Analysis of methylphenidate and its metabolite ritalinic acid in monkey plasma by liquid chromatography/electrospray ionization mass spectrometry

Abstract

Methylphenidate (MP, Ritalin) is a psychotropic drug widely prescribed to children for treating the symptoms of attention deficit disorder with and without hyperactivity. Because little information exists about the effects of chronic MP administration on cognitive function in children, measures of behavior changes in non-human primates are important surrogates. An essential component of such studies is the determination of MP plasma levels under chronic and acute dosing conditions. An analytical method was developed that provided sufficient sensitivity to measure low levels of the active parent drug (lower limit of quantitation = 0.25 ng/mL) and the inactive metabolite, ritalinic acid (RA), in monkey plasma as well as the ability to conveniently analyze large numbers of samples. The method uses a polymeric reversed-phase sorbent for solid phase extraction, an efficient reverse-phase high performance liquid chromatography (HPLC) separation, deuterated internal standards for isotope dilution quantification of MP and RA, and detection by sensitive electrospray ionization mass spectrometry (ES-MS) with a single quadrupole instrument. The method responses are linear over the range of plasma concentrations of MP and RA observed in monkeys, gives respective analyte recoveries of 75 and 60% with reasonable precision and accuracy, and demonstrates robust MS performance for rapid determination of MP/RA plasma levels. The average peak MP concentration (ca. 16 ng/mL) and half-lives for MP and RA elimination in monkeys (1.79 and 2.31 h, respectively) were not significantly different under acute vs. chronic dosing conditions and were comparable to values previously reported from human studies.

Methylphenidate Is Stereoselectively Hydrolyzed by Human Carboxylesterase CES1A1

“…The recovery was about 90% for all analytes. Ritalinic acid and methylphenidate were separated by liquid chromatography with a Luna C18 column (150 ϫ 4.6 mm, 3 m; Phenomenex) (Doerge et al, 2000). Thirty microliters of the extract was loaded onto the column.…”

Effects of modafinil and methylphenidate on visual attention capacity: a TVA-based study

“…Detection wavelength was 225 nm; the limit of quantitation was 0.05 mg/L. Determination of methylphenidate in plasma samples was performed by liquid chromatography/electrospray ionisation mass spectrometry according to Doerge et al (2000). After solid-phase extraction of plasma samples on Waters Oasis HLB cartridges, chromatographic separation was achieved by use of an Ultrasep RP18E column and deuterated methylphenidate as internal standard.…”

Methylphenidate does not enhance visual working memory but benefits motivation in macaque monkeys

“…This time frame was chosen as previous studies have shown that the blood peak concentration of MPH in rhesus macaques is reached after approximately 60 minutes (Doerge et al, 2000). MPH is a highly lipid soluble and readily crosses the blood-brain barrier.…”

“…A oneday washout period was deemed sufficiently long, because the elimination of MPH is fast. In monkeys, the half-life elimination is <2 h, which means that there is no amount of the drug detectable in plasma after 12 h (Doerge et al, 2000). A mouse study has also shown that basal extracellular levels of cortical NA and DA are not affected by daily MPH (3-mg/kg) treatment (Koda et al, 2010).…”