Journal Article

Enantioselective Gas Chromatography-Negative Ion Chemical Ionization Mass Spectrometry for Methylphenidate in Human Plasma

Shen-Nan Lin, David M. Andrenyak, David E. Moody and Rodger L. Foltz

in Journal of Analytical Toxicology

Volume 23, issue 6, pages 524-530
Published in print October 1999 | ISSN: 0146-4760
Published online October 1999 | e-ISSN: 1945-2403 | DOI: https://dx.doi.org/10.1093/jat/23.6.524
Enantioselective Gas Chromatography-Negative Ion Chemical Ionization Mass Spectrometry for Methylphenidate in Human Plasma

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Therapeutic doses of Ritalin, a racemic mixture of d- and l-threo-methyphenidate, result in low plasma concentrations of methylphenidate. In order to assess the safety and efficacy of methylphenidate, a sensitive analytical method is needed. A gas chromatography-negative ion chemical ionization mass spectrometry (GC-NCI-MS) assay capable of measuring both d- and l-enantiomers in human plasma was developed and validated to support clinical studies involving administration of d,l-methylphenidate, d,l-Methylphenidate-d3 is added to 1-mL plasma samples. The plasma samples are made basic, mixed with isopropanol and extracted with hexane. The hexane extracts are then back-extracted into 0.1 N HCl. The acidified aqueous extract is made basic, cooled to ice temperature, and the methylphenidate derivatized with heptafluorobutyryl-l-prolyl chloride. The two diastereomeric derivatives are then extracted into hexane. The hexane extract is evaporated to dryness, reconstituted in ethyl acetate, and analyzed by GC-NCI-MS. This method can accurately (± 5% target) and precisely (< 11.1% coefficient of variation) quantitate enantiomers of threo-methylphenidate in human plasma and in the whole blood at concentrations ranging from 0.75 to 100 ng/mL. Plasma samples are stable for up to five freeze-thaw cycles when the duration of each cycle did not exceed 0.5 h. The drug degraded gradually when plasma samples were left at room temperature; a 6% loss at 3 h progressed to 17% at 12 h and to 35% at 24 h. Therefore, it is important that extraction of plasma samples begins within 0.5 h after samples are removed from the freezer. Whole blood stability results show that concentrations of methylphenidate in whole blood, with or without NaF, stored for up to 6 h at room temperature did not deviate from the target concentration by more than 13%. The derivatized methylphenidate in extract is stable at 4°C for up to 10 days.

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Subjects: Medical Toxicology ; Toxicology (Non-medical)

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