Abstract
A tenable hypothesis is presented which explains disparities between older oral dl-MPH bioavailability data generated using chiral derivatization-gas chromatography versus more recent findings using chiral liquid chromatography. These disparities persist in current literature. The gas chromatographic methods found that the absolute bioavailability of d-MPH is 23% and that of l-MPH is 5% (i.e., 82% as the active d-isomer), while liquid chromatographic methods consistently report that approximately 99% of circulating MPH is d-MPH. 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 yields the (R,R,R)-MPH-prolyl diastereomer which, in being related as the opposite enantiomer of (S,S,S)-prolyl-MPH, co-elutes with l-(S,S)-MPH. This results in overestimation of the percent l-MPH at the expense of underestimating d-MPH. Unless compelling reasons exist to justify use of any chiral discriminators, less complex and less costly achiral analysis of plasma MPH appears appropriate for d-MPH quantitation since 99% exists as d-MPH. However, simultaneous plasma monitoring of d-MPH and l-MPH may be warranted when alterations in first-pass hepatic metabolism by carboxylesterase 1 (CES1) occurs. For example, (a) with transdermal dl-MPH delivery; (b) in cases of concomitant dl-MPH and a CES1 inhibitor, e.g., ethanol, which elevates l-MPH and d-MPH concentrations; (d) in forensic studies of intravenous or intranasal dl-MPH abuse; (e) were dl-MPH to be formulated as a free base sublingual product; or (f) as emerging advances in dl-MPH gene-dose effects warrant isomer correlations.