Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients With Depression.

PURPOSE: The aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression. METHODS: Patients combining BUP with venlafaxine were included from a therapeutic drug monitoring (TDM) database at the Diakonhjemmet Hospital (Oslo, Norway). The O/N-desmethylvenlafaxine metabolic ratio measured in TDM samples was used as a biomarker for CYP2D6 phenotype and was compared between patients treated with BUP 150 mg/d and 300 mg/d or greater. In addition, reference groups of venlafaxine-treated patients genotyped as CYP2D6 poor metabolizers (PMs, no CYP2D6 activity) and normal metabolizers (NMs, fully functional CYP2D6 activity) were included. FINDINGS: A total of 221 patients were included in the study. The median O/N-desmethylvenlafaxine metabolic ratio was significantly higher in patients treated with BUP 150 mg/d (n = 59) versus 300 mg/d or greater (n = 34, 1.77 vs 0.96, P < 0.001). In CYP2D6 NMs (n = 62) and PMs (n = 66), the median metabolic ratios were 40.55 and 0.48, respectively. For patients treated with BUP 150 mg/d, 11 (19%) of the 59 patients were phenoconverted to PMs, whereas this was the case for 17 (50%) of the 34 patients treated with BUP 300 mg/d or greater. CONCLUSIONS: Bupropion exhibits a clear dose-dependent CYP2D6 inhibitory effect during treatment of patients with depression. This finding is of clinical relevance when adjusting dosing of CYP2D6 substrates during comedication with BUP. Half of the patients treated with high-dose BUP are converted to CYP2D6 PM phenotype. Because of the variability in CYP2D6 inhibition, TDM of CYP2D6 substrates should be considered to provide individualized dose adjustments during comedication with BUP.

The inhibition of CYP1A2, CYP2C9, and CYP2D6 by pterostilbene in human liver microsomes.

This study used human liver microsomes to assess pterostilbene's effect on the metabolic activity of cytochrome P450 (CYP) 1A2, CYP2C9, and CYP2D6. The metabolism of their substrates (phenacetin, tolbutamide, and dextromethorphan) was assayed by quantifying their relevant metabolites by HPLC. The IC50 value was used to express the strength of inhibition, and the value of a volume per dose index (VDI) was used to indicate the metabolic ability of the enzyme. In this study, pterostilbene inhibited CYP1A2, CYP2C9, and CYP2D6's metabolic activities in vitro. CYP2C9's activity was most significantly inhibited by pterostilbene; its IC50 value was 0.12±0.04 µM. The IC50 value of CYP1A2 and CYP2D6 was 56.3±10.4 µM and 62.33±11.4 µM, respectively. The finding that suggests that pterostilbene has the potential to interact with CYP2C9 substrates in vivo. These results warrant clinical studies to assess the in vivo significance of these interactions.

Influence of Zuojin Pill on the Metabolism of Venlafaxine in Vitro and in Rats and Associated Herb-Drug Interaction.

Venlafaxine (VEN), a first-line antidepressant, and Zuojin Pill (ZJP), a common Chinese herbal medicine consisting of Rhizoma Coptidis and Fructus Evodiae, have a high likelihood of combination usage in patients with depression with gastrointestinal complications. ZJP exhibits inhibitory effects on recombinant human cytochrome P450 isoenzymes (rhP450s), especially on CYP2D6, whereas VEN undergoes extensive metabolism by CYP2D6. From this perspective, we investigated the influence of ZJP on the metabolism of VEN in vitro and in rats for the first time. In this study, ZJP significantly inhibited the metabolism of VEN in both rat liver microsomes (RLM) and human liver microsomes (HLM); meanwhile, it inhibited the O-demethylation catalytic activity of RLM, HLM, rhCYP2D6*1/*1, and rhCYP2D6*10/*10, primarily through CYP2D6, with IC50 values of 129.9, 30.5, 15.4, and 2.3 µg/ml, respectively. Furthermore, the inhibitory effects of ZJP on hepatic metabolism and pharmacokinetics of VEN could also be observed in the pharmacokinetic study of rats. The area under drug concentration-time curve0-24 hour of VEN and its major metabolite O-desmethylvenlafaxine (ODV) increased by 39.6% and 22.8%, respectively. The hepatic exposure of ODV decreased by 57.2% 2 hours after administration (P = 0.014). In conclusion, ZJP displayed inhibitory effects on hepatic metabolism and pharmacokinetics of VEN in vitro and in rats mainly through inhibition of CYP2D6 activity. The human pharmacokinetic interaction between ZJP and VEN and its associated clinical significance needed to be seriously considered. SIGNIFICANCE STATEMENT: Zuojin Pill, a commonly used Chinese herbal medicine, demonstrates significant inhibitory effects on hepatic metabolism and pharmacokinetics of venlafaxine in vitro and in rats mainly through suppression of CYP2D6 activity. The human pharmacokinetic interaction between Zuojin Pill and venlafaxine and its associated clinical significance needs to be seriously considered.

The impact of drug interactions on adverse effects of oral oxycodone in male geriatric patients.

WHAT IS KNOWN AND OBJECTIVE: With increased opioid use, drug-drug interactions (DDIs) and associated adverse events are growing among geriatric patients. However, the clinical significance of potential metabolic DDIs associated with opioid use has not been fully evaluated among geriatric patients. Particularly, cytochrome (CYP) P450 enzymes are important in drug metabolism of oxycodone and a black box warning for oxycodone reveals serious risks associated with drug-oxycodone interactions. This study focused on the use of oxycodone in geriatric patients to evaluate its adverse drug reactions (ADRs) and DDIs associated with CYP P450 enzymes. METHODS: A retrospective cohort study using patients treated at Korea Veterans Hospital was performed. Data from male patients aged 65 years and older who received oxycodone were analysed. Binomial variables describing patient-related characteristics, drug-related characteristics and CYP-mediating drugs were constructed. Associations between these variables and the frequency of ADRs were determined. The odds ratio (OR) and adjusted odds ratio (AOR) were calculated from univariable and multivariable analyses, respectively. RESULTS AND DISCUSSION: Among 111 patients, 32.4% experienced at least one ADR. The most common ADR was gastrointestinal-related (n = 21), followed by dizziness and drowsiness (n = 8). Use of either CYP2D6 inhibitors or CYP3A4 inhibitors increased the rate of ADRs by 20.4 and 25.4 times, respectively. In the case of patients taking both inhibitors, the adjusted OR was 48.6, and the attributable risk was 97.9%. WHAT IS NEW AND CONCLUSION: This study suggests that inappropriate combinations of oxycodone with CYP2D6 inhibitors and/or CYP3A4 inhibitors may warrant treatment modification to avoid ADRs in geriatric patients. Clinicians should monitor any signs of ADRs that may reflect DDIs while a geriatric patient is taking oxycodone.

How to Treat Hypertension in Venlafaxine-Medicated Patients-Pharmacokinetic Considerations in Prescribing Amlodipine and Ramipril.

BACKGROUND: Amlodipine (AMLO) and ramipril (RAMI) belong to the most prescribed drugs in patients with hypertension, a condition also encountered in depression. Venlafaxine may worsen hypertension because of noradrenergic properties. Although of special clinical relevance, data on pharmacokinetic interactions between AMLO, RAMI, and venlafaxine (VEN) are lacking. METHODS: Two TDM databases consisting of plasma concentrations of VEN and its active metabolite O-desmethylvenlafaxine (ODVEN) were analyzed. We considered a group of patients comedicated with AMLO, VAMLO (n = 22); a group comedicated with RAMI, VRAMI (n = 20); and a 4:1 control group age matched to the VAMLO group receiving VEN without confounding medications, V0 (n = 88). Plasma concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN); metabolic ratio (ODVEN/VEN); and dose-adjusted plasma concentrations (C/D) were compared using nonparametric tests. RESULTS: Groups did not differ in daily VEN dose, age, or sex. The metabolic ratio (ODVEN/VEN) was lower in the AMLO group (P = 0.029), whereas the RAMI group showed lower values for ODVEN (P = 0.029). All other parameters showed no significant differences. CONCLUSIONS: Significantly lower values for the metabolic ratio in the AMLO group are unlikely to be explained by cytochrome P450 (CYP) 3A4 and weak CYP2D6 inhibition by AMLO. Other factors such as differences in CYP2D6 polymorphisms and metabolizer status may better explain the findings. Ramipril showed modest effects with changes in ODVEN concentrations that did not remain significant after dose-adjusted comparisons.

Discontinuation and dose adjustment of metoprolol after metoprolol-paroxetine/fluoxetine co-prescription in Dutch elderly.

PURPOSE: Co-prescription of paroxetine/fluoxetine (a strong CYP2D6 inhibitor) in metoprolol (a CYP2D6 substrate) users is common, but data on the clinical consequences of this drug-drug interaction are limited and inconclusive. Therefore, we assessed the effect of paroxetine/fluoxetine initiation on the existing treatment with metoprolol on the discontinuation and dose adjustment of metoprolol among elderly. METHODS: We performed a cohort study using the University of Groningen IADB.nl prescription database (www.IADB.nl). We selected all elderly (≥60 years) who had ever been prescribed metoprolol and had a first co-prescription of paroxetine/fluoxetine, citalopram (weak CYP2D6 inhibitor), or mirtazapine (negative control) from 1994 to 2015. The exposure group was metoprolol and paroxetine/fluoxetine co-prescription, and the other groups acted as controls. The outcomes were early discontinuation and dose adjustment of metoprolol. Logistic regression was applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Combinations of metoprolol-paroxetine/fluoxetine, metoprolol-citalopram, and metoprolol-mirtazapine were started in 528, 673, and 625 patients, respectively. Compared with metoprolol-citalopram, metoprolol-paroxetine/fluoxetine was not significantly associated with the early discontinuation and dose adjustment of metoprolol (OR = 1.07, 95% CI:0.77-1.48; OR = 0.87, 95% CI:0.57-1.33, respectively). In comparison with metoprolol-mirtazapine, metoprolol-paroxetine/fluoxetine was associated with a significant 43% relative increase in early discontinuation of metoprolol (OR = 1.43, 95% CI:1.01-2.02) but no difference in the risk of dose adjustment. Stratified analysis by gender showed that women have a significantly high risk of metoprolol early discontinuation (OR = 1.62, 95% CI:1.03-2.53). CONCLUSION: Paroxetine/fluoxetine initiation in metoprolol prescriptions, especially for female older patients, is associated with the risk of early discontinuation of metoprolol.

Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1A weak partial agonistic activity showing the antidepressant-like effect.

We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.

Delirium associated with concomitant use of duloxetine and bupropion in an elderly patient.

Delirium is common in daily practice. Drug-induced delirium constitutes approximately one-third of all cases of delirium. In cases characterized by the limited efficacy of a single antidepressant, a combination of two antidepressants is required, which may induce a complex drug-drug interaction. We reviewed a case of duloxetine- and bupropion-related delirium in an elderly male patient in our clinical practice. The patient was diagnosed with major depressive disorder and was treated with duloxetine. However, he developed delirium 10 days after bupropion was added to his treatment regimen. Three days after the cessation of bupropion, his delirious condition gradually improved. Duloxetine and bupropion are both cytochrome P450 2D6 inhibitors that may result in a higher level of hydroxybupropion. An increased level of hydroxybupropion may cause the elevation of dopamine and a risk of subsequent delirium. We should be aware of the risk of delirium induced by drug-drug interactions.

The Psychostimulant Khat (Catha edulis) Inhibits CYP2D6 Enzyme Activity in Humans.

The use of khat (Catha edulis) while on medication may alter treatment outcome. In particular, the influence of khat on the metabolic activities of drug-metabolizing enzymes is not known. We performed a comparative 1-way crossover study to evaluate the effect of khat on cytochrome P450 (CYP)2D6 and CYP3A4 enzyme activity. After 1 week of khat abstinence, baseline CYP2D6 and CYP3A4 metabolic activities were determined in 40 Ethiopian male volunteers using 30 mg dextromethorphan (DM) as a probe drug and then repeated after 1 week of daily use of 400 g fresh khat leaves. Urinary concentrations of cathinone and cathine were determined to monitor the subjects' compliance to the study protocol. Genotyping for CYP2D6*3 and CYP2D6*4 was done. Plasma DM, dextrorphan and 3-methoxymorphinan concentrations were quantified. CYP2D6 and CYP3A4 enzyme activities were assessed by comparing plasma log DM/dextrorphan and log DM/methoxymorphinan metabolic ratio (MR) respectively in the presence and absence of khat. Cytochrome 2D6 MR was significantly increased from baseline by concurrent khat use (paired t test, P = 0.003; geometric mean ratio, 1.38; 95% confidence interval [95% CI], 1.12-1.53). Moreover, the inhibition of CYP2D6 activity by khat was more pronounced in CYP2D6*1/*1 compared with CYP2D6*1/*4 genotypes (P = 0.01). A marginal inhibition of CYP3A4 activity in the presence of khat was observed (P = 0.24). The mean percentage increase of CYP2D6 and CYP3A4 MR from baseline by khat use was 46% (95% CI, 20-72) and 31% (95% CI, 8-54), respectively. This is the first report linking khat use with significant inhibition of CYP2D6 metabolic activity in humans.

Effect of the potent CYP2D6 inhibitor sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers.

1. Recently, we demonstrated that sarpogrelate is a potent and selective CYP2D6 inhibitor in vitro. Here, we evaluated the effect of sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy subjects. 2. Nine healthy male subjects genotyped for CYP2D6*1/*1 or *1/*2 were included in an open-label, randomized, three treatment-period and crossover study. A single oral dose of metoprolol (100 mg) was administered with water (treatment A) and sarpogrelate (100 mg bid.; a total dose of 200 mg and treatment B), or after pretreatment of sarpogrelate for three days (100 mg tid.; treatment C). Plasma levels of metoprolol and α-hydroxymetoprolol were determined using a validated LC-MS/MS method. Changes in heart rate and blood pressure were monitored as pharmacodynamic responses to metoprolol. 3. Metoprolol was well tolerated in the three treatment groups. In treatment B and C groups, the AUCt of metoprolol increased by 53% (GMR, 1.53; 90% CI, 1.17-2.31) and by 51% (1.51; 1.17-2.31), respectively. Similar patterns were observed for the increase in Cmax of metoprolol by sarpogrelate. However, the pharmacodynamics of metoprolol did not differ significantly among the three treatment groups. 4. Greater systemic exposure to metoprolol after co-administration or pretreatment with sarpogrelate did not result in clinically relevant effects. Co-administration of both agents is well tolerated and can be employed without the need for dose adjustments.

Evaluation of the likelihood of a selective CHK1 inhibitor (LY2603618) to inhibit CYP2D6 with desipramine as a probe substrate in cancer patients.

LY2603618 is a selective inhibitor of deoxyribonucleic acid damage checkpoint kinase 1 (CHK1) and has been in development for the enhancement of chemotherapeutic agents. The study described was to assess the potential interaction between LY2603618 and cytochrome P450 isoform 2D6 (CYP2D6) substrate desipramine in patients with cancer. Before clinical investigation, in silico simulations (using Simcyp®) were conducted. An open-label, two-period, fixed-sequence study was planned in 30 patients with advanced or metastatic cancers, in which a 50 mg oral dose of desipramine was administered alone and in combination with 275 mg of LY2603618 (i.v. infusion). An interim analysis was planned after 15 patients completed both periods. Ratios of geometric least squares means (LSMs) of primary pharmacokinetic (PK) parameters and 90% repeated confidence intervals (RCIs) between desipramine plus LY2603618 and desipramine alone were calculated. Lack of an interaction was declared if the 90% RCI fell between 0.8 and 1.25. The LSM ratios (90% RCI) for areas under the plasma concentration-time curve from time zero to tlast (AUC[0-tlast]) and to infinity (AUC[0-∞]) and maximum plasma concentration (Cmax) were 1.14 (1.04, 1.25), 1.09 (0.99, 1.21) and 1.16 (1.05, 1.29). In silico simulations were predictive of clinical results. Single doses of 275 mg LY2603618 administered with 50 mg desipramine were generally well tolerated. In conclusion, no clinically significant interaction was observed between LY2603618 and desipramine in patients with cancer. In silico predictions of clinical results demonstrated that mechanistic and physiologically based PK approaches may inform clinical study design in cancer patients.

Pharmacokinetics and Safety of Atogepant Co-administered with Quinidine Gluconate in Healthy Participants: A Phase 1, Open-Label, Drug-Drug Interaction Study.

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, is approved for the preventive treatment of migraine. Atogepant is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein, organic anion transporting polypeptide transporters, and cytochrome P450 (CYP)3A4 and 2D6. Quinidine is a strong P-gp and CYP2D6 inhibitor. A phase 1 open-label study evaluated the effect of P-gp and CYP2D6 inhibition by quinidine on the pharmacokinetics of atogepant, and the safety and tolerability of atogepant and quinidine gluconate (QG) when co-administered and when given alone in 33 healthy adults. There was no significant change in the atogepant maximum plasma concentration with QG co-administration. The overall systemic exposure, the area under the plasma concentration-time curve (from time 0 to time t or to infinity), of atogepant increased by 25% when co-administered with QG. However, such an increase was not considered clinically relevant. Atogepant did not alter the mean plasma concentration of quinidine at steady state. The incidence of treatment-emergent adverse events (TEAEs) was highest when QG was administered alone (42.4%), which was primarily due to QT prolongation. Most TEAEs reported were mild in severity and resolved within 1-2 days. Co-administration of atogepant with QG did not result in any unexpected tolerability findings in this phase 1 study in healthy participants. The increase in atogepant exposure during QG co-administration could be due to inhibition of CYP2D6 (a minor contributor to atogepant clearance) as well as inhibition of P-gp.

Development and evaluation of a physiologically based pharmacokinetic model to predict carvedilol-paroxetine metabolic drug-drug interaction in healthy adults and its extrapolation to virtual chronic heart failure patients for dose optimization.

Purpose: The metabolic drug-drug interactions (mDDIs) are one of the most important challenges faced by the pharmaceutical industry during the drug development stage and are frequently associated with labeling restrictions and withdrawal of drugs. The capacity of physiologically based pharmacokinetic (PBPK) models to absorb and upgrade with the newly available information on drug and population-specific parameters, makes them a preferred choice over the conventional pharmacokinetic models for predicting mDDIs.Method: A PBPK model capable of predicting the stereo-selective disposition of carvedilol after administering paroxetine by incorporating mechanism (time) based inhibition of CYP2D6 and CYP3A4 was developed by using the population-based absorption, distribution, metabolism and elimination (ADME) simulator, Simcyp®.Results: The model predictions for both carvedilol enantiomers were in close agreement with the observed PK data, as the ratios for observed/predicted PK parameters were within the 2-fold error range. The developed PBPK model was successful in capturing an increase in exposures of R and S-carvedilol, due to the time-based inhibition of CYP2D6 enzyme caused by paroxetine.Conclusion: The developed model can be used for exploring complex clinical scenarios, where multiple drugs are given concurrently, particularly in diseased populations where no clinical trial data is available.

Characterization of the Effect of Upadacitinib on the Pharmacokinetics of Bupropion, a Sensitive Cytochrome P450 2B6 Probe Substrate.

This phase 1 study characterized the effect of multiple doses of upadacitinib, an oral Janus kinase 1 selective inhibitor, on the pharmacokinetics of the cytochrome P450 (CYP) 2B6 substrate bupropion. Healthy subjects (n = 22) received a single oral dose of bupropion 150 mg alone (study period 1) and on day 12 of a 16-day regimen of upadacitinib 30 mg once daily (study period 2). Serial blood samples for measurement of bupropion and hydroxybupropion plasma concentrations were collected in each study period. The central values (90% confidence intervals) for the ratios of change were 0.87 (0.79-0.96) for bupropion maximum plasma concentration (Cmax ), 0.92 (0.87-0.98) for bupropion area under the plasma-concentration time curve from time 0 to infinity (AUCinf ), 0.78 (0.72-0.85) for hydroxybupropion Cmax , and 0.72 (0.67-0.78) for hydroxybupropion AUCinf when administered with, relative to when administered without, upadacitinib. After multiple-dose administration of upadacitinib 30 mg once daily, upadacitinib mean ± SD AUC0-24 was 641 ± 177 ng·h/mL, and Cmax was 83.3 ± 30.7 ng/mL. These results confirm that upadacitinib has no relevant effect on pharmacokinetics of substrates metabolized by CYP2B6.

Effect of Paroxetine-Mediated G-Protein Receptor Kinase 2 Inhibition vs Placebo in Patients With Anterior Myocardial Infarction: A Randomized Clinical Trial.

Importance: Left ventricular remodeling following acute myocardial infarction results in progressive myocardial dysfunction and adversely affects prognosis. Objective: To investigate the efficacy of paroxetine-mediated G-protein-coupled receptor kinase 2 inhibition to mitigate adverse left ventricular remodeling in patients presenting with acute myocardial infarction. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial was conducted at Bern University Hospital, Bern, Switzerland. Patients with acute anterior ST-segment elevation myocardial infarction with left ventricular ejection fraction (LVEF) of 45% or less were randomly allocated to 2 study arms between October 26, 2017, and September 21, 2020. Interventions: Patients in the experimental arm received 20 mg of paroxetine daily; patients in the control group received a placebo daily. Both treatments were provided for 12 weeks. Main Outcomes and Measures: The primary end point was the difference in patient-level improvement of LVEF between baseline and 12 weeks as assessed by cardiac magnetic resonance tomography. Secondary end points were changes in left ventricular dimensions and late gadolinium enhancement between baseline and follow-up. Results: Fifty patients (mean [SD] age, 62 [13] years; 41 men [82%]) with acute anterior myocardial infarction were randomly allocated to paroxetine or placebo, of whom 38 patients underwent cardiac magnetic resonance imaging both at baseline and 12 weeks. There was no difference in recovery of LVEF between the experimental group (mean [SD] change, 4.0% [7.0%]) and the control group (mean [SD] change, 6.3% [6.3%]; mean difference, -2.4% [95% CI, -6.8% to 2.1%]; P = .29) or changes in left ventricular end-diastolic volume (mean difference, 13.4 [95% CI, -12.3 to 39.0] mL; P = .30) and end-systolic volume (mean difference, 11.4 [95% CI, -3.6 to 26.4] mL; P = .13). Late gadolinium enhancement as a percentage of the total left ventricular mass decreased to a larger extent in the experimental group (mean [SD], -13.6% [12.9%]) compared with the control group (mean [SD], -4.5% [9.5%]; mean difference, -9.1% [95% CI, -16.6% to -1.6%]; P = .02). Conclusions and Relevance: In this trial, treatment with paroxetine did not improve LVEF after myocardial infarction compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03274752.

Combining Antidepressants with ß-Blockers: Evidence of a Clinically Significant CYP2D6 Drug Interaction.

BACKGROUND: The ß-blockers and antidepressants are two of the most commonly prescribed drug classes in the United States. Several antidepressants are potent inhibitors of cytochrome P450 2D6 liver enzymes (CYP2D6) and can increase the plasma concentrations of certain ß-blockers when administered concomitantly, potentially leading to serious medical consequences such as hypotension, bradycardia, and falls. OBJECTIVE: The primary objective of this investigation was to determine whether initiating an antidepressant in patients receiving ß-blockers increased the risk of hemodynamic adverse events. Our primary outcome was time to hospital admissions or emergency department (ED) visits for an International Classification of Diseases-9 diagnosis suggestive of excessive ß-blockade. METHODS: We conducted a survival analysis for adults continuously enrolled in the California Medicaid system (Medi-Cal) between 2004 and 2012. Eligible patients were required to be receiving ß-blocker medications that are primarily CYP2D6 substrates (e.g., metoprolol, propranolol, or carvedilol). Univariate and multivariable analyses were performed for patients who concurrently received antidepressants with ß-blockers. An additional multivariable analysis analyzed the association of this combination upon hospitalizations or ED visits for all causes. RESULTS: A total of 21,292 beneficiaries met the inclusion criteria, and 4.3% of patients required hospitalization or ED visits within 30 days of co-medication. In multivariable analysis, patients receiving antidepressants with moderate to strong CYP2D6 inhibitory potential (fluoxetine, paroxetine, duloxetine, or bupropion) had a greater risk for hospitalization or ED visits for hemodynamic events than those initiated on antidepressants with weak CYP2D6 inhibition for 30 days or less when each was compared with patients receiving no antidepressants (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.03-2.81; p=0.04 vs HR 1.24; 95% CI 0.82-1.88; p=0.30). Other demographic variables associated with increased morbidity included advanced age, male sex, higher ß-blocker doses, and African American race or Hispanic ethnicity. CONCLUSIONS: Results of this analysis suggest that initiation of certain antidepressants was associated with an increased risk for serious medical sequelae among patients concurrently receiving ß-blockers. Greater risk was observed with antidepressants that potently inhibit the CYP2D6 enzyme, implying that increased morbidity may be mediated by a metabolic drug interaction.

Assessment of the rapid and sustained antidepressant-like effects of dextromethorphan in mice.

The glutamatergic system has emerged as a novel pathway for treating major depressive disorder (MDD) with the focus on producing both rapid and sustained antidepressant effects. Dextromethorphan is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has produced antidepressant-like effects in forced swim and tail suspension tests (TST); however, the rapid and sustained antidepressant-like effects of dextromethorphan have not been evaluated. This study evaluated the rapid and sustained (24 h) antidepressant-like effects of dextromethorphan (0-32 mg/kg) in C56BL/6 mice using the novelty-induced hypophagia (NIH) test and TST, respectively. Additionally, we evaluated anxiety-related behavior and locomotor effects of dextromethorphan (0-56.0 mg/kg) using the light-dark and open field tests. Dextromethorphan (32 mg/kg) produced acute (30 min) antidepressant-like effects in TST, but failed to produce antidepressant-like effects 24 h after drug administration. Treatment of dextromethorphan (32 mg/kg) alone or in combination with CYP2D6 enzyme inhibitor Quinidine (32 mg/kg) failed to produce rapid antidepressant-like effects by increasing the latency to drink in the NIH test rather than decreasing the latency to drink. Dextromethorphan (56 mg/kg) produced an anxiogenic-like effect by decreasing the time spent in the light side, number of entries, and latency to enter the light side in the light-dark test. Administration of dextromethorphan (0-56 mg/kg) did not significantly alter locomotor activity. Although dextromethorphan is considered a noncompetitive NMDA receptor antagonist, dextromethorphan binds to several monoaminergic receptors (SERT and NET) and likely produces the antidepressant-like effects through these receptors similar to traditional antidepressant drugs. Additionally, these results suggest that the therapeutic window for dextromethorphan in the clinical population is small as similar doses produce antidepressant-like and anxiogenic-like behaviors.

Drug interactions with Bruton's tyrosine kinase inhibitors: clinical implications and management.

Bruton's tyrosine kinase (BTK) plays an essential role in B-cell development, differentiation and B-cell receptor (BCR) signaling. The use of Bruton's tyrosine kinase inhibitors (BTKi) in the treatment of lymphoid malignancies has dramatically increased, owing to both impressive efficacy and ease of administration. However, BTKi have a range of drug-drug and drug-food interactions, which may alter drug efficacy and/or increase toxicity. Healthcare professionals should be aware of the probability of drug interactions with BTKi and make recommendations accordingly. In this article, we discuss the relevant drug-drug and drug-food interactions associated with ibrutinib, acalabrutinib, and zanubrutinib, and provide clinical practice recommendations for managing these interactions based on the available literature.

Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition.

Bupropion hydroxylation is a bioactivation and metabolic pathway, and the standard clinical CYP2B6 probe. This investigation determined the influence of CYP2B6 allelic variants on clinical concentrations and metabolism of bupropion enantiomers. Secondary objectives evaluated the influence of CYP2C19 and P450 oxidoreductase variants. Healthy volunteers in specific cohorts (CYP2B6*1/*1, CYP2B6*1/*6, CYP2B6*6/*6, and also CYP2B6*4 carriers) received single-dose oral bupropion. Plasma and urine bupropion and hydroxybupropion was quantified. Subjects were also genotyped for CYP2C19 and P450 oxidoreductase variants. Hydroxylation of both bupropion enantiomers, assessed by plasma hydroxybupropion/bupropion AUC ratios and urine hydroxybupropion formation clearances, was lower in CYP2B6*6/*6 but not CYP2B6*1/*6 compared with CYP2B6*1/*1 genotypes, and numerically greater in CYP2B6*4 carriers. CYP2C19 and P450 oxidoreductase variants did not influence bupropion enantiomers hydroxylation or plasma concentrations. The results show that clinical hydroxylation of both bupropion enantiomers was equivalently influenced by CYP2B6 allelic variation. CYP2B6 polymorphisms affect S-bupropion bioactivation, which may affect therapeutic outcomes.