Extensive and enantioselective presystemic metabolism of dl-threo-methylphenidate in humans.
1. Two pilot studies were carried out to investigate the enantioselective pharmacokinetics of methylphenidate (MPH) in children with attention deficit-hyperactivity disorder (ADHD). A more definitive study, which included administration of an intravenous dose, was carried out in healthy young men. 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. 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. 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Srinivas
N R
NR
College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
Hubbard
J W
JW
Quinn
D
D
Korchinski
E D
ED
Midha
K K
KK
D000284:Administration, Oral; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000097:blood / Q000378:metabolism; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008774:Methylphenidate / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011446:Prospective Studies; D013237:Stereoisomerism
D003692:Delayed-Action Preparations; D008774:Methylphenidate