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

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 efficacy of the appetite suppressant, diethylpropion, is dependent on both when it is given (day vs. night) and under conditions of high fat dietary restriction.

Obesity is a public health problem caused by excessive consumption of high caloric diets and/or lack of physical activity. Although treatments for obesity include low caloric diets and exercise programs, these activities frequently are supplemented with appetite suppressants. For the short-term treatment of weight loss, diethylpropion (DEP) is a commonly used appetite suppressant. However, little is known with regard to how to improve its weight loss efficacy. We therefore evaluated, in rats, two administration protocols where the animals received daily injections of DEP. First, when these nocturnal animals were normally active (at night) and when they were normally inactive (daytime), and second, with or without high fat dietary restriction (HFDR). We observed that DEP induced a greater weight-loss administered when the animals were in their active phase than in their inactive phase. Moreover, DEP's administration during the inactive phase (and to a lesser degree in the active phase) promotes the consumption of food during normal sleeping time. In addition, we found that DEP-induced weight loss under ad libitum access to a HF diet, but its efficacy significantly improved under conditions of HFDR. In summary, the efficacy of DEP, and presumably other like appetite suppressants, is enhanced by carefully controlling the time it is administered and under dietary restriction of HF diets.

Simultaneous analysis of amphetamine-type stimulants in plasma by solid-phase microextraction and gas chromatography-mass spectrometry.

Brazil is considered one of the countries with the highest number of amphetamine-type stimulant (ATS) users worldwide, mainly diethylpropion (DIE) and fenproporex (FEN). The use of ATS is mostly linked to diverted prescription stimulants and this misuse is widely associated with (ab)use by drivers. A validated method was developed for the simultaneous analysis of amphetamine (AMP), DIE and FEN in plasma samples employing direct immersion-solid-phase microextraction, and gas chromatographic/mass spectrometric analysis. Trichloroacetic acid 10% was used for plasma deproteinization. In situ derivatization with propylchloroformate was employed. The linear range of the method covered from 5.0 to 100 ng/mL. The detection limits were 1.0 (AMP), 1.5 (DIE) and 2.0 ng/mL (FEN). The accuracy assessment of the control samples was within 85.58-108.33% of the target plasma concentrations. Recoveries ranged from 46.35 to 84.46% and precision was <15% of the value of relative standard deviation. This method is appropriate for screening and confirmation in plasma forensic toxicology analyses of these basic drugs.

Simultaneous determination of amfepramon and its two major metabolites in biological fluids by gas liquid chromatography.

Sensitive and specific procedures based on gas liquid chromatography for the identification, separation and determination of amfepramon (diethylpropion) and its major metabolites ethylaminopropiophenone and diethylnorpseudoephedrine in human plasma, saliva and urine have been described. Acidification of the biological fluid samples has improved the stability of the compounds under conditions of storage.

The objective and timing of drug disposition studies, appendix III. Diethylpropion and its metabolites in the blood plasma of the human after subcutaneous and oral administration.

Diethylpropion hydrochloride is an effective anorexiant at the recommended dose of 25 mg three times a day. Previous work in volunteers to evaluate the effects of much larger doses showed that 400 mg given orally was equipotent with 600 mg subcutaneously in terms of subjective and physiologic effects, i.e., the drug was more potent orally than subcutaneously. In one volunteer, blood level studies after a 600-mg subcutaneous dose showed concentrations of unchanged diethylpropion in the plasma about three times as high as those found after the equipotent 400 mg oral dose. In nine other volunteers, the plasma concentrations of unchanged diethylpropion found after a 75-mg oral dose was less than 1/100 of that observed after a 400-mg oral dose. These observations suggest a rapid but limited metabolic capacity for conversion of diethylpropion to its metabolites. The data indicate that the metabolites, rather than the parent drug, are responsible for the pharmacologic responses seen with doses much larger than those necessary for inducting anorexia.