PT - JOURNAL ARTICLE AU - Kennerly S. Patrick AU - Wendy Rodriquez TI - Potential for Underestimation of d-Methylphenidate Bioavailability Using Chiral Derivatization-Gas Chromatography AID - 10.1124/dmd.119.087189 DP - 2019 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.119.087189 4099 - http://dmd.aspetjournals.org/content/early/2019/04/29/dmd.119.087189.short 4100 - http://dmd.aspetjournals.org/content/early/2019/04/29/dmd.119.087189.full AB - A tenable hypothesis is presented which explains disparities between the older oral dl-MPH bioavailability data generated using chiral derivatization gas chromatography versus more recent findings using chiral liquid chromatography. These disparities continue to persist in current literature. The gas chromatographic methods found that the absolute bioavailability of d-(R,R)-MPH is 23% and that of l-(S,S)-MPH is 5% (i.e., 82% exists as the active d-isomer), while liquid chromatographic methods consistently report that approximately 99% of circulating MPH is d-MPH. The older methods used perfluoroacylated S-prolyl derivatizing agents which have a history of imprecision due to the susceptibility of the prolyl S-configuration to isomerize to the R-enantiomer. Accordingly, any R-prolyl impurity in the chiral derivatization reagent will yield the (R,R,R)-MPH-prolyl diastereomer from d-MPH which, in being related as the opposite enantiomer of (S,S,S)-prolyl-MPH, co-elutes with l-(S,S)-MPH. This results in overestimating the percent l-MPH at the expense of underestimating d-MPH. Thus, unless compelling reasons exist to justify use of any chiral discriminators, then less complex and less costly achiral analyses of plasma dl-MPH fundamentally allows d-MPH quantitation since 99% exists as d-MPH. However, simultaneous monitoring of both d-MPH and l-MPH appear warranted when alterations in first-pass hepatic metabolism by carboxylesterase 1 (CES1) occurs. For examples: (a) using transdermal dl-MPH delivery; (b) in cases of concomitant dl-MPH and a CES1 inhibitor, e.g., ethanol, which especially elevates l-MPH concentrations; (d) in forensic studies of intravenous/intranasal dl-MPH abuse or (e) were dl-MPH to be formulated as a free base sublingual product for direct oral mucosal transport.SIGNIFICANCE STATEMENT N/A