Hydrolysis: Fenethylline, the major compound in captagon, undergoes enzymatic hydrolysis in the gastrointestinal tract, primarily in the liver, to release its active metabolites (Lucchetti et al., 2021, Wenthur et al., 2017). This hydrolysis process involves enzymatic cleavage of the ester bond in fenethylline, resulting in the formation of amphetamine and theophylline and Fenethylline-Captagon.

Metabolic conversion: Fenethylline (captagon) is metabolized in the body through the cytochrome P450 (CYP450) enzyme system when taken orally, which generates approximately 24.5 % amphetamine and 13.7 % theophylline (Wu et al., 2019). The study by Katselou et al. (2016) revealed that fenethylline undergoes a complex metabolic process involving multiple stages. Initially, it is hydroxylated (oxidized), producing two primary metabolites: oxyethyltheophylline and amphetamine. Fenethylline-Captagon Oxyethyltheophylline is metabolized into theophylline, with only a tiny portion of theophylline excreted unchanged (Ellison et al., 1970). Additional intermediate metabolites include 1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine, which contribute to the pharmacodynamic effects of fenethylline (Goenechea and Brzezinka, 1984). An alternative metabolic pathway suggests the formation of 7-aminoethyltheophylline and phenylacetone, with subsequent metabolites such as hippuric acid and possibly theophylline undergoing further transformations (Ellison et al., 1970, Goenechea and Brzezinka, 1984). Studies by Yoshimura et al. (1988) revealed six metabolites in the urine of rats and human volunteers following oral administration, including amphetamine, p-hydroxyamphetamine, acetylaminoethyl theophylline, 7-aminoethyltheophylline, hydroxyethyl theophylline, and carboxymethyl theophylline. The metabolism Fenethylline-Captagon involves oxidative cleavage at two distinct sites, forming aminoethyl theophylline and amphetamine. Among the major metabolites, amphetamine remains detectable in human urine for 24–48 hours, whereas carboxymethyl theophylline is present only in trace amounts after the same period (Katselou et al., 2016). Fenethylline-Captagon

Release of neurotransmitters: Amphetamine, one of the primary metabolites of captagon, undergoes further metabolism in the liver by various cytochrome P450 enzymes, particularly CYP2D6 and CYP3A4 (Zhao et al., 2021). These enzymes catalyze the conversion of amphetamine into its active enantiomers: d-amphetamine (dextroamphetamine or (+)-amphetamine) and l-amphetamine (levoamphetamine or (–)-amphetamine). Specifically, d-amphetamine is more potent in stimulating the central nervous system, while l-amphetamine exhibits relatively weaker stimulant effects but contributes to cardiovascular activity. This clarification aligns with the specific isomeric forms relevant to fenethylline’s metabolism and their contributions to its pharmacological profile. The pharmacodynamics of fenethylline involve its action on monoamine transporters, which are crucial for regulating neurotransmitters such as dopamine, serotonin, and norepinephrine (Ferrucci et al., 2019). These neurotransmitters play significant roles in mood regulation, alertness, and overall cognitive function (Katselou et al., 2016). The presence of the xanthine component, derived from theophylline, adds another layer of complexity, as it can influence the stimulant effects by modulating adenosine receptors, which are known to affect arousal and sedation of Fenethylline-Captagon.