Inhibition Of 2D6 Research Articles

Inhibitory effects characteristics of polysaccharide of Polygonati Rhizome on cytochrome P450 enzymes.

As the major active ingredient of Polygonatum sibriricum Red., polysaccharide of Polygonati Rhizome (PSP) has been reported to possess various pharmacological activities, especially for the treatment of chronic disorders in the elderly. This study evaluated the effect of PSP on the activities of major cytochrome P450 enzymes (CYP450) isoforms, aiming to provide theoretical reference for its co-prescription with other drugs and prevent the risk of adverse drug-drug interaction. The activities of CYP450 isoforms were assessed in human liver microsomes with specific probe substances. Through Lineweaver-Burk fitting models, the effect of PSP on the activity of inhibited CYP450 isoforms was characterized by competitive and non-competitive models. Dose-dependent and time-dependent experiments were also performed to completely understand the inhibition. Among experimental isoforms, PSP significantly inhibited the activities of CYP2C9, 2D6, and 3A4 in a concentration-dependent manner with IC50 values of 14.01, 17.63, and 5.33 μM. The inhibition of CYP2C9 and 2D6 was best fitted with the competitive model with the Ki values of 7.15 and 8.92 μM, respectively, while the inhibition of CYP3A4 was non-competitive with the Ki value of 2.63 μM. Additionally, the inhibition of CYP3A4 by PSP also showed time-dependent characteristics with the inhibition parameters, KI of 1.273 μM-1 and Kinact of 0.036 min-1. PSP exerted moderate inhibition on CYP2C9 and 2D6 and strong inhibition of CYP3A4. The dosage of CYP2C9-, 2D6-, and 3A4-metabolized drugs should be adjusted when co-administrated with PSP and its sourced herbs.

Probe substrates assay estimates the effect of polyphyllin H on the activity of cytochrome P450 enzymes in human liver microsomes.

Cytochrome P450 enzymes (CYPs) play a crucial role in phase I metabolic reactions. The activity of CYPs would affect therapeutic efficacy and may even induce toxicity. Given the complex components of traditional Chinese medicine, it is important to understand the effect of active ingredients on CYPs activity to guide their prescription. This study aimed to evaluate the effect of polyphyllin H on the activity of CYPs major isoforms providing a reference for the clinical prescription of polyphyllin H and its source herbs. The effects of polyphyllin H were evaluated in pooled human liver microsomes using probe substrates of CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 to determine their activities. The Lineweaver-Burk was used to model the inhibition, and a time-dependent inhibition experiment was performed to understand the characteristics of the inhibition. Polyphyllin H significantly suppressed the activity of CYP1A2, 2D6, and 3A4 with IC50 values of 6.44, 13.88, and 4.52 μM, respectively. The inhibition of CYP1A2 and 2D6 was best fitted with a competitive model, yielding the inhibition constant (Ki) values of 3.18 and 6.77 μM, respectively. The inhibition of CYP3A4 was fitted with the non-competitive model with the Ki value of 2.38 μM. Moreover, the inhibition of CYP3A4 was revealed to be time-dependent with the inhibition parameters inhibition constant (KI) and inactivation rate constant (Kinact) values of 2.26 μM-1 and 0.045 min-1. Polyphyllin H acted as a competitive inhibitor of CYP1A2 and 2D6 and a non-competitive and time-dependent inhibitor of CYP3A4.

Evaluation of machine learning models for cytochrome P450 3A4, 2D6, and 2C9 inhibition.

Cytochrome P450 (CYP) enzymes are involved in the metabolism of approximately 75% of marketed drugs. Inhibition of the major drug-metabolizing P450s could alter drug metabolism and lead to undesirable drug-drug interactions. Therefore, it is of great significance to explore the inhibition of P450s in drug discovery. Currently, machine learning including deep learning algorithms has been widely used for constructing in silico models for the prediction of P450 inhibition. These models exhibited varying predictive performance depending on the use of machine learning algorithms and molecular representations. This leads to the difficulty in the selection of appropriate models for practical use. In this study, we systematically evaluated the conventional machine learning and deep learning models for three major P450 enzymes, CYP3A4, CYP2D6, and CYP2C9 from several perspectives, such as algorithms, molecular representation, and data partitioning strategies. Our results showed that the XGBoost and CatBoost algorithms coupled with the combined fingerprint/physicochemical descriptor features exhibited the best performance with Area Under Curve (AUC) of 0.92, while the deep learning models were generally inferior to the conventional machine learning models (average AUC reached 0.89) on the same test sets. We also found that data volume and sampling strategy had a minor effect on model performance. We anticipate that these results are helpful for the selection of molecular representations and machine learning/deep learning algorithms in the P450 model construction and the future model development of P450 inhibition.

Abstract 3298: Unlocking the potential of OPM-383: A novel LRRK2 inhibitor in cancer therapy

Abstract Background: Leucine-rich repeat kinase 2 (LRRK2) plays a pivotal role in regulating various cellular processes, such as cell proliferation, survival, and inflammation. LRRK2 exhibits dual functionality as a serine-threonine kinase and as a GTPase. It is involved in the modulation of multiple signaling pathways, including WNT, MAPK, NF-kB and mTOR. Germline mutations in LRRK2 are associated with an increased risk of cancer, particularly hormone-related and colorectal cancers. LRRK2 also promotes tumor cell growth and survival in papillary renal and thyroid carcinomas, DLBCL and cholangiocarcinoma cells. OPM has designed and developed a novel oral LRRK2 inhibitor, OPM383, using its proprietary Nanocyclix® technology. In this study, we have evaluated the pharmacokinetic (PK) properties, efficacy and tolerability of OPM383 in a colon carcinoma model and a panel of patient-derived organoids. Materials and Methods: In vitro potency of our Type I inhibitor, OPM383, against full-length wild-type LRRK2 and the G2019S pathogenic LRRK2 mutant was assessed in in a Lanthascreen cell assay. For PK studies, we analyzed OPM383 plasma levels using UPLVC/MS-MS. Evaluation of inhibition of LRRK2 phosphorylation (Ser935) was assessed by western blot. MC-38 cells were inoculated into C57BL/6 mice. When tumor masses reached 75 mm³, mice were randomized to receive OPM383 (50 mg/kg, orally, daily), anti-PD1 antibody (10 mg/kg, ip, twice weekly), or their combination. OPM383 was also evaluated in patient-derived organoids using the SEngine-Paris® platform. Results: OPM-383 inhibited wild-type LRRK2 and LRRK2[G2019S] with an IC50 of 42 nM and 33 nM, respectively. OPM383 is highly selective among a panel of >400 protein kinases (only 6.7% cross-reactivity at 100 nM). The compound is permeable, metabolically stable and possesses drug-like properties. OPM-383 exhibited a favorable pharmacokinetic profile in mice (AUC of 11858 h*ng/mL and T max of 3 hours at a dose of 30 mg/kg via oral administration). Preliminary e-ADME results indicated moderate inhibition of CYP3A4BFC but no significant inhibition of CYPs 1A2, 2D6, 3A4BQ, 2C19, and 2C9 by OPM-383. After 90 minutes of oral administration in CD1 mice, we observed the inhibition of LRRK2 phosphorylation (Ser935) in the brain, kidney, and PBMCs. In assessing its potential antitumor effects, OPM383 was tested on a panel of patient-derived organoids. Notably, OPM383 inhibited the proliferation of 7 out of 29 patient-derived organoids after 6 days of exposure at various concentrations (<10 µM). In mice bearing subcutaneous MC38 tumors, OPM383 significantly inhibited tumor growth compared to the vehicle-treated group. Conclusion: This study characterizes a potent first-in-class LRRK2 inhibitor in cancer models. The findings suggest that OPM383 could serve as an attractive lead scaffold for designing and synthesizing a new class of kinase inhibitors for potential applications in cancer therapy. Citation Format: Maria Eugenia Riveiro, Petra Blom, Kenji Shoji, Jan Hoflack. Unlocking the potential of OPM-383: A novel LRRK2 inhibitor in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3298.

Screening of 16 major drug glucuronides for time-dependent inhibition of nine drug-metabolizing CYP enzymes – detailed studies on CYP3A inhibitors

Time-dependent inhibition of cytochrome P450 (CYP) enzymes has been observed for a few glucuronide metabolites of clinically used drugs. Here, we investigated the inhibitory potential of 16 glucuronide metabolites towards nine major CYP enzymes in vitro. Automated substrate cocktail methods were used to screen time-dependent inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2J2 and 3A in human liver microsomes. Seven glucuronides (carvedilol β-D-glucuronide, diclofenac acyl-β-D-glucuronide, 4-hydroxyduloxetine β-D-glucuronide, ezetimibe phenoxy-β-D-glucuronide, raloxifene 4′-glucuronide, repaglinide acyl-β-D-glucuronide and valproic acid β-D-glucuronide) caused NADPH- and time-dependent inhibition of at least one of the CYPs investigated, including CYP2A6, CYP2C19 and CYP3A. In more detailed experiments, we focused on the glucuronides of carvedilol and diclofenac, which inhibited CYP3A. Carvedilol β-D-glucuronide showed weak time-dependent inhibition of CYP3A, but the parent drug carvedilol was found to be a more potent inhibitor of CYP3A, with the half-maximal inhibitor concentration (IC50) decreasing from 7.0 to 1.1 µM after a 30-min preincubation with NADPH. The maximal inactivation constant (kinact) and the inhibitor concentration causing half of kinact (KI) for CYP3A inactivation by carvedilol were 0.051 1/min and 1.8 µM, respectively. Diclofenac acyl-β-D-glucuronide caused time-dependent inactivation of CYP3A at high concentrations, with a 4-fold IC50 shift (from 400 to 98 µM after a 30-min preincubation with NADPH) and KI and kinact values of >2,000 µM and >0.16 1/min. In static predictions, carvedilol caused significant (>1.25-fold) increase in the exposure of the CYP3A substrates midazolam and simvastatin. In conclusion, we identified several glucuronide metabolites with CYP inhibitory properties. Based on detailed experiments, the inactivation of CYP3A by carvedilol may cause clinically significant drug-drug interactions.

Projections of Drug-Drug Interactions Caused by Time-Dependent Inhibitors of Cytochrome P450 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 Using In Vitro Data in Static and Dynamic Models.

In vitro time-dependent inhibition (TDI) kinetic parameters for cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6, were determined in pooled human liver microsomes for 19 drugs (and 2 metabolites) for which clinical drug-drug interactions (DDI) are known. In vitro TDI data were incorporated into the projection of the magnitude of DDIs using mechanistic static models and Simcyp®. Results suggest that for the mechanistic static model, use of estimated average unbound exit concentration of the inhibitor from the liver resulted in a successful prediction of observed magnitude of clinical DDIs and was similar to Simcyp®. Overall, predictions of DDI magnitude (i.e., fold increase in AUC of a CYP-specific marker substrate) were within 2-fold of actual values. Geometric mean-fold errors were 1.7 and 1.6 for static and dynamic models, respectively. Projections of DDI from both models were also highly correlated to each other (r2 = 0.92). This investigation demonstrates that DDI can be reliably predicted from in vitro TDI data generated in HLM for several CYP enzymes. Simple mechanistic static model equations as well as more complex dynamic PBPK models can be employed in this process. Significance Statement Cytochrome P450 time-dependent inhibitors (TDI) can cause drug-drug interactions (DDI). An ability to reliably assess the potential for a new drug candidate to cause DDI is essential during drug development. In this report, TDI data for 19 drugs (and 2 metabolites) were measured and used in static and dynamic models to reliably project the magnitude of DDI resulting from inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6.

Physcion inhibition of CYP2C9, 2D6 and 3A4 in human liver microsomes

Context The effect of the active ingredients in traditional Chinese medicines on the activity of cytochrome P450 enzymes (CYP450s) is a critical factor that should be considered in TCM prescriptions. Physcion, the major active ingredient of Rheum spp. (Polygonaceae), possesses wide pharmacological activities. Objectives The effect of physcion on CYP450 activity was investigated to provide a theoretical basis for use. Materials and methods The experiments were conducted in pooled human liver microsomes (HLMs). The activity of CYP450 isoforms was evaluated with corresponding substrates and probe reactions. Blank HLMs were set as negative controls, and typical inhibitors were employed as positive controls. The inhibition model was fitted with Lineweaver Burk plots. The concentration (0, 2.5, 5, 10, 25, 50 and 100 μM physcion) and time-dependent (0, 5, 10, 15 and 30 min) effects of physcion were also assessed. Results Physcion suppressed CYP2C9, 2D6 and 3A4 in a concentration-dependent manner with IC50 values of 7.44, 17.84 and 13.50 μM, respectively. The inhibition of CYP2C9 and 2D6 was competitive with the Ki values of 3.69 and 8.66 μM, respectively. The inhibition of CYP3A4 was non-competitive with a Ki value of 6.70 μM. Additionally, only the inhibition of CYP3A4 was time-dependent with the KI and Kinact parameters of 3.10 μM−1 and 0.049 min−1, respectively. Conclusions The inhibition of CYP450s by physcion should be considered in its clinical prescription, and the study design can be employed to evaluate the interaction of CYP450s with other herbs.

Propafenona Bağlı Gelişen Takotsubo Kardiyomiyopatisi: Sadece Bir Tesadüf mü, Yeni Bir Nedensel İlişki mi?

Propafenone is a class 1C antiarrhythmic drug that blocks sodium channels and is used in the treatment of arrhythmia. Because of its rapid effect on terminating paroxysmal episodes of atrial fibrillation, it can be used as a pill-in-the-pocket. In patients with structural heart disease, it is less preferred due to cardiotoxic effects in long-term use. Although propafenone use is known to cause several cardiovascular side effects, the development of Takotsubo cardiomyopathy is unknown. Propafenone toxicity at standard doses is a rare condition. Propafenone plasma concentrations may increase through inhibition of cytochrome P450 2D6 and complete inhibition of 2D6 metabolism can increase propafenone levels by up to 3 to 10 times. In this case report, we aimed to present a 37-year-old female patient who developed Takotsubo cardiomyopathy and cardiogenic shock after the first dose of propafenone use and recovered with medical treatment.

A Phase I, Open-Label, Fixed Sequence Study to Investigate the Effect of Cytochrome P450 2D6 Inhibition on the Pharmacokinetics of Ulotaront in Healthy Subjects.

Ulotaront is a novel psychotropic agent with agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) receptors in phase III clinical development for the treatment of schizophrenia. This study aimed to investigate the effect of paroxetine, a strong cytochrome P450 (CYP) 2D6 inhibitor, on ulotaront pharmacokinetics (PK) in healthy volunteers. Subjects received a single oral dose of 25 mg ulotaront on Day 1 and an oral dose of 20 mg paroxetine once daily from Days 5 to 10 to achieve steady-state plasma paroxetine levels. On Day 11, subjects received another single oral dose of 25 mg ulotaront, with continued daily oral dosing of 20 mg paroxetine from Days 11 to 14. All 24 subjects were CYP2D6 normal metabolizers. Coadministration of paroxetine increased ulotaront maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 31% and 72%, respectively, and decreased ulotaront apparent clearance (CL/F) by approximately 42%. While coadministration of paroxetine increased AUC∞ of active but minor metabolite SEP-363854 by 32%, it had no effect on SEP-363854 Cmax, or on SEP-363854 to the ulotaront AUC from time zero to the last quantifiable concentration (AUClast) ratio. Based on the acceptable adverse event profile of ulotaront across previous phase II studies, the increase in ulotaront exposure is unlikely to be clinically meaningful. Weak drug-drug interactions were observed between ulotaront and the strong CYP2D6 inhibitor paroxetine; however, dose adjustment as a precondition when ulotaront is coadministered with strong CYP2D6 inhibitors or administered to CYP2D6 poor metabolizers should not be necessary.

Mechanistic study of cytochrome P450 enzyme-mediated cytotoxicity of psoralen and isopsoralen.

Psoralen and isopsoralen are the major components responsible for Psoraleae Fructus-induced hepatotoxicity. This study explored the role of metabolic activation by cytochrome P450 (CYP) enzymes in psoralen- and isopsoralen-induced cytotoxicity and its potential mechanisms. Inhibitors of CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 were used to screen specific CYP enzymes responsible for the metabolic activation of psoralen and isopsoralen in mouse primary hepatocytes, which was verified using the corresponding transfected cell lines. Network toxicology and transcriptome analyses were performed to explore the mechanisms underlying toxicity. Psoralen and isopsoralen decreased the viability of mouse primary hepatocytes, whereas the inhibition of CYP2C9, 2C19, 2D6, and 2E1 significantly increased their viability. Psoralen-induced cytotoxicity was significantly enhanced by the overexpression of CYP2C19 in Chinese hamster ovary cells, whereas the overexpression of the above CYP enzymes did not affect the cytotoxicity of isopsoralen. Psoralen- and isopsoralen-induced cytotoxic effects were associated with putative core targets (i.e., Fn1, Thbs1, and Tlr2) and multiple signaling pathways (e.g., PI3K-Akt, MAPK, and TNF pathways). Our results demonstrate that the metabolic activation of psoralen and isopsoralen is mediated by CYP enzymes, thereby regulating multiple core targets and signaling pathways and resulting in cytotoxicity.

Assessment of Codispensing Patterns of Mirabegron and Prespecified CYP2D6 Substrates in Patients with Overactive Bladder.

Patients with overactive bladder (OAB) experience sudden, intense urges to urinate, which may include urge urinary incontinence and nocturia. Pharmacotherapy includes β3-adrenergic receptor agonists such as mirabegron; however, mirabegron contains a label warning for cytochrome P450 (CYP) 2D6 inhibition, making coadministration with CYP2D6 substrates require monitoring and dose adjustment to avoid unintended increases in substrate concentration. To understand the codispensing patterns of mirabegron among patients using ten predefined CYP2D6 substrates with and before mirabegron dispensing. This retrospective claims database analysis used the IQVIA PharMetrics® Plus Database to assess codispensing of mirabegron with ten predefined CYP2D6 substrate groups identified on the basis of medications most frequently prescribed in the UnitedStates, those with high susceptibility to CYP2D6 inhibition, and those with evidence for exposure-related toxicity. Patients had to be ≥18 years old before initiation of the CYP2D6 substrate episode that overlapped with mirabegron. The cohort entry period was November 2012 to September 2019, and the overall study period was 1 January 2011 to 30 September 2019. Comparisons of patient profiles at dispensing were made between time periods with and before mirabegron use in the same patient. Descriptive statistics were used to assess the number of exposure episodes, total duration of exposure, and median duration of exposure of CYP2D6 substrate dispensing with and before mirabegron. CYP2D6 substrate exposure periods totaling ≥9000 person-months were available before overlapping exposure to mirabegron for all ten CYP2D6 substrate cohorts. Median codispensing duration for chronically administered CYP2D6 substrates was 62 (interquartile range [IQR] 91) days for citalopram/escitalopram, 71 (105) days for duloxetine/venlafaxine, and 75 (115) days for metoprolol/carvedilol; median codispensing duration for acutely administered CYP2D6 substrates was 15 (33) days for tramadol and 9 (18) days for hydrocodone. In this claims database analysis, the dispensing patterns of CYP2D6 substrates with mirabegron displayed frequent overlapping of exposure. Thus, a need exists to better understand the outcomes experienced by patients with OAB who are at increased risk for drug‒drug interactions when taking multiple CYP2D6 substrates concurrently with a CYP2D6 inhibitor.

Pharmacokinetic Interactions Between Abiraterone, Apalutamide, Darolutamide or Enzalutamide and Antithrombotic Drugs: Prediction of Clinical Events and Review of Pharmacological Information.

Abiraterone, apalutamide, darolutamide and enzalutamide are second-generation hormone therapies used for advanced prostate cancer; the majority of patients receiving these treatments are elderly, poly-medicated patients. Since their first market authorizations, their pharmacokinetic (PK) characteristics are increasingly well known. A potential risk of drug-drug interaction (DDI), especially with cardiovascular drugs, needs to be considered. In the case of antithrombotics, treatment imbalance can lead to severe consequences. To describe PK profiles of hormone therapies and antithrombotics and to predict DDIs and potentially related clinical events. PK profiles (CYP450 and P-gp substrate, inducer or inhibitor) are described by cross-referencing data sources (summary of product characteristics, European public assessment reports, PubMed database, Micromedex®, etc.); a description of the potential interactions with anti-cancer drugs for each DDI and related clinical events is provided. We discuss management recommendations, including those set out in international guidelines. Antithrombotics are mainly metabolized by CYP 2C9, 2C19 or 3A4. For abiraterone (CYP 2C8, 2D6 inhibitor) and darolutamide (CYP 3A4 inducer), no interaction was identified with antithrombotics. For apalutamide (CYP 2C9, 2C19, 3A4 and P-gp inducer) and enzalutamide (CYP 2C9, 2C19, 3A4 inducer and P-gp inhibitor), several PK interactions were identified with antithrombotics, which could lead to various clinical events (haemorrhage or thromboembolism). Numerous interactions are expected between enzalutamide or apalutamide and antithrombotics, for which management should be deployed on a case-by-case basis. PK and pharmaco-epidemiological studies could shed light on whether or not there are clinically significant events related to DDIs with antithrombotics.

Effect of polypharmacy on plasma bepridil concentration in patients with heart failure: a multicenter retrospective study

BackgroundPolypharmacy, defined as the concurrent use of over six drugs, is common in the treatment of heart failure (HF); however, unpredictable drug interactions with bepridil may occur. In this study, we have elucidated the influence of polypharmacy on plasma bepridil concentrations in patients with HF.MethodsWe conducted a multicenter retrospective study involving 359 adult patients with HF who received oral bepridil. Because QT prolongation is an adverse effect following plasma bepridil concentrations ≥800 ng/mL, the risk factors for patients achieving these concentrations at steady state were elucidated via multivariate logistic regression. The correlation between bepridil dose and plasma concentration was examined. The effect of polypharmacy on the value of the concentration-to-dose (C/D) ratio was investigated.ResultsA significant relationship was observed between bepridil dose and plasma concentration (p < 0.001), and the intensity of the correlation was moderate (r = 0.503). Based on multivariate logistic regression, the adjusted odds ratios for a daily dose of bepridil ≥1.6 mg/kg, polypharmacy, and concomitant of aprindine, a cytochrome P450 2D6 inhibitor, were 6.82 (95% coefficient interval: 2.104–22.132, p = 0.001), 2.96 (95% coefficient interval: 1.014–8.643, p = 0.047), and 8.63 (95% coefficient interval: 1.684–44.215, p = 0.010), respectively. Despite the moderate correlation in non-polypharmacy, the correlation was not observed in polypharmacy. Therefore, inhibiting metabolism, along with other mechanisms, may contribute to the polypharmacy-induced increase in plasma bepridil concentrations. Moreover, the C/D ratios in the groups receiving 6–9 and 10≤ concomitant drugs were 1.28- and 1.70-fold higher than in those receiving <6 drugs, respectively.ConclusionsPlasma bepridil concentrations may be influenced by polypharmacy. Moreover, the plasma bepridil concentration increased in correlation with the number of concomitant drugs used. Although the mechanism of this increase could not be determined, plasma bepridil concentrations should be periodically monitored for safe use in patients with HF.Trial registrationRetrospectively registered.

CYP2D6 Substrate Dispensing Among Patients Dispensed Mirabegron: An Administrative Claims Analysis.

Overactive bladder (OAB) is characterized by the presence of bothersome urinary symptoms. Pharmacologic treatment options for OAB include anticholinergics and β3-adrenergic agonists. Use of β3-adrenergic agonists may result in similar treatment efficacy with a decreased side effect profile compared with anticholinergics because high anticholinergic burden is associated with cardiovascular and neurologic side effects. However, the β3-adrenergic agonist mirabegron, one of two approved drugs within this class, is a moderate cytochrome P450 (CYP) 2D6 inhibitor, and coadministration of drugs that are CYP2D6 substrates with mirabegron may lead to adverse drug effects. The aim of this study was to quantify how often CYP2D6 substrates were dispensed in patients receiving mirabegron among adults of any age and among those ≥ 65 years of age. In this retrospective descriptive analysis, a deidentified administrative claims database in the United States, IQVIA PharMetrics® Plus, was used to identify dispensing claims for CYP2D6 substrates and mirabegron from November 2012 to September 2019. Prevalence of CYP2D6 substrate dispensing was assessed in patients dispensed mirabegron among all adults ≥ 18 years old and additionally among a cohort of those ≥ 65 years old. Patient baseline profiles at the time of mirabegron and CYP2D6 substrate codispensing and at the time of mirabegron dispensing were compared. CYP2D6 substrates were categorized as those with the potential for increased risk of QT prolongation, with anticholinergic properties, with narrow therapeutic index (NTI), contraindicated or having a black box warning when used with CYP2D6 inhibitors, or used for depression or other psychiatric disease. Dispensing data and patient profiles were summarized descriptively. Overall, 68.5% of adults ≥ 18 years old dispensed mirabegron had overlapping dispensings for one or more CYP2D6 substrate; 60.6% and 53.6% had overlapping dispensings for CYP2D6 substrates with anticholinergic properties or risk of QT prolongation, respectively. CYP2D6 substrates with NTI, contraindicated with CYP2D6 inhibitors, or for psychiatric use were codispensed in 17.7%, 16.6%, and 38.0% of adult mirabegron users, respectively. Mirabegron users receiving one or more concurrent CYP2D6 substrate were more likely to be older, have more comorbidities and baseline polypharmacy, and have increased healthcare resource utilization compared with those without concurrent CYP2D6 substrates. Commonly codispensed CYP2D6 substrates included hydrocodone, oxycodone, tramadol, metoprolol, and tamsulosin. Findings were similar for patients in the older cohort (≥ 65 years old), with 72.1% receiving overlapping CYP2D6 substrates. Codispensing of CYP2D6 substrates, especially those with anticholinergic properties or risk of QT prolongation, was common among adults and older adults receiving mirabegron. Results highlight the need for improved awareness of CYP2D6 substrate prescribing among patients receiving pharmacologic treatment for OAB that inhibits the CYP2D6 pathway.

In vitro effect of Withania somnifera, AYUSH-64, and remdesivir on the activity of CYP-450 enzymes: Implications for possible herb−drug interactions in the management of COVID-19

Ayurvedic medicines Withania somnifera Dunal (ashwagandha) and AYUSH-64 have been used for the prevention and management of COVID-19 in India. The present study explores the effect of Ashwagandha and AYUSH-64 on important human CYP enzymes (CYP3A4, CYP2C8, and CYP2D6) to assess their interaction with remdesivir, a drug used for COVID-19 management during the second wave. The study also implies possible herb−drug interactions as ashwagandha and AYUSH-64 are being used for managing various pathological conditions. Aqueous extracts of ashwagandha and AYUSH-64 were characterized using LC-MS/MS. A total of 11 and 24 phytoconstituents were identified putatively from ashwagandha and AYUSH-64 extracts, respectively. In addition, in silico studies revealed good ADME properties of most of the phytoconstituents of these herbal drugs and suggested that some of these might possess CYP-450 inhibitory activity. In vitro CYP-450 studies with human liver microsomes showed moderate inhibition of CYP3A4, 2C8, and 2D6 by remdesivir, while ashwagandha had no inhibitory effect alone or in combination with remdesivir. AYUSH-64 also exhibited a similar trend; however, a moderate inhibitory effect on CYP2C8 was noticed. Thus, ashwagandha seems to be safe to co-administer with the substrates of CYP3A4, CYP2C8, and CYP2D6. However, caution is warranted in prescribing AYUSH-64 along with CYP2C8 substrate drugs. Furthermore, preclinical and clinical PK studies would be helpful for their effective and safer use in the management of various ailments along with other drugs.

Human liver microsomes study on the inhibitory effect of plantainoside D on the activity of cytochrome P450 activity

BackgroundPlantainoside D is widely existed in the herbs and possesses various pharmacological activities, making it possible to co-administrate with other herbs. Its effect on cytochrome P450 enzymes (P450) is a risk factor for inducing adverse drug-drug interactions. To assess the effect of plantainoside D on the activity of major P450 isoenzymes in human liver microsomes.MethodsThe Cocktail method was conducted in human liver microsomes in the presence of probe substrates. The activity of P450 isoenzymes was evaluated by the production of corresponding metabolites. The concentration-dependent and time-dependent inhibition assays were performed in the presence of 0, 2.5, 5, 10, 25, 50, and 100 μM plantainoside D to characterize the inhibitory effect of plantainoside D.ResultsSignificant inhibition was observed in the activity of CYP1A2, 2D6, and 3A, which was concentration-dependent with the IC50 values of 12.83, 8.39, and 14.66 μM, respectively. The non-competitive manner and competitive manner were observed in the CYP3A inhibition (Ki = 7.16 μM) and CYP1A2 (Ki = 6.26 μM) and 2D6 inhibition (Ki = 4.54 μM), respectively. Additionally, the inhibition of CYP3A was found to be time-dependent with the KI of 1.28 μM−1 and Kinact of 0.039 min−1.ConclusionsWeak inhibitory effects of plantainoside D on the activity of CYP1A2, 2D6, and 3A were revealed in vitro, implying its potential of inducing interactions with CYP1A2-, 2D6-, and 3A-metabolized drugs. Although further in vivo validations are needed, the feasibility of the Cocktail method in evaluating P450 activity has been verified.

Kratom: History, pharmacology, current user trends, adverse health effects and potential benefits

Kratom (Mitragyna speciosa Korth.) is a tree native to Southeast Asia with dose-dependent stimulant and opioid-like effects. Dried, powdered leaf material is among the kratom products most commonly consumed in the US and Europe, but other formulations also exist including enriched extracts, resins, tinctures, and edibles. Its prevalence in the US remains debated and the use pattern includes self-treatment of mood disorders, pain, and substance use disorders. Most of the adverse effects of kratom and its alkaloid mitragynine have been reported in the literature as case reports or part of surveys necessitating confirmation by clinical trials. Toxicities associated with kratom consumption have focused on hepatic, cardiac, and CNS effects with the potential to cause fatalities primarily as part of polydrug exposures. Kratom may also present with drug-drug interactions primarily through CYP 3A4 and 2D6 inhibition, although the clinical significance remains unknown to date. The variability in composition of commercially available kratom products complicates generalization of findings and requires further investigation by employing clinical trials. Healthcare professionals should remain cautious in counseling patients on the use of kratom in a therapeutic setting.

In Vitro Investigation on the Effect of Dendrobine on the Activity of Cytochrome P450 Enzymes.

Dendrobine is the major active ingredient of Dendrobium nobile, Dendrobium chrysotoxum, and Dendrobium fimbriatum, all of which are used in traditional Chinese medicine owing to their antitumor and anti-inflammation activities. Hence, investigation on the interaction of dendrobine with cytochrome P450 enzymes could provide a reference for the clinical application of Dendrobium. The effects of dendrobine on cytochrome P450 enzymes activities were investigated in the presence of 0, 2.5, 5, 10, 25, 50, and 100 µM dendrobine in pooled human liver microsomes. The specific inhibitors were employed as the positive control and the blank groups were set as the negative control. The Lineweaver-Burk plots were plotted to characterize the specific inhibition model and obtain the kinetic parameters. The study reveals that dendrobine significantly inhibited the activity of CYP3A4, 2C19, and 2D6 with IC50 values of 12.72, 10.84, and 15.47 µM, respectively. Moreover, the inhibition of CYP3A4 was found to be noncompetitive (Ki = 6.41 µM) and time dependent (KI = 2.541 µM-1, Kinact = 0.0452 min-1), while the inhibition of CYP2C19 and 2D6 was found to be competitive with the Ki values of 5.22 and 7.78 µM, respectively, and showed no time-dependent trends. The in vitro inhibitory effect of dendrobine implies the potential drug-drug interaction between dendrobine and CYP3A4-, 2C9-, and 2D6-metabolized drugs. Nonetheless, these findings need further in vivo validation.

Synthesis and Evaluation of Novel Tetrahydronaphthyridine CXCR4 Antagonists with Improved Drug-like Profiles.

Our first-generation CXCR4 antagonist TIQ15 was rationally modified to improve drug-like properties. Introducing a nitrogen atom into the aromatic portion of the tetrahydroisoquinoline ring led to several heterocyclic variants including the 5,6,7,8-tetrahydro-1,6-naphthyridine series, greatly reducing the inhibition of the CYP 2D6 enzyme. Compound 12a demonstrated the best overall properties after profiling a series of isomeric tetrahydronaphthyridine analogues in a battery of biochemical assays including CXCR4 antagonism, CYP 2D6 inhibition, metabolic stability, and permeability. The butyl amine side chain of 12a was substituted with various lipophilic groups to improve the permeability. These efforts culminated in the discovery of compound 30 as a potent CXCR4 antagonist (IC50 = 24 nM) with diminished CYP 2D6 activity, improved PAMPA permeability (309 nm/s), potent inhibition of human immunodeficiency virus entry (IC50 = 7 nM), a cleaner off-target in vitro safety profile, lower human ether a-go-go-related gene channel activity, and higher oral bioavailability in mice (% FPO = 27) compared to AMD11070 and TIQ15.

Pre-clinical drug-drug interactions (DDIs) of gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine

ObjectiveTo evaluate drug-drug interactions (DDIs) between gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs). MethodsIn vitro supersomes were used to identify CYP isoenzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4) involved in drug metabolism, and in vitro pooled cryopreserved primary human hepatocytes were employed to investigate DDIs. ResultsThe isoenzymes that showed drug degradation are listed in parentheses beside the respective drug: gefitinib (CYP2D6, 3A4, 1A2, 2C9, and 2C19), losartan (CYP2C9 and 3A4), citalopram (CYP2D6, 2C19, 3A4, and 2C9), fluoxetine (CYP2D6, 2C9, and 2C19), fluvoxamine (CYP2D6, 2C9, and 2C19), paroxetine (CYP2D6, 3A4, and 2C9), sertraline (CYP2D6, 2C9, 2C19, 1A2, and 3A4), and venlafaxine (CYP2D6 and 2C19).DDIs from human hepatocytes assays revealed that gefitinib had significant metabolic changes in (1:1) combination with paroxetine or sertraline (p-value ​= ​0.042 and 0.025 respectively) and (1:1:1) combination with losartan and fluoxetine, fluvoxamine, paroxetine, or sertraline (p-value ​= ​0.009, 0.027, 0.048, and 0.037 respectively). Losartan showed significant changes in (1:1:1) combination with gefitinib and fluoxetine or sertraline (p-value ​= ​0.026 and 0.008 respectively). Fluoxetine, fluvoxamine, and paroxetine underwent significant changes in (1:1:1) combination with gefitinib and losartan (p-value ​= ​0.003, 0.022, and 0.046 respectively). Sertraline had significant changes within all combinations: DDIs with gefitinib alone and in combination with gefitinib and losartan (p-value ​= ​0.009 and 0.008 respectively). Citalopram and venlafaxine appeared to be unaffected by any combination. ConclusionThe study provides a clear proof-of concept for in vitro metabolic DDI testing. While identifying compounds by their inhibition potential can help better predict their metabolism, it cannot resolve problems that arise from DDIs since the overall degree of effectiveness is unknown. As shown in this study, gefitinib has been identified as a weak CYP2C19 and 2D6 inhibitor, however, gefitinib can have significant DDIs with sertraline. Furthermore, multiple drug combinations (1:1:1) can change the significance of previously determined DDIs in (1:1) combination. Thus, in vitro assays can potentially provide better guidance for multidrug regimens with minimal risk for DDIs.