Investigations Into the Metabolism and Elimination of Flmodafinil and Fladrafinil for Sports Drug Testing Purposes

Flmodafinil (CRL-40,940; 2-[bis(4-fluorophenyl)methylsulfinyl]acetamide) and fladrafinil (CRL-40,941; 2-[bis(4-fluorophenyl)methylsulfinyl]-N-hydroxyacetamide) are structural analogs of modafinil. Their reported stimulating effects on the central nervous system have contributed to an increasing popularity outside the medical field, particularly for the enhancement of cognitive performance. In recent years, there has been a notable increase in interest within the sporting community regarding substances such as modafinil. Flmodafinil and fladrafinil are subjects of class "S6 stimulants" of the World Anti-Doping Agency (WADA) Prohibited List, and therefore prohibited in-competition. In this study, the elimination profiles of flmodafinil, fladrafinil, and their metabolites in urine and blood were investigated. Six volunteers ingested 20 mg of either flmodafinil or fladrafinil. Urine and blood (DBS) samples were analyzed by means of LC-HRMS, where limits of detection between 0.2 and 4 ng/mL were accomplished. After ingestion of flmodafinil, the metabolites flmodafinil acid and flmodafinil sulfone were detected. Since fladrafinil acts as a prodrug for flmodafinil, these metabolites were likewise detected after ingestion of fladrafinil. It was found that urinary maximum concentrations ranged from 191 to 891 ng/mL for flmodafinil and from 52 to 111 ng/mL for fladrafinil. The maximum concentrations in blood ranged from 45 to 98 ng/mL for flmodafinil and from 11 to 35 ng/mL for fladrafinil. When fladrafinil is administered, a slight offset can be seen until the maximum concentration of flmodafinil is reached, related to the conversion of the prodrug fladrafinil to flmodafinil. In consideration of the relatively long detection windows of both the intact drugs and their metabolites, careful result interpretation is indicated in case of an AAF.