Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and l-threo-methylphenidate in the human and baboon brain

  title={Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and l-threo-methylphenidate in the human and baboon brain},
  author={Y.‐S. Ding and Joanna S. Fowler and Nora D. Volkow and Stephen L. Dewey and G.‐J. Wang and Jean Logan and S. John Gatley and Naomi R. Pappas},
Abstract  Methylphenidate (Ritalin) is the most commonly prescribed psychoactive medication for children in the US where it is used for the treatment of attention deficit hyperactivity disorder. Methylphenidate is marketed as a racemic mixture of the d-threo and l-threo enantiomers. It is believed that the d enantiomer is responsible for the therapeutic effect of methylphenidate. In this study we labeled the individual enantiomers with carbon-11 and compared their binding and pharmacokinetics… 

Methylphenidate and its Isomers

It is concluded that d-threo-methylphenidate, which is the more potent and abundant of the two isomers, is the major contributor of both efficacy and adverse effects, irrespective of the formulation or route of administration of the racemate.

Sex differences in the kinetic profiles of d- and l- methylphenidate in the brains of adult rats.

Females exhibited consistently higher brain concentrations of both d- and l- methylphenidate and a slower clearance ofethylphenidate from brain as compared to males, particularly with the active d-enantiomer.

Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?

Data from in vitro, animal, and human studies support the premise that the d-enantiomer of MPH mediates the neurophysiological actions of MPH and therefore likely mediates its clinical efficacy.

Evaluation of a new norepinephrine transporter PET ligand in baboons, both in brain and peripheral organs

An evaluation of the racemate and individual enantiomers of [11C]MRB as radioligands for PET imaging studies of NET systems in baboons both in brain and in peripheral organs suggests the enantioselectivity of MRB in vivo, consistent with previous in vitro and in vivo studies in rodents.

Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration

Results suggest that, in animal models, l‐threo‐MP or its metabolite(s) is (are) absorbed from the gastrointestinal tract and enters the brain after oral administration, but that l‐thano‐ MP may not be pharmacologically active.

D-methylphenidate and D,L-methylphenidate are not developmental toxicants in rats and rabbits.

Rats and rabbits dosed with D,L-MPH exhibited significantly greater incidence of maternal clinical observations at twice the dose of D- MPH, and both compounds were not teratogenic in rats and rabbits at higher exposure levels compared to humans.

Kinetic modeling of [99mTc]TRODAT-1: a dopamine transporter imaging agent.

It is suggested that the binding potential and corresponding kinetic rate constants can be reliably estimated in nonhuman primates with dynamic SPECT imaging of the dopamine transporter using a technetium-based tropane analogue.



Carbon-11-d-threo-methylphenidate binding to dopamine transporter in baboon brain.

These results demonstrate the saturable, reversible and specific binding of [11C]d-threo-MP to the dopamine transporter on the baboon brain, suggesting that [11D-thReo- MP will be a useful PET tracer for the presynaptic dopaminergic neuron in living human brain.

Synthesis of the racemate and individual enantiomers of [11C]methylphenidate for studying presynaptic dopaminergic neuron with positron emission tomography

Carbon-11 labeled dl-threo-methylphenidate (methyl-2-phenyl-2-(2-piperidyl)acetate, Ritalin), a psychostimulant drug widely used to treat attention deficit hyperactivity disorder, was prepared in two

Pharmacology of the enantiomers of threo-methylphenidate.

Results suggest that synaptic inhibition of catecholaminergic uptake by d-threo-MPH may be involved fundamentally in behavioral and pressor effects of the racemic drug.

A new PET ligand for the dopamine transporter: studies in the human brain.

  • N. VolkowY. Ding N. Pappas
  • Biology, Medicine
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine
  • 1995
It is demonstrated that [11C]d-threo-methylphenidate binding in the human brain is reversible, highly reproducible and saturable and is an appropriate PET ligand to measure dopamine transporter availability.

[3H]Threo‐(±)‐Methylphenidate Binding to 3,4‐Dihydroxyphenylethylamine Uptake Sites in Corpus Striatum: Correlation with the Stimulant Properties of Ritalinic Acid Esters

The observations suggest that the binding sites for [3H]threo‐(±)‐methyl‐phenidate described here are associated with a dopamine uptake or transport complex, and that these sites may mediate the motor stimulant properties of ritalinic acid esters such as methylphenidate.

Binding of bromine-substituted analogs of methylphenidate to monoamine transporters.

Pharmacokinetics and in vivo specificity of [LLC]dl‐threo‐methylphenidate for the presynaptic dopaminergic neuron

The results demonstrate the saturable [11C]MP binding to the dopamine transporter in the baboon brain and that [11 C]MP is sensitive to dopamine neuron degeneration in Parkinson's disease.

Stereoselective urinary pharmacokinetics of dl-threo-methylphenidate and its major metabolite in humans.

Observations suggest that, after oral administration of dl-MPH, the distortion in the ratio of MPH or RA enantiomers in urine samples was attributable to enantioselective presystemic conversion of MPH to RA rather than to en Anti-inflammatory excretion.

Comparison of two pet radioligands for imaging extrastriatal dopamine transporters in human brain.

A comparison of the capacities of isomers of amphetamine, deoxypipradrol and methylphenidate to inhibit the uptake of tritiated catecholamines into rat cerebral cortex slices, synaptosomal preparations of rat cerebral cortex, hypothalamus and striatum and into adrenergic nerves of rabbit aorta.

The suggestion is made that the receptor in the striatum is capable of receiving two phenyl rings but that the position of the two receptive areas for these rings is different in the stniatum than it is in those Pumps in which the tricyclic antidepressants are potent inhibitors of catecholamine uptake.