Plasma concentrations of methylphenidate enantiomers in adults with ADHD and substance use disorder, with focus on high doses and relationship to carboxylesterase activity

Basic Clin Pharmacol Toxicol. 2022 Apr;130(4):492-500. doi: 10.1111/bcpt.13707. Epub 2022 Jan 26.


Scarce data are available on methylphenidate (MPH) plasma concentrations reached after doses higher than 180 mg. The interindividual and intraindividual variability in the exposure of MPH and ritalinic acid (RA) enantiomers was examined in 28 patients with ADHD and substance use disorders, with MPH daily doses between 30 and 600 mg (median 160 mg). MPH and RA plasma concentrations were analysed with an enantioselective LC-MS/MS method. d-MPH plasma concentration/dose varied 25-fold between subjects but was reasonably stable within an individual. Twelve subjects had quantifiable l-MPH plasma concentrations, which accounted for up to 48% of the total MPH plasma concentration. The less active l-MPH enantiomer could, in individuals with low carboxylesterase 1 (CES1) activity, contribute significantly to the total MPH plasma drug concentration and hamper the estimation of the exposure to the more active d-MPH enantiomer. However, the high correlation between the total (d + l) RA/MPH metabolic ratio and the d-RA/d-MPH metabolic ratio (rs = 0.94) indicates that the ratio based on non-enantioselective analysis could be used as a marker of CES1 activity. Whether this holds true for subjects with aberrant metabolism due to genetic variants or during concomitant treatment with inhibitors or inducers of the enzyme remains to be studied.

Keywords: ADHD; metabolic ratios; methylphenidate; pharmacokinetics; ritalinic acid; substance use disorder.

MeSH terms

  • Adult
  • Attention Deficit Disorder with Hyperactivity* / drug therapy
  • Carboxylic Ester Hydrolases
  • Central Nervous System Stimulants* / therapeutic use
  • Chromatography, Liquid
  • Humans
  • Methylphenidate* / therapeutic use
  • Stereoisomerism
  • Substance-Related Disorders*
  • Tandem Mass Spectrometry


  • Central Nervous System Stimulants
  • Methylphenidate
  • Carboxylic Ester Hydrolases