhibition of human cytochrome P4502D6 (CYP2D6)-catalysed metabolism can lead to clinically significant alterations in pharmacokinetics. Since there is evidence that the selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs might inhibit CYP2D6, the effects of five SSRIs on human liver microsomal CYP2D6 activity were compared with each other and with three tricyclic antidepressant drugs. On a molar basis, paroxetine was the most potent of the SSRIs at inhibiting the CYP2D6-catalysed oxidation of sparteine (Ki = 0.15 microM), although fluoxetine (0.60 microM) and sertaline (0.70 microM) had Ki values in the same range. Fluvoxamine (8.2 microM) and citalopram (5.1 microM) also inhibited CYP2D6 activity. The major circulating metabolites of paroxetine in man produced negligible inhibition. In contrast, norfluoxetine the active metabolite of fluoxetine, was a potent CYP2D6 inhibitor (0.43 microM). CYP2D6 activity was also diminished by the tricyclic antidepressant drugs clomipramine (2.2 microM), desipramine (2.3 microM) and amitriptyline (4.0 microM). These findings suggest that compounds with SSRI activity are likely to interact with human CYP2D6 in vivo with the potential of causing drug interactions.

Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers.

Duloxetine, a potent dual reuptake inhibitor of serotonin and norepinephrine currently undergoing clinical investigation for treatment of depression and stress urinary incontinence, has the potential to act as both a substrate and an inhibitor of cytochrome P4502D6 (CYP2D6). Our objectives were to determine the effect of duloxetine on the pharmacokinetics of desipramine, a tricyclic antidepressant metabolized by CYP2D6 (study 1), and the effect of paroxetine, a potent CYP2D6 inhibitor, on duloxetine pharmacokinetics (study 2). Subjects were healthy men and women between 21 and 63 years old. All subjects were genotypically CYP2D6 extensive metabolizers. In study 1, 50 mg of desipramine was administered as a single dose alone and in the presence of steady-state duloxetine 60 mg twice daily. In study 2, steady-state pharmacokinetics of duloxetine 40 mg once daily were determined in the presence and absence of steady-state paroxetine 20 mg once daily. Duloxetine increased the maximum plasma concentration of desipramine 1.7-fold and the area under the concentration-time curve 2.9-fold. Paroxetine increased the maximum plasma concentration of duloxetine and the area under the concentration-time curve at steady state 1.6-fold. Reports of adverse events were similar whether duloxetine was administered alone or in combination with desipramine or paroxetine. Duloxetine 60 mg twice daily is a moderately potent CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations. The results of these 2 studies suggest that caution should be used when CYP2D6 substrates and inhibitors are coadministered with duloxetine.

Dose-Dependent Pharmacokinetic Interaction of Clozapine and Paroxetine in an Extensive Metabolizer

A 53-year-old patient suffering from delusional disorder developed an anticholinergic syndrome 19 days after initiation of paroxetine in addition to a steady dose of clozapine. The clozapine plasma concentration had doubled and was in the toxic range. On re-exposition with a lower clozapine dosage the increase was significantly lower. The importance of a dose-dependent interaction of both drugs is emphasized and a possible pharmacological explanation described. With regard to interactions of SSRIs and clozapine, fluvoxamine, a potent inhibitor of cytochrome P450 1A2, gives rise to higher clozapine levels at an earlier time, compared to other SSRIs (paroxetine, fluoxetine and sertraline), which are potent cytochrome P450 2D6 inhibitors.