RESUMO
Ulotaront (SEP-363856) is a TAAR1 agonist, with 5-HT1A agonist activity, currently in clinical development for the treatment of schizophrenia. In vitro studies indicate ulotaront is an OCT2-specific inhibitor with IC50 of 1.27 µM. The primary objective of this study is to determine if a single dose of ulotaront affects the PK of metformin, an index substrate of OCT2, in subjects with schizophrenia. In a randomized, single-blind, 2-period crossover study, 25 adults with schizophrenia received a single dose of metformin-HCl 850 mg (approximately 663 mg metformin) with and without coadministration of 100 mg ulotaront. The plasma samples were analyzed by fully validated LC-MS/MS methods. The primary PK endpoints for metformin were AUCinf, AUClast, Cmax, and tmax. The highest-anticipated clinical dose of ulotaront (100 mg) had no statistically significant effect on the PK of a single dose of metformin based on Cmax and AUCinf. Geometric least squares mean ratios were 89.98% and 110.63%, respectively, with the 90% confidential interval (CI) for each parameter contained within 80%-125%. Median tmax was comparable across the treatments. Ulotaront does not act as a perpetrator of OCT2-mediated DDI against metformin. Co-administration of ulotaront is not expected to require dose adjustment of metformin or other drugs cleared by OCT2.
Assuntos
Metformina , Piranos , Esquizofrenia , Adulto , Humanos , Cromatografia Líquida , Estudos Cross-Over , Interações Medicamentosas/genética , Metformina/uso terapêutico , Metformina/farmacologia , Esquizofrenia/tratamento farmacológico , Método Simples-Cego , Espectrometria de Massas em Tandem , Transportador 2 de Cátion Orgânico/efeitos dos fármacosRESUMO
While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC50 values in the low micromolar range). Furthermore, uptake inhibition assays at low-affinity monoamine transporters, i.e., the human organic cation transporters (hOCT) 1-3 and human plasma membrane monoamine transporter (hPMAT), bring to light that all compounds inhibit hOCT1 and 2 (IC50 values in the low micromolar range) while less potently interacting with hPMAT and hOCT3. In conclusion, this study describes (i) three new hybrid compounds that efficaciously block hDAT while being partial releasers at hNET, and (ii) highlights the interactions of α-PPP-derivatives with low-affinity monoamine transporters, giving impetus to further studies investigating the interaction of drugs of abuse with OCT1-3 and PMAT.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Norepinefrina/efeitos dos fármacos , Norepinefrina/metabolismo , Propiofenonas/farmacologia , Pirróis/farmacologia , Pirrolidinas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteínas de Transporte de Nucleosídeo Equilibrativas/efeitos dos fármacos , Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo , Células HEK293 , Humanos , Técnicas In Vitro , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas de Transporte de Cátions Orgânicos/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 1 de Cátions Orgânicos/efeitos dos fármacos , Transportador 1 de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/efeitos dos fármacos , Transportador 2 de Cátion Orgânico/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
PURPOSE: Major depressive disorder (MDD) and anxiety disorders (AD) are both highly prevalent among individuals with arrhythmia, ischemic heart disease, heart failure, hypertension, and dyslipidemia. There should be increased support for MDD and AD diagnosis and treatment in individuals with cardiac diseases, because treatment rates have been low. However, cardiac-psychiatric drug interaction can make pharmacologic treatment challenging. METHODS: The objective of the present systematic review was to investigate cardiac-psychiatric drug interactions in three different widely used pharmacological databases (Micromedex, Up to Date, and ClinicalKey). RESULTS: Among 4914 cardiac-psychiatric drug combinations, 293 significant interactions were found (6.0%). When a problematic interaction is detected, it may be easier to find an alternative cardiac medication (32.6% presented some interaction) than a psychiatric one (76.9%). Antiarrhythmics are the major class of concern. The most common problems produced by these interactions are related to cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest), increased exposure of cytochrome P450 2D6 (CYP2D6) substrates, or reduced renal clearance of organic cation transporter 2 (OCT2) substrates and include hypertensive crisis, increased risk of bleeding, myopathy, and/or rhabdomyolysis. CONCLUSION: Unfortunately, there is considerable inconsistency among the databases searched, such that a clinician's discretion and clinical experience remain invaluable tools for the management of patients with comorbidities present in psychiatric and cardiac disorders. The possibility of an interaction should be considered. With a multidisciplinary approach, particularly involving a pharmacist, the prescriber should be alerted to the possibility of an interaction. MDD and AD pharmacologic treatment in cardiac patients could be implemented safely both by cardiologists and psychiatrists. TRIAL REGISTRATION: PROSPERO Systematic Review Registration Number: CRD42018100424.
Assuntos
Antipsicóticos/farmacologia , Fármacos Cardiovasculares/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Bases de Dados de Produtos Farmacêuticos/estatística & dados numéricos , Transtorno Depressivo Maior/tratamento farmacológico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/farmacocinética , Doenças Cardiovasculares/epidemiologia , Citocromo P-450 CYP2D6/efeitos dos fármacos , Transtorno Depressivo Maior/epidemiologia , Interações Medicamentosas , Humanos , Taxa de Depuração Metabólica , Transportador 2 de Cátion Orgânico/efeitos dos fármacosRESUMO
Background: Human organic cation transporter 2 (OCT2) is the most abundant and important uptake transporter involved in the renal excretion of cationic drugs. Abnormal hypermethylation- mediated silencing of OCT2 results in oxaliplatin resistance in renal cell carcinoma (RCC). The epigenetic activation of OCT2 by decitabine (DAC) reversed this resistance in normoxic conditions. Given the hypoxic characteristic of RCC, it is still unclear whether hypoxia promotes DAC resistance and is involved in the regulation of OCT2. Methods: The mRNA and protein expression of OCT2 was determined by qRT-PCR and Western blotting. MSRE-qPCR and BSP were used to examine methylation modifications at the OCT2 promoter. The ChIP-qPCR analysis was performed to detect the abundance of histone modification and HIF-1α. The accumulation of DAC and 5-mC were detected using LC-MS, and the amount of 5-hmC was determined by dot blot analysis. To understand the role of hypoxia in the regulation of equilibrative nucleoside transporter 1 (ENT1) expression, the HIF-1α KO cell model was constructed. The re-emulsion method was used for the construction of H-NPs, an oxygen nanocarrier based on hemoglobin, to alleviate the drug resistance of DAC under hypoxia. Results: DAC was unable to upregulate OCT2 expression in hypoxic conditions because of the hypermethylation and low H3K4me3 modification in its promoter region. Hypoxia-mediated repression of human ENT1, which was markedly suppressed in RCC, resulted in a decrease in the cellular accumulation of DAC. Besides, hypoxia-induced upregulation of histone deacetylase HDAC9, which impaired the enrichment of H3K27ac modification in the OCT2 promoter, led to the transcriptional repression of OCT2. H-NPs could attenuate the hypoxia-induced loss of DAC activity and sensitize RCC cells to the sequential combination therapy of DAC and oxaliplatin. Conclusions: Hypoxia-mediated repression of ENT1 led to the inability of DAC to upregulate the expression of OCT2 under hypoxia. H-NPs could alleviate resistance to oxaliplatin and DAC in RCC cells under hypoxia and may have potential clinical applications.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Decitabina/farmacologia , Neoplasias Renais/patologia , Transportador 2 de Cátion Orgânico/efeitos dos fármacos , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/metabolismo , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Epigenômica , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Hemoglobinas/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Hipóxia/etiologia , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/metabolismo , Transportador 2 de Cátion Orgânico/metabolismo , Oxaliplatina/farmacologia , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Proteínas Repressoras , Regulação para CimaRESUMO
OBJECTIVES: To study the functional consequences of the human and rat forms of OCT2 in the presence of phenothiazines. METHODS: MDCK cells expressing human or rat OCT2 were established, and MPP+ transport was determined by uptake assays. Concentration dependency was studied for the stimulatory/inhibitory effects of phenothiazines on MPP+ transport. KEY FINDINGS: Among the 11 phenothiazines examined, the majority were found to have comparable effects on transporter function between the orthologous forms, while three phenothiazines, particularly mesoridazine, had complex impacts on transporter function. For rOCT2, mesoridazine stimulated transport at 0.1 and 1 µmMPP+ with the mesoridazine concentration-uptake curve becoming bell-shaped. This conditional effect became less pronounced at 30 µmMPP+, resulting in an inhibition curve with a typical profile. For hOCT2, mesoridazine behaved as a typical inhibitor of transporter function at all MPP+ concentrations, although the kinetics of inhibition were still affected by the substrate concentration. CONCLUSIONS: The conditional stimulation by mesoridazine in rOCT2, and the lack thereof in hOCT2, may be a manifestation of the interaction of phenothiazine with substrate binding at the high-affinity site of the OCT2. As OCT2 was previously indicated in some drug-drug interactions, the conditional stimulation of OCT2 and its potential species-differences may be of practical relevance.
Assuntos
1-Metil-4-fenilpiridínio/farmacocinética , Mesoridazina/farmacologia , Transportador 2 de Cátion Orgânico/efeitos dos fármacos , Fenotiazinas/farmacologia , 1-Metil-4-fenilpiridínio/administração & dosagem , Animais , Sítios de Ligação , Transporte Biológico/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Células Madin Darby de Rim Canino , Mesoridazina/administração & dosagem , Transportador 2 de Cátion Orgânico/metabolismo , Fenotiazinas/administração & dosagem , Ratos , Especificidade da EspécieRESUMO
Ranolazine and metformin may be frequently co-administered in subjects with chronic angina and co-morbid type 2 diabetes mellitus (T2DM). The potential for a drug-drug interaction was explored in two phase 1 clinical studies in subjects with T2DM to evaluate the pharmacokinetics and safety of metformin 1000 mg BID when administered with ranolazine 1000 mg BID (Study 1, N = 28) or ranolazine 500 mg BID (Study 2, N = 25) as compared to metformin alone. Co-administration of ranolazine 1000 mg BID with metformin 1000 mg BID resulted in 1.53- and 1.79-fold increases in steady-state metformin Cmax and AUCtau , respectively; co-administration of ranolazine 500 mg BID with metformin 1000 mg BID resulted in 1.22- and 1.37-fold increases in steady-state metformin Cmax and AUCtau , respectively. Co-administration of ranolazine and metformin was well tolerated in these T2DM subjects, with no serious adverse events or drug-related adverse events leading to discontinuation. The most common adverse events were nausea, diarrhea, and dizziness. These findings are consistent with a dose-related interaction between ranolazine and metformin, and suggest that a dose adjustment of metformin may not be required with ranolazine 500 mg BID; whereas, the metformin dose should not exceed 1700 mg of total daily dose when using ranolazine 1000 mg BID.