The L125F MATE1 variant enriched in populations of Amerindian origin is associated with increased plasma levels of metformin and lactate.
Biomed Pharmacother
; 142: 112009, 2021 Oct.
Article
em En
| MEDLINE
| ID: mdl-34388523
ABSTRACT
Genetic factors that affect variability in metformin response have been poorly studied in the Latin American population, despite its being the initial drug therapy for type 2 diabetes, one of the most prevalent diseases in that region. Metformin pharmacokinetics is carried out by members of the membrane transporters superfamily (SLCs), being the multidrug and toxin extrusion protein 1 (MATE1), one of the most studied. Some genetic variants in MATE1 have been associated with reduced in vitro metformin transport. They include rs77474263 p.[L125F], a variant present at a frequency of 13.8% in Latin Americans, but rare worldwide (less than 1%). Using exome sequence data and TaqMan genotyping, we revealed that the Mexican population has the highest frequency of this variant 16% in Mestizos and 27% in Amerindians, suggesting a possible Amerindian origin. To elucidate the metformin pharmacogenetics, a children cohort was genotyped, allowing us to describe, for the first time, a MATE1 rs77474263 TT homozygous individual. An additive effect of the L125F variant was observed on blood metformin accumulation, revealing the highest metformin and lactate serum levels in the TT homozygote, and intermediate metformin values in the heterozygotes. Moreover, a molecular dynamics analysis suggested that the genetic variant effect on metformin efflux could be due to a decreased protein permeability. We conclude that pharmacogenetics could be useful in enhancing metformin pharmacovigilance in populations having a high frequency of the risk genotype, especially considering that these populations also have a higher susceptibility to the diseases for which metformin is the first-choice drug.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Farmacogenética
/
Proteínas de Transporte de Cátions Orgânicos
/
Hipoglicemiantes
/
Metformina
Tipo de estudo:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Risk_factors_studies
Limite:
Adolescent
/
Adult
/
Child
/
Female
/
Humans
/
Male
País/Região como assunto:
Mexico
Idioma:
En
Revista:
Biomed Pharmacother
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
México