ethylphenidate and ritalinic-acid

In view of the widespread application of methylphenidate for attention-deficit/ hyperactivity disorder (ADHD) therapy its interaction with alcohol was investigated in an in-vitro assay and in a study involving 9 male volunteers. The study conditions were: methylphenidate (20 mg) only, methylphenidate followed by ethanol (0.8 g/kg body weight) and ethanol followed by methylphenidate. Methylphenidate (CAS 113-45-1), ritalinic acid (CAS 19395-41-6) and ethylphenidate (CAS 57413-43-1) were assayed in blood samples collected up to 7 h after ingestion using liquid chromatography-mass spectrometry (LC/MS). It was found that methylphenidate is hydrolyzed to ritalinic acid by the same esterase that degrades cocaine. In the presence of ethanol this is inhibited and the active metabolite ethylphenidate is formed. The pharmacokinetic evaluation showed that methylphenidate concentrations were not markedly affected by ethanol, but ritalinic acid concentrations were lower, especially if ethanol was ingested first. Ethylphenidate concentrations were low with only about 10% of methylphenidate concentrations suggesting that concurrent ethanol use does not impair methylphenidate's therapeutic efficacy. Unexpectedly one subject exhibited a methylphenidate hydrolysis defect yielding very high methylphenidate and low ritalinic acid concentrations in all study conditions.

Topics: Adult; Biotransformation; Central Nervous System Depressants; Central Nervous System Stimulants; Chromatography, High Pressure Liquid; Drug Interactions; Ethanol; Female; Humans; In Vitro Techniques; Liver; Male; Mass Spectrometry; Methylphenidate; Middle Aged; Reference Standards; Young Adult

Supercritical fluid chromatography (SFC) is a technique that analyzes compounds that are temperature-labile, have moderately low weight, or are chiral compounds. Methylphenidate (MPH) is a chiral compound with two chiral centers. MPH has two chiral metabolites, ethylphenidate (EPH) and ritalinic acid (RA). MPH is sold as a racemic mixture. The d-enantiomer of threo-MPH is responsible for medicinal effects. Due to the differing effects of the enantiomers, it is important to analyze the enantiomers individually to better understand their effects. This method utilizes SFCand solid-phase extraction (SPE) to separate and analyze the enantiomers of MPH, EPH, and RA in postmortem blood. The objective of this method was to assess a unique approach with SFC for enantiomeric separation of MPH, EPH, and RA. A SPE method was developed and optimized to isolate the analytes in blood and validated as fit-for-purpose following international guidelines. The linear range for MPH and EPH was 0.25-25 and 10-1000 ng/mL for RA in blood. Bias was -8.6% to 0.8%, and precision was within 15.4% for all analytes. Following method validation, this technique was applied to the analysis of 49 authentic samples previously analyzed with an achiral method. Quantitative results for RA were comparable to achiral technique, whereas there was loss of MPH and EPH over time. The l:d enantiomer ratio was calculated, and MPH demonstrated greater abundance of the d-enantiomer. This is the first known method to separate and quantify the enantiomers of all three analytes utilizing SFC and SPE.

Topics: Chromatography, Supercritical Fluid; Methylphenidate; Stereoisomerism

Ethylphenidate is a psychostimulant and analog of the commonly prescribed compound, methylphenidate (Ritalin®). There are a limited number of studies describing the disposition and pharmacologic/toxicological effects of ethylphenidate in any species. The abuse potential in equine athletes along with the limited data available regarding administration in horses necessitates further study. The objectives of the current study were to describe drug concentrations, develop an analytical method that could be used to regulate its use, and describe the pharmacodynamic effects of ethylphenidate in horses. To that end, 12 horses were randomized into 3 dose groups (intravenous: 10 mg or 40 mg, oral: 40 mg). Ethylphenidate was administered and blood and urine samples were collected prior to and for up to 72 hours post drug administration. Concentrations of D-threo ethylphenidate and the metabolite ritalinic acid were measured using Liquid Chromatography-tandem Mass Spectrometry. L-threo ethylphenidate concentrations were estimated from D-threo ethylphenidate concentrations. Serum concentrations of ethylphenidate were below detectable levels by 8, 18, and 12 hours following intravenous administration of 10 mg and 40 mg and oral administration of 40 mg, respectively. Ritalinic acid was non-detectable at 72 hours in the group that received a 10-mg intravenous and 40-mg oral dose of ethylphenidate. Ritalinic acid concentrations were below the LOQ at 72 hours following intravenous administration of 40 mg of ethylphenidate. While the number of animals per dose group were small, no stimulatory behavior or significant changes in heart rate were noted. Untoward effects including gastrointestinal adverse effects were noted in all dose groups.

Topics: Animals; Central Nervous System Stimulants; Chromatography, Liquid; Female; Heart Rate; Horses; Limit of Detection; Male; Methylphenidate; Random Allocation; Tandem Mass Spectrometry

Ethylphenidate is a new potent synthetic psychoactive drug, structurally related to methylphenidate. Using human liver microsomes and cytosol, we have investigated for the first time the Phase-I and Phase-II in vitro metabolism of ethylphenidate. The structure of the metabolites was elucidated by hybrid quadrupole time-of-flight mass spectrometry. Overall, seven Phase-I, but no Phase-II metabolites were detected. Ethylphenidate underwent hydroxylation forming two primary mono-hydroxylated metabolites and, subsequently, dehydration and ring opening with an additional hydroxylation, forming secondary metabolites. The involvement of different human cytochrome P450 (CYP) enzymes in the formation of ethylphenidate metabolites was investigated using a panel of human recombinant CYPs (rCYPs). rCYP2C19 was the most active recombinant enzyme involved in the formation of all seven ethylphenidate metabolites detected, although other rCYPs (rCYP1A2, rCYP2B6, rCYPC9, rCYP2D6, and rCYP3A4, but not rCYP2E1) played a role in the metabolism of ethylphenidate. All metabolites identified in the present study can be considered as potential specific biomarkers of ethylphenidate in toxicological studies. Additionally, ritalinic acid and methylphenidate were formed by non-enzymatic hydrolysis and trans-esterification, and, therefore, they cannot be considered as (oxidative) metabolites of ethylphenidate. The presence of methylphenidate and ritalinic acid cannot be exclusively associated to the use of ethylphenidate, since methylphenidate is a drug itself and ritanilic acid can be formed from both ethylphenidate and methylphenidate.

Topics: Chromatography, Liquid; Cytochrome P-450 Enzyme System; Humans; Methylphenidate; Microsomes, Liver; Tandem Mass Spectrometry

Methylphenidate is the most commonly prescribed psychostimulant in clinical use today. Known methylphenidate metabolites include ritalinic acid, corresponding lactams, and p-hydroxymethylphenidate. Recent in vitro work using rat liver preparations has indicated that the methylphenidate ethyl ester, ethylphenidate, is formed upon incubation with ethanol. This report describes the first detection of ethylphenidate in human blood and liver samples obtained from two suicide victims who had overdosed on methylphenidate and coingested ethanol. Amounts of ethylphenidate detected in whole blood specimens in these two cases (8 ng/mL and 1 ng/mL, respectively) were small relative to methylphenidate and ritalinic acid concentrations. Nonetheless, given the high likelihood that methylphenidate and ethanol coingestion frequently occurs, the detection of ethylphenidate in humans warrants further investigation into the extent of its formation as well as into any associated toxicity in nonoverdose situations.

Topics: Adult; Alcohol Drinking; Dose-Response Relationship, Drug; Drug Overdose; Drug Synergism; Female; Gas Chromatography-Mass Spectrometry; Humans; Liver; Methylphenidate; Suicide