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

Magdalena Gómez-Silva,Mario Bermúdez De León,Adrián Llerena,Rigoberto Vargas-Zapata,Armando León-García,Rafael B R León-Cachón,María Elena Gamino-Peña,Everardo Piñeyro-Garza

doi:10.1038/s41598-019-54436-z

Abstract

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.

Highlights

Amfepramone (AFP) is an appetite-suppressant drug used in the treatment of obesity
Because variations in genes involved in the ADME processes may affect the pharmacokinetic profile and, the effectivity of a drug, the aims of this study were: (1) to classify the AFP metabolism, (2) to evaluate the impact of genetic polymorphism related to drug metabolism in the Mexican population on AFP pharmacokinetics, and (3) to assess a possible association between genotypes and metabolizer phenotypes
Despite the fact that height and weight values were significantly higher in males than in females (P ≤ 6.97 × 10−5); the Body Mass Index (BMI) was not significantly different

Summary

Introduction

Amfepramone (AFP) is an appetite-suppressant drug used in the treatment of obesity. 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. The drug AFP, is classified as a schedule IV controlled substance in the United States and Canada because it acts on the central nervous system[10], where it induces the release of the neurotransmitters noradrenaline (NA) and dopamine (DA) and suppresses their reuptake This mechanism of action results in less appetite[11,12].

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Conclusion