title: Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice.
abstract: Methylphenidate is a frequently prescribed stimulant for the treatment of attention deficit hyperactivity disorder (ADHD). An important assumption in the animal models that have been employed to study methylphenidate's effects on the brain and behavior is that bioavailability of methylphenidate in the animal models reflects that in human subjects. From this perspective, the dose and route of administration of methylphenidate assume critical importance because both these factors likely influence rate of uptake, plasma and brain concentrations of the drug. In the present study, plasma and brain concentrations of d- and l-methylphenidate and d- and l-ritalinic acid were measured in 2-month old mice (equivalent to young adulthood in humans) following a single oral administration of a racemic mixture. Our data show that oral administration of 0.75 mg/kg dose produced within 15 min, plasma levels of d-methylphenidate that correspond to the clinically effective plasma levels in human subjects (estimated to be 6-10 ng/ml). Brain concentrations of d- and l-methylphenidate tended to exceed their plasma concentrations, while the plasma concentrations of d- and l-ritalinic acid exceeded their brain concentrations. A single oral administration at 0.75 mg/kg dose increased dopamine content of the frontal cortex within 1 h, without producing statistically significant changes in serotonin or noradrenaline contents. Striatal monoamine levels remained unaltered. These data highlight disparities between plasma and brain concentrations of methylphenidate and its metabolites following oral administration and illustrate brain region- and monoamine-specific changes produced by the low oral dose of methylphenidate.
authors.affiliation: Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Aygul
authors.initials: A
authors.lastname: Balcioglu
authors.forename: Jia-Qian
authors.initials: JQ
authors.lastname: Ren
authors.forename: Deirdre
authors.initials: D
authors.lastname: McCarthy
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Spencer
authors.forename: Joseph
authors.initials: J
authors.lastname: Biederman
authors.forename: Pradeep G
authors.initials: PG
authors.lastname: Bhide
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015306:Biogenic Monoamines / Q000097:blood / Q000378:metabolism*; D001682:Biological Availability; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000097:blood / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008774:Methylphenidate / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D051379:Mice; D010949:Plasma; D013237:Stereoisomerism
chemical_list: D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D008774:Methylphenidate; C009189:ritalinic acid