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

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.

The atorvastatin metabolic phenotype shift is influenced by interaction of drug-transporter polymorphisms in Mexican population: results of a randomized trial

“…These data on rs1045642 are consistent with previous findings, even for different drugs and populations. T/T carriers had a higher C max for ATV among Americans and for rosuvastatin among Chinese, while C/C carriers had a lower C max and AUC for edoxaban and also in Mexicans for amfepramone 17,18,25,26 . Contrasting data, however, were found in a Korean population, where T/T carriers had a lower C max and longer half-life than C allele carriers.…”

“…The V d was calculated as Cl divided by Ke. The AUC's and C max values were adjusted for dose and weight (AUC's/dW and C max /dW) 17,56 . The pharmacokinetic analysis was performed using WinNonlin software v5.3 (Pharsight Corp., Mountain View, CA, USA).…”

Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function

“…The CYP3A4*1G allele has been associated with increased clearance of amfepramone, 20 tacrolimus, 21 , 22 imatinib mesylate, 23 and finasteride. 24 Additionally, the CYP3A4*1G allele has been associated with lower rates of clopidogrel resistance 25 , 26 and higher rates of sodium valproate‐response in pediatric patients.…”

“… 5 , 6 , 7 Whereas the CYP3A4*22 allele has been associated consistently with reduced enzyme activity and reduced clearance of substrates, such as tacrolimus, simvastatin, cyclosporine, and atorvastatin, CYP3A4*1B and CYP3A4*1G remain poorly characterized, each having been associated with both decreased and increased enzyme activity. 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 Most variation in CYP3A5 is associated with loss‐of‐function alleles, conferred primarily by three alleles, including a common variant ( CYP3A5*3 ) that results in aberrant mRNA splicing. The other two, CYP3A5*6 and CYP3A5*7 , are splicing defect and frameshift variants, respectively, and are seen more often in populations of African descent.…”

“…SNVs that have received the most research attention are CYP3A4*1B , CYP3A4*1G , and CYP3A4*22 , which arise from noncoding variants thought to affect gene transcription or the stability of mRNA 5–7 . Whereas the CYP3A4*22 allele has been associated consistently with reduced enzyme activity and reduced clearance of substrates, such as tacrolimus, simvastatin, cyclosporine, and atorvastatin, CYP3A4*1B and CYP3A4*1G remain poorly characterized, each having been associated with both decreased and increased enzyme activity 6–30 . Most variation in CYP3A5 is associated with loss‐of‐function alleles, conferred primarily by three alleles, including a common variant ( CYP3A5*3 ) that results in aberrant mRNA splicing.…”