RESUMEN
BACKGROUND: Stress-related mechanisms are implicated in the pathophysiology of bipolar disorder and may contribute to heterogeneity in illness course. Yet, there is a lack of study investigating the neural mechanisms underlying the stress response in this condition. This study investigated changes in amygdala activation and functional connectivity in response to acute psychosocial stress in young adults with bipolar disorder and explored relations with clinical phenotype and prospective mood symptoms. METHODS: 42 young adults [19 with bipolar disorder, agemean ± SD =21.4 ± 2.2 years] completed a modified version of the Montreal Imaging Stress Task. Amygdala activation and functional connectivity with prefrontal cortex (PFC) regions of interest was calculated for control and stress conditions. Main effects of group, condition, and group by condition interaction on amygdala activation and connectivity were modeled. A subset of bipolar participants completed 1-year follow-up assessments. Relations between neural responses to stress with concurrent substance use and prospective mood symptoms were explored. RESULTS: There were no between-group differences in amygdala activation or functional connectivity during the control condition. Increased right amygdala-right rostral PFC (rPFC) functional connectivity to stress was observed in bipolar disorder, compared to typically developing controls. In bipolar disorder, greater increase in right amygdala-right rPFC functional connectivity to stress was associated with less frequent cannabis use, and prospectively with shorter duration and lower severity of depression symptoms over follow-up. CONCLUSION: Results from this preliminary study suggest differences in frontolimbic functional connectivity responses to stress in young adults with bipolar disorder and associations with cannabis use and prospective mood symptoms.
Asunto(s)
Trastorno Bipolar , Amígdala del Cerebelo/diagnóstico por imagen , Trastorno Bipolar/complicaciones , Trastorno Bipolar/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Vías Nerviosas/diagnóstico por imagen , Corteza Prefrontal/diagnóstico por imagen , Estudios Prospectivos , Estrés Psicológico/diagnóstico por imagen , Adulto JovenRESUMEN
PURPOSE: Improving primary care quality is a national priority, but little is known about the extent to which small to medium-size practices use quality improvement (QI) strategies to improve care. We examined variations in use of QI strategies among 1,181 small to medium-size primary care practices engaged in a national initiative spanning 12 US states to improve quality of care for heart health and assessed factors associated with those variations. METHODS: In this cross-sectional study, practice characteristics were assessed by surveying practice leaders. Practice use of QI strategies was measured by the validated Change Process Capability Questionnaire (CPCQ) Strategies Scale (scores range from -28 to 28, with higher scores indicating more use of QI strategies). Multivariable linear regression was used to examine the association between practice characteristics and the CPCQ strategies score. RESULTS: The mean CPCQ strategies score was 9.1 (SD = 12.2). Practices that participated in accountable care organizations and those that had someone in the practice to configure clinical quality reports from electronic health records (EHRs), had produced quality reports, or had discussed clinical quality data during meetings had higher CPCQ strategies scores. Health system-owned practices and those experiencing major disruptive changes, such as implementing a new EHR system or clinician turnover, had lower CPCQ strategies scores. CONCLUSION: There is substantial variation in the use of QI strategies among small to medium-size primary care practices across 12 US states. Findings suggest that practices may need external support to strengthen their ability to do QI and to be prepared for new payment and delivery models.
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Evaluación de Resultado en la Atención de Salud , Atención Primaria de Salud/normas , Mejoramiento de la Calidad/organización & administración , Indicadores de Calidad de la Atención de Salud , Estudios Transversales , Atención a la Salud/normas , Adhesión a Directriz/estadística & datos numéricos , Humanos , Atención Primaria de Salud/estadística & datos numéricos , Encuestas y Cuestionarios , Estados Unidos , United States Agency for Healthcare Research and QualityRESUMEN
The optimisation of the azanaphthyridine series of Spleen Tyrosine Kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay.
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Naftiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Humanos , Pruebas de Mutagenicidad , Naftiridinas/administración & dosificación , Naftiridinas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The 1,3-dihydro-2H-benzo[d]azepin-2-ones are potent and ligand-efficient pan-BET bromodomain inhibitors. Here we describe the extension of this template to exploit a bivalent mode of action, binding simultaneously to both bromodomains. Initially the linker length and attachment vectors compatible with bivalent binding were explored, leading to the discovery of exceptionally potent bivalent BET inhibitors within druglike rule-of-5 space.
RESUMEN
Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous N-acetyl-lysine group and disrupting the protein-protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free-Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.
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Aminoquinolinas/química , Diseño de Fármacos , Proteínas/metabolismo , Administración Oral , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacocinética , Aminoquinolinas/uso terapéutico , Animales , Benzoatos/química , Benzoatos/metabolismo , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Semivida , Humanos , Masculino , Ratones , Conformación Molecular , Simulación de Dinámica Molecular , Neoplasias/tratamiento farmacológico , Proteínas/antagonistas & inhibidores , Ratas , Relación Estructura-ActividadRESUMEN
HIV-1 is a master at deceiving the immune system and usurping host biosynthetic machinery. Although HIV-1 is coated with host-derived glycoproteins, only glycosylation of viral gp120 has been described. Here we use lectin microarray technology to analyze the glycome of intact HIV-1 virions. We show that the glycan coat of human T cell line-derived HIV-1 matches that of native immunomodulatory microvesicles. The carbohydrate composition of both virus and microvesicles is cell-line dependent, which suggests a mechanism to rapidly camouflage the virus within the host. In addition, binding of both virus and microvesicles to antiviral lectins is enriched over the host cell, raising concern about targeting these glycans for therapeutics. This work also sheds light on the binding of HIV-1 to galectin-1, an important human immune lectin. Overall, our work strongly supports the theory that HIV-1 co-opts the exocytic pathway of microvesicles, thus potentially explaining why eliciting a protective antiviral immune response is difficult.
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Carbohidratos/genética , VIH-1/metabolismo , Lectinas/metabolismo , Linfocitos T/metabolismo , Carbohidratos/fisiología , Línea Celular , Biología Computacional , Galectina 1/metabolismo , Perfilación de la Expresión Génica , Glicómica , VIH-1/genética , Humanos , Lectinas/genética , Manosa/metabolismo , Análisis por MicromatricesRESUMEN
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.
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Compuestos de Anilina/química , Compuestos de Anilina/uso terapéutico , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Reacción de Arthus/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/uso terapéutico , Administración Oral , Compuestos de Anilina/farmacología , Animales , Antiinflamatorios/farmacología , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/metabolismo , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Quinasa SykRESUMEN
Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.
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Benzofuranos/farmacología , Proteínas/antagonistas & inhibidores , Benzofuranos/síntesis química , Benzofuranos/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Proteínas/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.
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Proteínas de Ciclo Celular/antagonistas & inhibidores , Piridinas/farmacología , Factores de Transcripción/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Piridinas/química , Relación Estructura-Actividad , Factores de Transcripción/metabolismoRESUMEN
Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.
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ADN/química , Descubrimiento de Drogas , Proteínas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Dominios Proteicos/efectos de los fármacos , Proteínas/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Dominios Proteicos/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Factores de Transcripción/antagonistas & inhibidores , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Factores de Transcripción/química , Factores de Transcripción/metabolismoRESUMEN
The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.
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Furanos/farmacología , Proteínas/antagonistas & inhibidores , Pirazoles/farmacología , Relación Dosis-Respuesta a Droga , Furanos/química , Humanos , Estructura Molecular , Proteínas/metabolismo , Pirazoles/química , Relación Estructura-ActividadRESUMEN
Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of in vitro phenotypic assays and in vivo pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical in vitro and in vivo characterization.
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Amidas/síntesis química , Diseño de Fármacos , Factores de Transcripción/antagonistas & inhibidores , Amidas/química , Amidas/metabolismo , Animales , Derivados del Benceno/química , Sitios de Unión , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Cristalografía por Rayos X , Humanos , Microsomas Hepáticos/metabolismo , Simulación de Dinámica Molecular , Dominios Proteicos , Teoría Cuántica , Ratas , Relación Estructura-Actividad , Factores de Transcripción/metabolismoRESUMEN
Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.
RESUMEN
The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, 20 (GSK620) and 56 (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.
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Antiinflamatorios/química , Ligandos , Factores de Transcripción/antagonistas & inhibidores , Administración Oral , Amidas/química , Amidas/metabolismo , Amidas/farmacocinética , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacocinética , Sitios de Unión , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Cristalografía por Rayos X , Perros , Semivida , Humanos , Enlace de Hidrógeno , Masculino , Simulación de Dinámica Molecular , Dominios Proteicos , Ratas , Ratas Wistar , Relación Estructura-Actividad , Factores de Transcripción/metabolismoRESUMEN
The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.
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Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Histona Acetiltransferasas/antagonistas & inhibidores , Factores Inmunológicos/farmacología , Terapia Molecular Dirigida , Factores de Transcripción/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Antineoplásicos/uso terapéutico , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Descubrimiento de Drogas , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Histona Acetiltransferasas/química , Histona Acetiltransferasas/genética , Humanos , Enfermedades del Sistema Inmune/tratamiento farmacológico , Factores Inmunológicos/química , Factores Inmunológicos/uso terapéutico , Inflamación/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Dominios Proteicos/efectos de los fármacos , Factores de Transcripción/química , Factores de Transcripción/genéticaRESUMEN
Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.
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Inhibidores de Fosfodiesterasa 4 , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/química , Quinolinas/administración & dosificación , Quinolinas/química , Administración Oral , Animales , Bovinos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Masculino , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacología , Línea Celular , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacocinética , Histona Demetilasas/química , Histona Demetilasas/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/química , Histona Demetilasas con Dominio de Jumonji/metabolismo , Modelos Moleculares , Simulación del Acoplamiento Molecular , Pirimidinonas/farmacocinética , Relación Estructura-ActividadRESUMEN
Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥ 50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6-8 µM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100-125 nM).
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Inhibidores Enzimáticos/química , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Piridinas/química , Aminación , Línea Celular , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/química , Histona Demetilasas/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/química , Histona Demetilasas con Dominio de Jumonji/metabolismo , Modelos Moleculares , Piridinas/farmacocinética , Piridinas/farmacologíaRESUMEN
The physiology of the nonlactating human breast likely plays a key role in factors that contribute to the etiology of breast cancer and other breast conditions. Although there has been extensive research into the physiology of lactation, few reports explore the physiology of the resting mammary gland, including mechanisms by which compounds such as hormones, drugs, and potential carcinogens enter the breast ducts. The purpose of this study was to explore transport of exogenous drugs into ductal fluid in nonlactating women and determine if their concentrations in the fluid are similar to those observed in the breast milk of lactating women. We selected two compounds that have been well characterized during lactation, caffeine and cimetidine. Caffeine passively diffuses into breast milk, but cimetidine is actively transported and concentrated in breast milk. After ingestion of caffeine and cimetidine, 14 nonlactating subjects had blood drawn and underwent ductal lavage at five time points over 12 h to measure drug levels in the fluid and blood. The concentrations of both caffeine and cimetidine in lavage fluid were substantially less than those observed in breast milk. Our results support recent evidence that the cimetidine transporter is not expressed in the nonlactating mammary gland, and highlight intriguing differences in the physiology and molecular transport of the lactating and nonlactating breast. The findings of this exploratory study warrant further exploration into the physiology of the nonlactating mammary gland to elucidate factors involved in disease initiation and progression.