Pharmacokinetics and Clinical Effectiveness of Methylphenidate
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Methylphenidate is prescribed for over 90% of children in the US diagnosed as having attention-deficit hyperactivity disorder (ADHD). Although ADHD has been widely studied, the use of methylphenidate in ADHD still poses a number of unresolved questions, including its pharmacodynamic characteristics (drug concentration-effect relationship) and the effect of long term treatment on the patient’s psychopathology later in life. The objective of this review is to provide an analysis of the pharmacokinetic-pharmacodynamic properties and therapeutic effectiveness of methylphenidate that may help to answer some of these questions.
Methylphenidate has 2 chiral centres, but the drug used in therapy comprises only the threo pair of enantiomers. d-threo-Methylphenidate is more potent than the l-enantiomer. Methylphenidate is administered as a racemic mixture that undergoes stereoselective clearance.
Methylphenidate is a short-acting stimulant with a duration of action of 1 to 4 hours and a pharmacokinetic half-life of 2 to 3 hours. Maximum drug concentration after oral administration occurs at about 2 hours. Methylphenidate is absorbed well from the gastrointestinal tract and easily passes to the brain.
Methylphenidate is efficacious for short term treatment for children with ADHD. Its mechanism of action is not understood, but may be associated with its influence on multiple neurotransmitters, especially the release and reuptake of dopamine in the striatum.
There is marked individual variability in the dose-response relationship for methylphenidate, and therefore dosage must be titrated for optimal effect and avoidance of toxicity in each child. It is unclear whether this variability is predominantly pharmacokinetic or pharmacodynamic. If variable stereoselective metabolism occurs clinically, therapeutic drug monitoring of methylphenidate will require the application of chiral assay methods for the analysis of the active component, d-threo-methylphenidate.
It is difficult to predict which children will have a favourable response to methylphenidate. Nonetheless, several studies have been published linking the severity of ADHD in children with improved clinical response to methylphenidate. The use of individual single-blind medication trials may be a practical solution to this problem. Additionally, the targeted condition warrants careful consideration, since different conditions (e.g. misbehaviour or poor academic performance) may require different regimens. Further studies of the relationship between the pharmacokinetic and pharmacodynamic properties of methylphenidate are required to allow the development of optimal dosage regimens.
- Ferris RM, Tang FLM. Comparison of the effects of the isomers of amphetamine, methylphenidate and deoxypipradol on the uptake of 1-[3H]-norepinephrine and [3H]-dopamine by synaptic vesicles from rat whole brain, striatum and hypothalamus. J Pharmacol Exp Ther 1979; 210: 422–8.
- Patrick KS, Caldwee RW, Ferris RM, et al. Pharmacology of the enantiomers of threo-methylphenidate. J Pharmacol Exp Ther 1987; 241 (1): 152–8.
- Volkow N, Wang G, Fowler J, et al. Association of methylphenidate-induced craving with changes in right striato-orbito-frontal metabolism in cocaine abusers: implications in addiction. Am J Psychiatry 1999; 156 (1): 19–26.
- Solanto MV. Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res 1998; 94: 127–52. CrossRef
- Safer DJ, Krager JM. A survey of medication treatment for hyperactive/inattentive students. JAMA 1988; 260: 2256–8. CrossRef
- Glock MH, Jensen PS, Cooper JR, editors. Diagnosis and treatment of attention deficit hyperactivity disorder [bibliography online]. Bethesda (MD): National Library of Medicine, 1998: http://www.nlm.nih.gov/pubs/cbm/adhd.html [accessed 1999 Nov 10].
- Faraj BA, Israili ZH, Perel JM, et al. Metabolism and disposition of methylphenidate-14C: studies in man and animals. J Pharmacol Exp Ther 1974; 191 (3): 535–47.
- Gualtieri CT, Wargin W, Kanoy R, et al. Clinical studies of methylphenidate serum levels in children and adults. J Am Acad Child Psychiatry 1982; 21 (1): 19–26. CrossRef
- Milberg RM, Rinehart Jr KL, Sprague RL, et al. A reproducible gas Chromatographic mass spectrometric assay for low levels of methylphenidate and ritalinic acid in blood and urine. Biomed Mass Spectrometry 1975; 2: 2–8. CrossRef
- Srinivas NR, Hubbard JW, Korchinski ED, et al. Enantioselective pharmacokinetics of d-threo-methylphenidate in humans. Pharm Res 1993; 10 (1): 14–21. CrossRef
- Srinivas NR, Hubbard JW, Quinn D, et al. Enantioselective pharmacokinetics and pharmacodynamics of dl-threo-methylphenidate in children with attention deficit hyperactivity disorder. Clin Pharmacol Ther 1992; 52: 561–8. CrossRef
- Shaywitz SE, Hunt RD, Jatlow P, et al. Psychopharmacology of attention deficit disorder: pharmacokinetic, neuroendocrine, and behavioral measures following acute and chronic treatment with methylphenidate. Pediatrics 1982; 69 (6): 688–94.
- Physicians’ desk reference. 50th ed. Montvale (NJ): Medical Economics, 1996.
- Yoss RE, Daly DD. On the treatment of narcolepsy. Med Clin North Am 1968; 69: 161–3.
- Oettinger Jr L, Majovski LV. 1976. Methylphenidate: a review. South Med J 1976; 69 (2): 161–3. CrossRef
- Gualtieri CT, Wargin W, Kannoy R, et al. The effects of eating and fasting on the absorption of methylphenidate. Res Commun Psychol Psychiatry Behav 1982; 7: 381–4.
- Chan YM, Swanson JM, Soldin SJ, et al. Methylphenidate hydrochloride given with of before breakfast: II. Effects on plasma concentration of methylphenidate and ritalinic acid. Pediatrics 1983; 72 (1): 56–9.
- Swanson JM, Sandman CA, Deutsch C, et al. Methylphenidate hydrochloride given with or before breakfast: I. Behavioral, cognitive, and electrophysiologic effects. Pediatrics 1983; 72: 49–55.
- Ding YS, Fowler JS, Volkow ND, et al. Pharmacokinetics and in vivo specificity of [11C]dl-threo-methylphenidate for the presynaptic dopaminergic neuron. Synapse 1994; 18: 152–60. CrossRef
- Volkow ND, Ding YS, Fowler JS, et al. Is methylphenidate like cocaine? Arch Gen Psychiatry 1995; 52: 456–63. CrossRef
- Hungund BL, Perel JM, Hurwic MJ, et al. Pharmacokinetics of methylphenidate in hyperkinetic children. J Clin Pharmacol 1979; 8: 571–6.
- Mendel CM. The free hormone hypothesis: a physiologically based mathematical model. Endocrin Rev 1989; 10: 232–74. CrossRef
- Srinivas NR, Quinn D, Hubbard JW, et al. Stereoselective disposition of methylphenidate in children with attention-deficit disorder. J Pharmacol Exp Ther 1987; 241: 300–6.
- Hubbard JW, Srinivas NR, Quinn D, et al. Enantioselective aspects of the disposition of dl-threo-methylphenidate after the administration of a sustained-release formulation to children with attention deficit-hyperactiviry disorder. J Pharm Sci 1989; 78 (11): 944–7. CrossRef
- Srinivas NR, Hubbard JW, Midha KK. Enantioselective gas Chromatographic assay with electron-capture detection for dlritalinic acid in plasma. J Chromatogr 1990; 530: 327–36. CrossRef
- Aoyama T, Kotaki H, Honda Y, et al. Kinetic analysis of enantiomers of threo-methylphenidate and its metabolite in two healthy subjects after oral administration as determined by a gas chromatographic-mass spectrometric method. J Pharm Sci 1990; 79 (6): 465–9. CrossRef
- Wargin W, Patrick KS, Gualtieri CT, et al. Pharmacokinetics of methylphenidate in man, rat and monkey. J Pharmacol Exp Ther 1983; 226 (2): 382–6.
- Egger H, Bartlett F, Dreyfuss R, et al. Metabolism of methylphenidate in dog and rat. Drug Metab Disp 1981; 9 (5): 415–23.
- Birmaher B, Greenhill LL, Cooper TB, et al. Sustained release methylphenidate: pharmacokinetic studies in ADHD males. J Am Acad Child Adolesc Psychiatry 1989; 28 (5): 768–72. CrossRef
- Pelham WE, Sturges J, Hoza J, et al. Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder. Pediatrics 1987; 80 (4): 491–501.
- Srinivas NR, Hubbard JW, Korchinski ED, et al. Stereoselective urinary pharmacokinetics of dl-threo-methylphenidate and its major metabolite in humans. J Pharm Sci 1992; 81 (8): 747–9. CrossRef
- Aoyama T, Kotaki H, Sasaki T, et al. Nonlinear kinetics of threo-methylphenidate enantiomers in a patient with narcolepsy and in healthy volunteers. Eur J Clin Pharmacol 1993; 44: 79–84. CrossRef
- Aoyama T, Kotaki H, Iga T. Dose-dependent kinetics of methylphenidate enantiomers after oral administration of racemic methylphenidate to rats. J Pharmacobio-Dynam 1990; 13: 647–52. CrossRef
- Patrick KS, Straughn AB, Jarvi EJ, et al. The absorption of sustained-release methylphenidate formulations compared to an immediate-release formulation. Biopharm Drug Disp 1989; 10: 165–71. CrossRef
- Rapport MD, DuPaul GJ, Kelly KL. Attention deficit hyperactivity disorder and methylphenidate: the relationship between gross body weight and drug response in children. Psychopharmacol Bull 1989; 25 (2): 285–90.
- Rapport MD, Denney MA. Titrating methylphenidate in children with attention-deficit/hyperactivity disorder: is body mass predictive of clinical response? J Am Acad Child Adolesc Psychiatry 1997; 36 (4): 523–30. CrossRef
- Gualtieri CT, Hicks RE, Patrick K, et al. Clinical correlates of methylphenidate blood levels. Ther Drug Monit 1984; 6 (4): 379–92. CrossRef
- Janowsky DS, Leichner P, Clopton P, et al. Comparison of oral and intravenous methylphenidate. Psychopharmacology 1978; 59: 75–8. CrossRef
- Aoyama R, Kotaki H, Sawada Y, et al. Pharmacokinetics and pharmacodynamics of methylphenidate enantiomers in rats. Psychopharmacology 1996; 127: 117–22. CrossRef
- Patrick KS, Ellington KR, Breese GR. Distribution of methylphenidate and p-hydroxymethylphenidate in rats. J Pharmacol Exp Ther 1984; 231 (1): 61–5.
- Swanson J, Kinsbourne M, Roberts W, et al. Time-response analysis of the effect of stimulant medication on the learning ability of children referred for hyperactivity. Pediatrics 1978; 61 (1): 21–9.
- Stoner G, Carey SP, Ikeda MJ, et al. The utility of curriculumbased measurement for evaluating the effects of methylphenidate on academic performance. J App Behav Anal 1994; 27: 101–13. CrossRef
- Taylor E, Schachar R, Thorley HM, et al. Which boys respond to stimulant medication? A controlled trial of methylphenidate in boys with disruptive behaviour. Psychol Med 1987; 17: 121–43. CrossRef
- Buitelaar JK, Rutger JVG, Swaab-Barneveld H, et al. Prediction of clinical response to methylphenidate in children with attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1995; 34 (8): 1025–32. CrossRef
- Sprague RL, Sleator EK. Methylphenidate in hyperkinetic children: differences in dose effects on learning and social behavior. Science 1977; 198: 1274–6. CrossRef
- Kupietz SS, Winsberg BG, Richardson E, et al. Effects of methylphenidate dosage in hyperactive reading-disabled children: I. Behavior and cognitive performance effects. J Am Acad Child Adolesc Psychiatry 1988; 22: 70–7. CrossRef
- Rapport MD, DuPaul GJ, Stoner G, et al. Comparing classroom and clinic measures of attention deficit disorder: differential, idiosyncratic, and dose-response effects of methylphenidate. J Consult Clin Psychol 1986; 54: 334–41. CrossRef
- Rapport MD, Stoner G, DuPaul GH, et al. Methylphenidate in hyperactive children: differential effects of dose on academic, learning, and social behavior. J Abnorm Child Psychol 1985; 13: 227–44. CrossRef
- Logan GD, Burkeil J. Dependence and independence in responding to double stimulation: a comparison of stop, change and dual-task paradigms. J Exp Psychol Human Percept Perform 1986; 10: 549–63. CrossRef
- Tannock R, Schachar R, Logan G. Methylphenidate and cognitive flexibility: dissociated dose effects in hyperactive children. J Abnorm Child Psychol 1995; 23 (2): 235–66. CrossRef
- Solanto MV. Neuropharmacological basis of stimulant drug action in attention deficit disorder with hyperactivity. Psychol Bull 1984; 95: 387–409. CrossRef
- Solanto MV, Wender EH. Does methylphenidate constrict cognitive functioning? J Am Acad Child Adolesc Psychiatry 1989; 28: 897–902. CrossRef
- Tannock R, Schachar RJ, Carr RP, et al. Dose-response effects of methylphenidate on academic performance and overt behavior in hyperactive children. Pediatrics 1989; 84 (4): 648–57.
- Tannock R, Schachar R. Methylphenidate and cognitive perseveration in hyperactive children. J Child Psychol Psychiatry 1992; 33 (7): 1217–28. CrossRef
- Rapport MD, Kelly KL. Psychostimulant effects on learning and cognitive function: findings and implications for children with attention deficit hyperactivity disorder. Clin Psychol Rev 1991; 11: 61–92. CrossRef
- Rapport MD, Denney MA, DuPaul GJ, et al. Attention deficit disorder and methylphenidate: normalization rates, clinical effectiveness, and response prediction in 76 children. J Am Acad Child Adolesc Psychiatry 1994; 33 (6): 882–93. CrossRef
- Borcherding BG, Keysor BG, Cooper TB, et al. Differential effects of methylphenidate and dextroamphetamine on the motor activity level of hyperactive children. Neuropsychopharmacology 1989; 2: 255–63. CrossRef
- Rapport MD, Stoner G, DuPaul GJ, et al. Attention deficit disorder and methylphenidate: a multilevel analysis of dose-response effects on children’s impulsivity across settings. J Am Acad Child Adolesc Psychiatry 1988; 27: 60–9. CrossRef
- Tannock R, Schachar RJ, Carr RP, et al. Effects of methylphenidate on inhibitory control in hyperactive children. J Abnorm Child Psychol 1989; 17: 473–91. CrossRef
- Abikoff H, Gittelman R. The normalizing effect of methylphenidate on the classroom behavior of ADHD children. J Abnorm Child Psychol 1985; 13: 33–44. CrossRef
- Klein R. Clinical efficacy of methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder. Arch Gen Psychiatry 1997; 54: 1073–80. CrossRef
- Barkley RA, Cunningham E. The effect of methylphenidate on the mother-child interactions of hyperactive children. Arch Gen Pscyhiatry 1979; 36: 201–8. CrossRef
- Barkley RA, Karlsson J, Strzelecki E, et al. Effects of age and ritalin dosage on mother-child interactions of hyperactive children. J Consult Clin Psychol 1984; 52: 750–8. CrossRef
- Schachar R, Taylor E, Wieselberg M, et al. Changes in family function and relationships in children who respond to methylphenidate. J Am Acad Child Adolesc Psychiatry 1987; 26: 728–32. CrossRef
- Whalen CK, Henker B, Dotemoto S, et al. Hyperactivity and methylphenidate: peer interaction styles. In: Gasow KD, Loney J, editors. Psychosocial aspects of drug treatment for hyperactivity. Boulder (CO): Westview Press, 1981.
- Whalen CK, Henker B, Granger DA. Social judgment processes in hyperactive boys: effects of methylphenidate and comparisons with normal peers. J Abnorm Child Psychol 1990; 18: 297–316. CrossRef
- Weiss G, Kruger E, Danielson R, et al. Effect of long term treatment of hyperactive children with methylphenidate. Can Med Assoc J 1975; 112: 159–65.
- Hechtman LT, Weiss G, Perlman T. Young adult outcome of hyperactive children who received long-term stimulant treatment. J Am Acad Child Adolesc Psychiatry 1984; 23 (3): 261–9. CrossRef
- Charles L, Schain R. A four-year follow-up study of the effects of methylphenidate on the behavior and academic achievement of hyperactive children. J Abnorm Child Psychol 1981; 9 (4): 495–505. CrossRef
- Arnold L. National Institute of Mental Health Collaborative Multimodal Treatment Study of children with ADHD (the MTA). Arch Gen Psychiatry 1997; 54 (8): 65–70.
- Barkley RA, McMurray MB, Edelbrock CS, et al. Side effects of methylphenidate in children with attention deficit hyperactivity disorder: a systemic, placebo-controlled evaluation. Pediatrics 1990; 86: 184–92.
- Kelly KL, Rapport MD, DuPaul GJ. Attention deficit disorder and methylphenidate: a multi-step analysis of dose-response effects on children’s cardiovascular functioning. Int Clin Psychopharmacol 1988; 3: 167–81. CrossRef
- Golden G. The effect of central nervous system stimulants on Tourette’s syndrome. Ann Neurol 1977; 2: 69–70. CrossRef
- Law SF, Schachar MD. Do typical clinical doses of methylphenidate cause tics in children treated for attention-deficit hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 1999; 38 (8): 944–51. CrossRef
- Markowitz JS, Morrison SD, DeVane CL. Drug interactions with psychostimulants. Int Clin Psychohpharmacol 1999; 14: 1–18. CrossRef
- Pharmacokinetics and Clinical Effectiveness of Methylphenidate
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- 1. Department of Pharmacology, Center for Drug Development Science, Georgetown University Medical Center, Room NE405, Med-Dent Bldg., 3900 Reservoir Road, NW, Washington, DC, 20007, USA
- 2. Laboratory of Clinical Investigation, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, USA