Extensive and enantioselective presystemic metabolism of dl-threo-methylphenidate in humans

doi:10.1016/0278-5846(91)90083-D

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 15, Issue 2, 1991, Pages 213-220

https://doi.org/10.1016/0278-5846(91)90083-D Get rights and content

Abstract

1.
1. Two pilot studies were carried out to investigate the enantioselective pharmacokinetics of methylphenidate (MPH) in children with attention deficit-hyperactivity disorder (DAHD). A more definitive study, which included administration of an intravenous dose, was carried out in healthy young men.
2.
2. Serial plasma samples were harvested from predose to 8 hours in the first pilot study, predose to 12 hours in the second pilot study and predose to 16 hours in the definitive study. Plasma levels of the separate isomers d-MPH and 1-MPH were determined by an enantioselective gas Chromatographic method.
3.
3. In the first pilot study, 6 boys with ADHD each received his regular dose of MPH (10mg n = 5, 5mg n = 1), which contained equal proportions of d-MPH and 1-MPH in an immediate release formulation (MPH-IR). No MPH was detectable in the predose plasma. Thereafter, plasma levels of the more active d-MPH were 4 to 10 fold higher than those of 1-MPH. Plasma levels of 1-MPH were so low that it was not possible to monitor them beyond 4 hours in some children.
4.
4. In the second pilot study, 5 boys and 1 girl with ADHD each received their regular dose (20mg) of a slow release formulation (MPH-SR). No MPH was detectable in the predose plasma. Thereafter, plasma levels of the more active d-MPH were 5 to 10 fold higher than those of 1-MPH. It was possible to monitor plasma levels of 1-MPH over the full 12 hour period of study in 5 of the 6 children. ANOVA revealed no significant differences in plasma levels of either isomer at 4, 6 and 8 hours which may be taken as evidence of “sustained release”.
5.
5. In both pilot studies, there were highly significant differences between d-MPH and 1-MPH in pharmacokinetic parameters such as maximum plasma concentration (C_max ), area under the plasma concentration versus time curve (AUC_0−inf), and apparent oral clearance (Cl_o).
6.
6. In the definitive study, 11 healthy young men were given 4 doses with 1 week between administrations. Three oral doses, administered in random order, comprised 40mg MPH-IR, 40mg MPH-SR swallowed whole, or 40mg MPH-SR chewed before swallowing (MPH-CH). The IV dose (MPH-IV) was not randomised for administrative reasons.
7.
7. In the definitive study, results obtained after MPH-IR and MPH-SR mirrored those obtained in the pilot studies in children. After MPH-IV, however, there was no significant difference in plasma concentrations of d-HPH and 1-WPH until 1.5 hours after dosing. The oral bioavailability of d-MpH was 0.22 (± 0.08 SD) and that for 1-MPH was 0.05 (± 0.03 SD). These data indicate extensive presystemic stereoselective metabolism after oral MPH.
8.
8. ANOVA revealed significant differences in time to maximum plasma concentrations (t_max) between MPH-IR and MPH-SR, suggesting that MPH-SR showed slow release properties.
9.
9. ANOVA revealed no significant differences between MPH-IR and MPH-CH in AUC_0−inf, t_max or C_max for either isomer. Moreover, C_max of d-MPH after MPH-CH was significantly higher than that observed after MPH-SR, suggesting that it may be unwise to prescribe MPH-SR for children who tend to chew tablets.

References (2)

J.W. Hubbard et al.
Enantioselective aspects of the disposition of dl- $threo$ -methylphenidate after the administration of a sustained-release formulation to children with attention deficit-hyperactivity disorder
J. Phara. Sci.
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N.R. Srinivas et al.
Stereoselective disposition of methylphenidate in children with attention-deficit disorder
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Extensive and enantioselective presystemic metabolism of dl-threo-methylphenidate in humans

Abstract

J. Phara. Sci.

Stereoselective disposition of methylphenidate in children with attention-deficit disorder

J. Pharmacol. Exp. Therap.