Pharmacogenetics of amfepramone in healthy Mexican subjects reveals potential markers for tailoring pharmacotherapy of obesity: results of a randomised trial

• Published in: Scientific reports Vol. 9; no. 1; pp. 17833 - 10
• Main Authors: Gómez-Silva, Magdalena, Piñeyro-Garza, Everardo, Vargas-Zapata, Rigoberto, Gamino-Peña, María Elena, León-García, Armando, de León, Mario Bermúdez, Llerena, Adrián, León-Cachón, Rafael B. R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28-11-2019; Nature Publishing Group
• Subjects: 45/41; 59; 631/208/2489/1512; 64; 692/308/53/2423; Adult; Appetite; Appetite Depressants - administration & dosage; Appetite Depressants - blood; Appetite Depressants - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B - genetics; Body mass index; CYP3A4 gene; Cytochrome P-450 CYP3A - genetics; Diethylpropion - administration & dosage; Diethylpropion - blood; Diethylpropion - pharmacokinetics; Drug dosages; Drug therapy; Enzymes; Female; Genes; Genetic diversity; Genetic markers; Genetic variance; Genotyping; High-performance liquid chromatography; Humanities and Social Sciences; Humans; Liquid chromatography; Male; Mass spectrometry; Mass spectroscopy; Metabolic Clearance Rate - genetics; Metabolism; Metabolites; Middle Aged; multidisciplinary; Obesity; Pharmacogenetics; Pharmacogenomic Variants; Pharmacokinetics; Pharmacology; Phenotypes; Plasma; Plasma levels; Polymorphism, Single Nucleotide; Population; Research centers; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-54436-z

Amfepramone (AFP) is an appetite-suppressant drug used in the treatment of obesity. Nonetheless, studies on interindividual pharmacokinetic variability and its association with genetic variants are limited. We employed a pharmacokinetic and pharmacogenetic approach to determine possible metabolic phenotypes of AFP and identify genetic markers that could affect the pharmacokinetic variability in a Mexican population. A controlled, randomized, crossover, single-blind, two-treatment, two-period, and two sequence clinical study of AFP (a single 75 mg dose) was conducted in 36 healthy Mexican volunteers who fulfilled the study requirements. Amfepramone plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed using real-time PCR with TaqMan probes. Four AFP metabolizer phenotypes were found in our population: slow, normal, intermediate, and fast. Additionally, two gene polymorphisms,
ABCB1
-rs1045642 and
CYP3A4
-rs2242480, had a significant effect on AFP pharmacokinetics (
P
 < 0.05) and were the predictor factors in a log-linear regression model. The
ABCB1
and
CYP3A4
gene polymorphisms were associated with a fast metabolizer phenotype. These results suggest that metabolism of AFP in the Mexican population is variable. In addition, the genetic variants
ABCB1
-rs1045642 and
CYP3A4
-rs2242480 may partially explain the AFP pharmacokinetic variability.