Human In Vivo Metabolism and Elimination Behavior of Micro-Dosed Selective Androgen Receptor Modulator RAD140 for Doping Control Purposes

Abstract

RAD140 is a selective androgen receptor modulator which has been abused in sporting competitions. Its use is prohibited by the World Anti-Doping Agency (WADA) for athletes at all times. In addition to its illicit use, adverse analytical findings of RAD140 in doping control samples might result from other scenarios, e.g., the ingestion of contaminated dietary supplements. The differentiation between samples resulting from such contamination scenarios and intentional doping presents a considerable challenge, as little is known about the metabolism and elimination behavior of RAD140 in humans. In this study, six micro-dose excretion studies with five adult male volunteers each were conducted, and urine samples were analyzed by means of LC-HRMS/MS. Multiple metabolites, firstly detected in human urine, are described in this study. The sample preparation included an enzymatic hydrolysis step, which facilitated the estimation of RAD140 concentrations in urine. The elimination profiles and detection times for six metabolites as well as the intact drug are presented. The method was extensively characterized and deemed fit-for-purpose. The metabolite ratios were investigated for their predictive power in estimating the dose of RAD140 intake. The presented data will aid in better case result management in future doping cases involving RAD140.

Systematic Review of Safety of Selective Androgen Receptor Modulators in Healthy Adults: Implications for Recreational Users

“…The mechanism underlying proposed anabolic steroid-induced rhabdomyolysis is unknown, and the causality is not fully established. However, SARMs have many metabolites and high potential for off-target effects [ 35 , 59 , 60 , 61 , 62 ]. Furthermore, it is rational to hypothesize that individuals starting a workout supplement may perform more strenuous activity if the individual believes that the supplement will enhance performance.…”

Drug transfer during intimate moments: A key issue in doping control that can be documented by hair tests of the athlete and the partner

“…There is no need for a transfer of a large dose of doping agent. In addition to what has been published 15 about ostarine (detection for several days in urine of a single 1 µg oral dose), other studies have confirmed that a single 1 µg dose of ligandrol 16 or RAD140 17 are detectable over several days in urine. The pharmacologically active doses of these oral selective androgen receptor modulators, controlled under section S1.2 (other anabolic agents) by the World Anti-Doping Agency (WADA) are in the range 10 to 30 mg per day.…”

“…However, I am not aware of any report dealing with drug consumption by subject 1 and subsequent urine measurement in subject 2 after kissing or sexual relationship. Nevertheless, administration of drugs in a micro-dose of 1−10 µg, [15][16][17] which obviously can be in the range of what is present in oral fluid or semen, has resulted in detectable amounts in urine for several days. This also allows the crossing of "possible" to "probable" for drug transfer during intimate moments.…”

Annual banned‐substance review—Analytical approaches in human sports drug testing 2021/2022–

“…In order to provide additional data into elimination profiles of frequently observed SARMs, LGD-4033 and RAD140 (Figure 1, 2 and 4) were each administered to five male volunteers in single and multiple microdoses of 1, 10, and 50 μg, and urine was collected up to 47 days after administration. 50,51 The studies aimed at mimicking scenarios of contamination, where individuals (e.g., athletes) are exposed to low amounts of prohibited substances and how such an exposure is Moreover, no enantiomeric depletion was observed, in contrast to reports published for clenbuterol contamination scenarios 53,54 and urinary elimination profiles.…”

“…Similarly, the interpretation of urinary SARM findings has been the subject of considerable debate in the past, with low concentrations of prohibited substances or their metabolites potentially originating from either recent contamination or past doping practices. In order to provide additional data into elimination profiles of frequently observed SARMs, LGD‐4033 and RAD140 (Figure 1, 2 and 4 ) were each administered to five male volunteers in single and multiple microdoses of 1, 10, and 50 μg, and urine was collected up to 47 days after administration 50,51 . The studies aimed at mimicking scenarios of contamination, where individuals (e.g., athletes) are exposed to low amounts of prohibited substances and how such an exposure is traceable in urine.…”