RESUMEN
Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.-66T â C, rs2252281) and MATE2 (g.-130G â A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Hipoglucemiantes/farmacocinética , Metformina/farmacocinética , Proteínas de Transporte de Catión Orgánico/genética , Diabetes Mellitus Tipo 2/genética , Femenino , Genotipo , Humanos , Hipoglucemiantes/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Metformina/farmacología , Proteínas de Transporte de Catión Orgánico/metabolismoRESUMEN
Drug transporters play a key role in the absorption, distribution, and elimination of many drugs, and they appear to be important determinants of therapeutic and adverse drug activities. Although a large body of data pertaining to drug transporters is available, there are few databases that inform drug developers, regulatory agencies, and academic scientists about transporters that are important in drug action and disposition. In this article, we inform the scientific community about the UCSF-FDA TransPortal, a new and valuable online resource for research and drug development.
Asunto(s)
Bases de Datos Factuales , Diseño de Fármacos , Proteínas de Transporte de Membrana , Farmacocinética , Transporte Biológico , California , Humanos , Proteínas de Transporte de Membrana/metabolismo , Preparaciones Farmacéuticas/metabolismo , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Multidrug and toxin extrusion 2 (MATE2-K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized genetic variants of MATE2-K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2-K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants-c.485C>T and c.1177G>A-were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2-K basal promoter haplotypes containing the most common variant, g.-130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF-1). Patients with diabetes who were homozygous for g.-130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (-0.027 (-0.076, 0.033)), as compared with carriers of the reference allele, g.-130G (-0.15 (-0.17, -0.13)) (P=0.002). Our study showed that MATE2-K plays a role in the antidiabetes response to metformin.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacocinética , Metformina/farmacocinética , Proteínas de Transporte de Catión Orgánico/genética , Adulto , Anciano , Alelos , Animales , Femenino , Variación Genética , Hemoglobina Glucada/metabolismo , Células HCT116 , Células HEK293 , Haplotipos , Humanos , Hipoglucemiantes/farmacología , Células LLC-PK1 , Luciferasas/metabolismo , Masculino , Metformina/farmacología , Persona de Mediana Edad , Polimorfismo Genético , Regiones Promotoras Genéticas , Grupos Raciales/genética , Estudios Retrospectivos , Porcinos , Resultado del TratamientoRESUMEN
An amber yellow organic liquid was found in a munition shell at Dugway Proving Grounds, UT, USA, that was likely used as a simulant of chemical weapons. The primary analytical techniques to characterize the mixture were gas chromatography-infrared detection-mass spectral detection (GC-IR-MS); liquid chromatography-mass spectrometry (LC-MS); nuclear magnetic resonance (NMR) using the nuclei 1H, 13C and 31P; and gas chromatography-atomic emission detection (GC-AED). Six major phosphorus-containing components were identified and confirmed by at least three techniques, and several additional phosphorus-containing components of lower concentration have been identified by GC-IR-MS and LC-MS. Five major non-phosphorus components, including ethyl acetate, diethyl sulfide and dibutylamine, have been identified by multiple techniques. The major phosphorus compound (23.9+/-0.4 wt.%) was O,O,O-triethyl phosphorothioate (I) and the second most abundant (14.4+/-0.2 wt.%) was O,O,S-triethyl phosphorothioate (III). No VX, G-agent, or pesticide was observed in the sample, although III may be a cholinesterase inhibitor which produces delayed toxic response. III also produces a false hit for the pesticide cyanthoate when analyzed by GC-MS-EI. The mixture appears to have been formulated as a chemical warfare agent simulant, most likely as a challenge of agent detection techniques.