EPH is described chemically as (RR/SS)-ethyl phenyl(piperidin-2-yl)acetate or ritalinic acid ethyl ester. It has been characterized in the literature as the racemic crystalline hydrochloride salt and as its separate enantiomers. Interestingly, EPH holds unique pharmacological significance in both legal and illicit arenas which will be touched upon in this paper.
The earliest investigation of EPH in the biomedical literature was reported over 50 years ago by Portoghese and Malspeis, who found EPH to be 80% as potent as MPH in antagonizing sedation in mice. Beyond this report, little to any information was published until Schweri and associates reported that EPH was ~50% as potent as MPH in inhibiting dopamine uptake in rat striatal synaptosomes. However, due to the structural similarity of EPH to MPH, it was frequently used as an internal standard for MPH pharmacokinetic studies from the 1970s–1990s. Analytical methods incorporating EPH as an internal standard became problematic once it became known that EPH was also a MPH metabolite. Contemporary analytical methods generally incorporate deuterated MPH as an internal standard.
In the late 1970s, the cocaine-ethanol transesterification pathway, which yields the active metabolite cocaethylene (ethyl cocaine or benzoylecgonine ethyl ester), emerged as a precedent for a methyl ester containing drug to be metabolically transformed into an ethyl ester. This unique drug interaction eventually became the focus of numerous investigations. This peculiar bioconversion requires a catalytic enzyme to extract two separate drugs from the bloodstream, and covalently bond them. In the context of cocaine-ethanol co-ingestion and potential toxicity, plasma cocaethylene concentrations can exceed those of the parent drug cocaine and this metabolite appears to be cardiotoxic.