Pharmacokinetic and Pharmacodynamic Drug Interactions

Methylphenidate, Amphetamine, or Atomoxetine in ADHD
  • John S. Markowitz
  • Kennerly S. Patrick
Part of the Contemporary Clinical Neuroscience book series (CCNE)


Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder and one of the most prevalent chronic health problems afflicting school-aged children in the United States (1). ADHD has a prevalence rate estimated to range from 4 to 9% of children and adolescents (1, 2, 3). Multimodal treatment approaches-those that combine medication treatment with psychotherapeutic, environmental, educational, and school-based interventions—are generally recommended to treat the disorder. Pharmacotherapy is established as both a common and an effective intervention (2,4,5). Although recently published practice guidelines, algorithms, and consensus statements support the judicious use of medication as a fundamental treatment for ADHD (2,6,7), pharmacotherapy is not universal. A recent survey performed by the US Centers for Disease Control and Prevention reported that only approx 54% of children 6–11 yr of age diagnosed with ADHD receive prescription medication, with this number increasing to 61% among children with ADHD and a learning disorder (8). Other data have suggested that these estimates may be conservative.


Dopamine Haloperidol Amiodarone Celecoxib Biotransformation 


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  1. 1.
    Goldman LS, Genel M, Bezman RJ, Slanetz PJ. Diagnosis and treatment of attention-deficit/hyper-activity disorder in children and adolescents. JAMA 1998;279:1100–7.PubMedGoogle Scholar
  2. 2.
    Swanson JM, Seargent JA, Taylor E, Sonuga-Barke EJS, Jensen PS, Cantwell DP. Attention deficit disorder and hyperkinetic disorder. Lancet 1998;351:429–33.PubMedGoogle Scholar
  3. 3.
    Dulcan M, the Work Group on Quality Issues. Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1997;36:85S–121S.PubMedGoogle Scholar
  4. 4.
    Homer CJ, Baltz RD, Hickson GB, et al. Clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder. Pediatrics 2000;105:1158–70.Google Scholar
  5. 5.
    The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1999;56:1073–86.Google Scholar
  6. 6.
    Zametkin AJ, Ernst M. Problems in the management of attention-deficit-hyperactivity disorder. N Eng J Med 1999;340:40–6.Google Scholar
  7. 7.
    American Academy of Pediatrics Subcommittee on Attention-Deficit/Hyperactivity Disorder Committee on Quality Improvement. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics 2001;108:1033–44.Google Scholar
  8. 8.
    Attention deficit disorder and learning disability: United States, 1997–98. Centers for Disease Control, Vital and Health Statistics, Series 10, No. 206, May 2002.Google Scholar
  9. 9.
    Wilens TE, Biederman J, Spencer TJ. Attention deficit/hyperactivity disorder across the lifespan. Annu Rev Med 2002;53:113–31.PubMedGoogle Scholar
  10. 10.
    Weiss M, Murray C. Assessment and management of attention-deficit hyperactivity disorder in adults. Can Med Assoc J 2003;168:715–22.Google Scholar
  11. 11.
    Safer DJ, Zito JM, dosReis S. Concomitant psychotropic medication for youths. Am J Psychiatry 2003;160:438–49.PubMedGoogle Scholar
  12. 12.
    Spencer T, Biederman J, Wilens T. Attention-deficit/hyperactivity disorder and comorbidity. Pediatr Clin North Am 1999;46:915–27.PubMedGoogle Scholar
  13. 13.
    Kowatch RA, Sethuraman G, Hume JH, Kromelis M, Weinberg WA. Combination pharmacotherapy in children and adolescents with bipolar disorder. Biol Psychiatry 2003;53:978–84.PubMedGoogle Scholar
  14. 14.
    Wilens TE, Spencer T, Biederman J, Wozniak J, Connor D. Combined pharmacotherapy: an emerging trend in pediatric psychopharmacology. J Am Acad Child Adolesc Psychiatry 1995;34:110–2.PubMedGoogle Scholar
  15. 15.
    Connor DF, Ozbayrak KR, Kusiak KA, Caponi AB, Melloni RH Jr. Combined pharmacotherapy in children and adolescents in a residential treatment center. J Am Acad Child Adolesc Psychiatry 1997;36:248–54.PubMedGoogle Scholar
  16. 16.
    Rushton JL, Whitmire JT. Pediatric stimulant and selective serotonin reuptake inhibitor prescription trends. 1992 to 1998. Arch Pediatr Adolesc Med 2001;155:560–5.PubMedGoogle Scholar
  17. 17.
    Guevara J, Lozano P, Wickizer T, Mell L, Gephart H. Psychotropic medication use in a population of children who have attention-deficit/hyperactivity disorder. Pediatrics 2002;109:733–9.PubMedGoogle Scholar
  18. 18.
    Zito JM, Safer DJ, dosReis S, Magder LS, Gardner JF, Zarin DA. Psychotherapeutic medication patterns for youths with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 1999;153:1257–63.PubMedGoogle Scholar
  19. 19.
    Olfson M, Gameroff MJ, Marcus SC, Jensen PS. National trends in the treatment of attention deficit hyperactivity disorder. Am J Psychiatry 2003;160:1071–7.PubMedGoogle Scholar
  20. 20.
    Pliszka SR, Greenhill LL, Crismon ML, et al. The Texas children’s medication algorithm project: Report of the Texas consensus conference panel on medication treatment of childhood attention-deficit/hyperactivity disorder. Part I. Attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2000;39:908–19.PubMedGoogle Scholar
  21. 21.
    Milberger S, Biederman J, Faraone SV, Chen L, Jones J. ADHD is associated with early initiation of cigarette smoking in children and adolescents. Am Acad Child Adolesc Psychiatry 1997;36:37–44.Google Scholar
  22. 22.
    Biederman J, Wilens T, Mick E, Spencer T, Faraone SV. Pharmacotherapy of attention deficit/hyperactivity disorder reduces risk for substance use disorder. Pediatrics 1999;104:e20–e4.PubMedGoogle Scholar
  23. 23.
    Leibson CL, Katusic SK, Barbaresi WJ, Ransom J, O’Brien PC. Use and costs of medical care for children and adolescents with and without attention-deficit/hyperactivity disorder. JAMA 2001;285:60–6.PubMedGoogle Scholar
  24. 24.
    Chan E, Zhan CL, Homer CJ. Health care use costs for children with attention-deficit/hyperactivity disorder: national estimates from the medical expenditure panel survey. Arch Pediatr Adolesc Med 2002;156:504–11.PubMedGoogle Scholar
  25. 25.
    Markowitz JS, Morrison SD, DeVane CL. Drug interactions with psychostimulants. Int Clin Psychopharmacol 1999;14:1–18.PubMedGoogle Scholar
  26. 26.
    Markowitz JS, Patrick KS. Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin Pharmacokinet 2001;40:753–72.PubMedGoogle Scholar
  27. 27.
    DeVane CL. Clinical significance of drug binding, protein binding, and binding displacement drug interactions. Psychopharmacol Bull 2002;36:5–21.PubMedGoogle Scholar
  28. 28.
    Balian JD, Rahman A. Metabolic drug-drug interactions: Perspective from FDA medical and clinical pharmacology reviewers. Adv Pharmacol 1997;43:231–8.PubMedGoogle Scholar
  29. 29.
    Alfaro CL. Emerging role of drug interaction studies in drug development: the good, the bad, and the unknown. Psychopharmacol Bull 2001;35:80–93.PubMedGoogle Scholar
  30. 30.
    Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacother 1998;18:84–112.Google Scholar
  31. 31.
    Oesterheld JR. A review of developmental aspects of cytochrome P450. J Child Adolesc Psychopharmacol 1998;8:161–74.PubMedGoogle Scholar
  32. 32.
    Evans WE, McLeod HL. Pharmacogenomics—drug disposition, drug targets, and side effects. N Eng J Med 2003;348:538–49.Google Scholar
  33. 33.
    Liston H, Markowitz JS, DeVane CL. Glucuronidation: Implications in psychopharmacology. J Clin Psychopharmacol 2001;21:500–15.PubMedGoogle Scholar
  34. 34.
    Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem 2002;71:537–92.PubMedGoogle Scholar
  35. 35.
    James RS, Sharp WS, Bastain TM, et al. Double-blind, placebo-controlled study of single-dose amphetamine formulations in ADHD. J Am Acad Child Adolesc Psychiatry 2001;40:1268–76.PubMedGoogle Scholar
  36. 36.
    Manos MJ, Short EJ, Findling RL. Differential effectiveness of methylphenidate and Adderall in school-age youths with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1999;38:813–89.PubMedGoogle Scholar
  37. 37.
    Pliszka SR, Brown R, Olvera RL, Wynne SK. A double-blind, placebo-controlled study of Adderall and methylphenidate in the treatment of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2000;39:619–26.PubMedGoogle Scholar
  38. 38.
    Faraone SV, Biederman J, Roe C. Comparative efficacy of Adderall and methylphenidate in attention deficit/hyperactivity disorder: a meta-analysis. J Clin Psychopharmacol 2002;22:468–73.PubMedGoogle Scholar
  39. 39.
    Zabik JE, Levin RM, Maickel RP. Drug interaction with brain biogenic amines and the effects of amphetamine isomers on locomotor activity. Pharmacol Biochem Behav 1978;8:429–35.PubMedGoogle Scholar
  40. 40.
    Arnold LE, Huestis RD, Smeltzer DJ, Scheib J, Wemmer D, Colner G. Levamphetamine vs. dextroamphetamine in minimal brain dysfuction. Arch Gen Psychiatry 1976;33:292–301.PubMedGoogle Scholar
  41. 41.
    Greenhill LL, Pliszka S, Dulcan MK, and the Work Group on Quality Issues: AACAP. Practice parameters for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 2002;41(2 Suppl):26S–49S.PubMedGoogle Scholar
  42. 42.
    NIH Consensus Development Program. Diagnosis and treatment of attention deficit hyperactivity disorder. NIH Consensus Statement 1998 Nov 16–18;16(2):1–37. Available from Accessed March 25, 2003.Google Scholar
  43. 43.
    Volkow ND, Wang GJ, Fowler JS, et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 1998;155:1325–31.PubMedGoogle Scholar
  44. 44.
    Volkow ND, Wang G-J, Fowler JS, et al. Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain. Life Sci 1999;65:PL7–12.PubMedGoogle Scholar
  45. 45.
    Volkow ND, Wang G-J, Fowler JS, et al. Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Synapse 2002;43:181–7.PubMedGoogle Scholar
  46. 46.
    Ruskin DN, Berstrom DA, Shenker A, Freeman LE, Back D, Walters JR. Drugs used in the treatment of attention-deficit/hyperactive disorder affect postsynaptic firing rate and oscillation without preferential dopamine autoreceptor action. Biol Psychiatry 2001;49:340–50.PubMedGoogle Scholar
  47. 47.
    Volkow ND, Wang G-J, Fowler JS, et al. “Nonhedonic” food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect. Synapse 2002;44:175–80.PubMedGoogle Scholar
  48. 48.
    Seeman P, Madras BK. Anti-hyperactivity medication: methylphenidate and amphetamine. Mol Psychiatry 1998;3:386–96.PubMedGoogle Scholar
  49. 49.
    Hitri A, Hurd YL, Wyatt RJ, Deutsch SI. Molecular, functional and biochemical characteristics of the dopamine transporter: regional differences and clinical relevance. J Clin Neuropharmacol 1994;17:1–22.Google Scholar
  50. 50.
    Solanto MV. Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res 1998;94:127–52.PubMedGoogle Scholar
  51. 51.
    Seeman P, Madras B. Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis. Behav Brain Res 2002;130:79–83.PubMedGoogle Scholar
  52. 52.
    Patrick KS and Markowitz JS. Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder: a review. Hum Psychopharmacol 1997;12:527–46.Google Scholar
  53. 53.
    Patrick KS, Caldwell RW, Ferris RM, Breese GR. Pharmacology of the enantiomers of threo-methylphenidate. J Pharmacol Exp Ther 1987;241:152–8.PubMedGoogle Scholar
  54. 54.
    Heron C, Costentin J, Bonnet J-J. Evidence that pure uptake inhibitors including cocaine interact slowly with the dopamine neuronal carrier. Eur J Pharmacol 1994;264:391–8.PubMedGoogle Scholar
  55. 55.
    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.PubMedGoogle Scholar
  56. 56.
    Aoyama T, Sasaki T, Kotaki J. Pharmacokinetics and pharmacodynamics of (+)-threo-methylphenidate enantiomer in patients with hypersomnia. Clin Pharmacol Ther 1994;55:270–6.PubMedGoogle Scholar
  57. 57.
    Findling RL, Short E, Manos MJ. Short-term cardiovascular effects of methylphenidate and Adderall. J Am Acad Child Adolesc Psychiatry 2001;40:525–9.PubMedGoogle Scholar
  58. 58.
    Stowe CD, Gardner SF, Gist CC, Schulz EG, Wells TG. 24-hour ambulatory blood pressure monitoring in male children receiving stimulant therapy. Pediatrics 2002;36:1142–9.Google Scholar
  59. 59.
    Efron D, Jarman F, Barker M. Side effects of methylphenidate and dexamphetamine in children with attention deficit disorder: A double-blind, crossover trial. Pediatrics 1997;100:662–6.PubMedGoogle Scholar
  60. 60.
    Eckerman DA, Moy SS, Perkins AN, Patrick KS, Breese GR. Enantioselective behavioral effects of threo methylphenidate in rats. Pharmacol Biochem Behav 40;875–80.Google Scholar
  61. 61.
    Rouhi AM. Chirality at work. Chem Engin News 2003; May 4:56–61.Google Scholar
  62. 62.
    Teo S, Stirling D, Thomas S, Hoberman A, Kiopes A, Khetani V. A 90-day oral gavage toxicity study of d-methylphenidate and d,l-methylphenidate in Sprague-Dawley rats. Toxicology 2002;179:183–96.PubMedGoogle Scholar
  63. 63.
    Davids E, Zhang K, Tarazi FI, Baldessarini RJ. Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning. Psychopharmacology 2002;160:92–8.PubMedGoogle Scholar
  64. 64.
    Teo SK, Stirling DI, Thomas SD, Khetani VD. Neurobehavioral effects of racemic threo-methylphenidate and its D and L enantiomers in rats. Pharmacol Biochem Behav 2003;74:747–54.PubMedGoogle Scholar
  65. 65.
    Patrick KS, Kilts CD, Breese GR. Synthesis and pharmacology of hydroxylated metabolites of methylphenidate. J Med Chem 1981;29:1237–40.Google Scholar
  66. 66.
    Bartlett MF, Egger HP. Disposition an metabolism of methylphenidate in dog and man. Fed Proc 1972;31:537.Google Scholar
  67. 67.
    Faraj BA, Israili ZH, Perel JM, et al. Metabolism and disposition of methylphenidate-14C: studies in man and animals. J Pharmacol Exp Ther 1974;191:535–47.PubMedGoogle Scholar
  68. 68.
    Redalieu E, Bartlett MF, Waldes LM, Darrow WR, Egger H, Wagner WE. A study of methylphenidate in man with respect to its major metabolite. Drug Metab Dispos 1982;10:708–9.PubMedGoogle Scholar
  69. 69.
    Chan Y-P, Swanson JM, Soldin SS, Thiessen JJ, Macleod SM, Logan W. Methylphenidate hydrochloride given with or before breakfast: II. Effects on plasma concentration of methylphenidate and ritalinic acid. Pediatrics 1983;72:56–9.PubMedGoogle Scholar
  70. 70.
    Wargin W, Patrick K, Kilts C, et al. Pharmacokinetics of methylphenidate in man, rat and monkey. J Pharmacol Exp Ther 1983;226:382–6.PubMedGoogle Scholar
  71. 71.
    Modi NB, Lindemulder G, Gupta SK. Single-and multiple-dose pharmacokinetics of oral once-a-day osmotic controlled-release OROS? (methylphenidate HCl) formulation. J Clin Pharmacol 2000;40:379–88.PubMedGoogle Scholar
  72. 72.
    Modi NB, Wang B, Hu WT, Gupta SK. Effect of food on the pharmacokinetics of osmotic controlled-release methylphenidate HCl in healthy subjects. Biopharm Drug Dispos 2000;21:23–31.PubMedGoogle Scholar
  73. 73.
    Modi NB, Wang B, Noveck RJ, Gupta SK. Dose-proportional and stereospecific pharmacokinetics of methylphenidate delivered using an osmotic controlled-release oral delivery system. J Clin Pharmacol 2000;40:1141–9.PubMedGoogle Scholar
  74. 74.
    Sun Z, Murry DJ, Sanghani SP, Davis WI, Kedishvili NY, Zou Q, Hurley TD, Bosron WF. Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1. J Pharmacol Exp Ther 2004;310:469–76.PubMedGoogle Scholar
  75. 75.
    Jonkman LM, Verbaten MN, deBoer D, et al. Differences in plasma concentrations of the D-and L-threo methylphenidate enantiomers in responding and non-responding children with attention-deficit hyperactivity disorder. Psychiatry Res 1998;78:115–8.PubMedGoogle Scholar
  76. 76.
    Ding Y-S, Fowler JS, Volkow ND. Is the l-threo enantiomer of methylphenidate (Ritalin) inactive in the brain when given orally [abstr] Am Col Neuropsychopharmacol 2002;Dec8–12:255.Google Scholar
  77. 77.
    Patrick KS, Ellington KR, Breese GR, Kilts CD. Gas chromatographic-mass spectrometric analysis of methylphenidate and p-hydroxymethylphenidate using deuterated internal standards. J Chromatogr B Biomed Appl 1985;343:329–38.Google Scholar
  78. 78.
    Markowitz JS, Straughn AB, Patrick KS. Advances in the pharmacotherapy of attention-deficit hyperactivity disorder: Focus on methylphenidate formulations. Pharmacotherapy 2003;23:(10):1281–99.PubMedGoogle Scholar
  79. 79.
    Meyer MC, Straughn AB, Jarvi EJ, et al. Bioequivalence of methylphenidate immediate-release tablets using a replicated study design to characterize intrasubject variability. Pharm Res 2000;17:381–4.PubMedGoogle Scholar
  80. 80.
    Shader RI, Harmatz JS, Osterheld JR, Parmalee DX, Sallee FR, Greenblatt DJ. Population pharmacokinetics of methylphenidate in children with attention-deficit hyperactivity disorder. J Clin Pharmacol 1999;39:775–85.PubMedGoogle Scholar
  81. 81.
    Concerta (methylphenidate HCI) Extended-Release Tablets. Company: Alza Corporation. Application No. 21–121. Available from Accessed April 15, 2003.
  82. 82.
    Chan Y-PM, Soldin SJ, Swanson JM, Deber CM, Thiessen JJ, Macleod S. Gas chromatographic/mass spectrometric analysis of methylphenidate (Ritalin) in serum. Clin Biochem 1980;13:266–72.PubMedGoogle Scholar
  83. 83.
    Keating GM, Figgitt DP. Dexmethylphenidate. Drugs 2002;62:1899–904.PubMedGoogle Scholar
  84. 84.
    Novartis Pharmaceuticals Corporation. Focalin™ (dexmethylphenidate HCl) package insert. East Hanover, NJ, 2001.Google Scholar
  85. 85.
    Sherman M, Hauser GC, Glover BH. Toxic reactions to tranylcypromine. Am J Psychiatry 1964;120:1019–21.PubMedGoogle Scholar
  86. 86.
    Newcorn JH, Schulz K, Harrison M, DeBellis MD, Udarbe JK, Halperin JM. α2-adrenergic agonists: neurochemistry, efficacy, and clinical guidelines for use in children. Pediatr Clin North Am 1998;45:1099–122.PubMedGoogle Scholar
  87. 87.
    Swanson JM, Flockhart D, Udrea D, et al. Clonidine in the treatment of ADHD: questions about safety and efficacy. J Child Adolesc Psychiatry 1995;5:301–4.Google Scholar
  88. 88.
    The Tourette’s Syndrome Study Group. Treatment of ADHD in children with tics-a randomized controlled trial. Neurology 2002;58:527–36.Google Scholar
  89. 89.
    Connor DF, Barkley RA, Davis HT. A pilot study of methylphenidate, clonidine, or the combination in ADHD comorbid with aggressive oppositional defiant or conduct disorder. Clin Pediatr 2000;39:15–25.Google Scholar
  90. 90.
    Levy F, Hobbes G. Does haloperidol block methylphenidate? Psychopharmacology 1996;126:70–4.PubMedGoogle Scholar
  91. 91.
    Janowski DS, Davis JM. Methylphenidate, dextroamphetamine and levamphetamine. Arch Gen Psychiatry 1976;33:304–8.Google Scholar
  92. 92.
    Volkow ND, Wang G-J, Fowler JS, et al. Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma. Psychopharmacology 2003;166:264–70.PubMedGoogle Scholar
  93. 93.
    Maxwell RA, Plummer AJ, Ross SD, Paytas JJ, Dennis AD. Antihypertensive effects of the central nervous stimulant, methylphenidate. Arch Int Pharmacodyn Ther 1957;CXII:26–35.Google Scholar
  94. 94.
    Maxwell RA, Plummer AJ, Ross SD, Daniel AL. Studies concerning the cardiovascular actions of the central nervous stimulant methylphenidate. J Pharmacol Exp Ther 1958;123:22–7.PubMedGoogle Scholar
  95. 95.
    Povalshi HJ, Goldsmith ED. Effect of methylphenidate on cardiovascular actions of pressor amines. Proc Soc Exp Biol Med 1959;101:717–21.Google Scholar
  96. 96.
    Tainter ML, Chang DK. The antagonism of the pressor action of tyramine by cocaine. J Pharmacol Exp Ther 1927;30:193–207.Google Scholar
  97. 97.
    DeVane CL, Markowitz JS, Carson SW, et al. Single dose methylphenidate pharmacokinetics in CYP 2D6 extensive and poor metabolizers. J Clin Psychopharmacol 2000;20:347–9.PubMedGoogle Scholar
  98. 98.
    Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 2003;42:59–98.PubMedGoogle Scholar
  99. 99.
    Remich SA, Desta Z, Soukhova NV, Flockhart DA. In vitro inhibition of cytochrome P450s by ephedrine, methylphenidate and its main metabolite ritalinic acid [abstr]. Clin Pharmacol Ther 2002;P60.Google Scholar
  100. 100.
    DeVane CL, Wang J-S, Pennick M, et al. Effects of amphetamine and methylphenidate on cytochrome P450 activity. Poster presentation; American Psychiatric Association 156th Annual Meeting, May 19, 2003, San Francisco, CA.Google Scholar
  101. 101.
    Le Nedelec MJ, Rosengren RJ. Methylphenidate inhibits cytochrome P450 in the Swiss Webster mouse. Hum Exp Toxicol 2002;21:273–80.PubMedGoogle Scholar
  102. 102.
    Markowitz JS, Logan BK, Diamond F, Patrick KS. Detection of the novel metabolite ethylphenidate following methylphenidate overdose with alcohol co-ingestion. J Clin Psychopharmacol 1999;19:362–6.PubMedGoogle Scholar
  103. 103.
    Markowitz JS, DeVane CL, Boulton DW, et al. Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and alcohol. Drug Metab Dispos 2000;28:620–4.PubMedGoogle Scholar
  104. 104.
    Thomson MR, Dowd JJ, Markowitz JS, DeVane CL, Patrick KS. Enantioselective transesterification of methylphenidate to ethylphenidate after coadministration with ethanol [abstr]. J Clin Pharmacol 2002;42:1069.Google Scholar
  105. 105.
    Satoh T, Hosokawa M. The mammalian carboxyesterases: From molecules to function. Annu Rev Pharmacol Toxicol 1998;38:257–88.PubMedGoogle Scholar
  106. 106.
    Roberts SM, Harbison RD, James RC. Inhibition by ethanol of the metabolism of cocaine to benzoylecgonine and ecgonine methyl ester in mouse and human liver. Drug Metab Dispos 1993;21:537–41.PubMedGoogle Scholar
  107. 107.
    Schenk JO. The functioning of neuronal transporter for dopamine: kinetic mechanisms and effects of amphetamine, cocaine and methylphenidate. Prog Drug Res 2002;59:111–37.PubMedGoogle Scholar
  108. 108.
    Angrist B, Corwin J, Bartlik B, Cooper T. Early pharmacokinetics and clinical effects of oral d-amphetamine in normal subjects. Biol Psychiatry 1987;22:1357–68.PubMedGoogle Scholar
  109. 109.
    Brown GL, Ebert MH, Mikkelsen RJ, Hunt RD. Behavior and motor activity response in hyperactive children and plasma amphetamine levels following a sustained release preparation. J Am Acad Child Psychiatry 1980;19:225–39.PubMedGoogle Scholar
  110. 110.
    Wan SH, Martin SB, Azarnoff DL. Kinetics, salivary excretion of amphetamine isomers and effect of urinary pH. Clin Pharmacol Ther 1978;23:585–90.PubMedGoogle Scholar
  111. 111.
    Brown GL, Hunt RD, Ebert MH, Bunney WH, Kopin IJ. Plasma levels of d-amphetamine in hyperative children. Serial behavior and motor response. Psychopharmacology 1979;62:133–40.PubMedGoogle Scholar
  112. 112.
    Goldstein M, Anagnoste B. The conversion in vivo of D-amphetamine to (+)-p-hydroxynorephedrine. Biochim Biophys Acta 1965;107:166–8.PubMedGoogle Scholar
  113. 113.
    Smith RL, Dring LJ. Patterns of metabolism of b-phenethylamines in man and other species. In: Costa E, Garattini S, eds. Amphetamines and related compounds. New York: Raven Press, 1970:121–39.Google Scholar
  114. 114.
    Caldwell J, Dring LG, Williams RT. Norephedrines as metabolites of [14C] amphetamine in urine in man. Biochem J 1972;129:23–4.PubMedGoogle Scholar
  115. 115.
    Van Kammen DP, Ninan PT, Hommer D. Amphetamine enantiomers: psychopharmacological effects. In: Smith DF, ed. CRC handbook of stereoisomers: drugs in psychopharmacology. Boca Raton, FL: CRC, 1984:297–315.Google Scholar
  116. 116.
    Beckett AH, Rowland M, Turner P. Influence of urinary pH on excretion of amphetamine. Lancet 1965;I:303.Google Scholar
  117. 117.
    Chouinard G, Annable L, Bardwejn J. An early phase II clinical trial of tomoxetine (LY139603) in the treatment of newly admitted depressed patients. Psychopharmacology 1984;83:126–8.PubMedGoogle Scholar
  118. 118.
    Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 2002;27:699–711.PubMedGoogle Scholar
  119. 119.
    Strattera™ (atomoxetine), Package Insert. Eli Lilly and Company: Indianapolis, IN, 2002.Google Scholar
  120. 120.
    Chalon SA, Desager JP, DeSante KA, et al. Effect of hepatic impairment on the pharmacokinetics of atomoxetine and metabolites. Clin Pharmacol Ther 2003;73:178–91.PubMedGoogle Scholar
  121. 121.
    Witcher JW, Long A, Smith B, et al. Atomoxetine pharmacokinetics in children and adolescents with attention deficit hyperactivity disorder. J Child Adol Psychopharmacol 2003;1:53–63.Google Scholar
  122. 122.
    Sauer JM, Ponsler GD, Mattiuz EL, Disposition and metabolic fate of atomoxetine hydrochloride: the role of CYP2D6 in human disposition and metabolism. Drug Metab Dispos 2003;31:98–107.PubMedGoogle Scholar
  123. 123.
    Farid NA, Bergstrom RF, Ziege EA, Parli CJ, Lemberger L. Single-dose and steady-state pharmacokinetics of tomoxetine in normal subjects. J Clin Pharmacol 1985;25:296–301.PubMedGoogle Scholar
  124. 124.
    Belle DJ, Ernest CS, Sauer J-M, Smith BP, Thomasson HR, Witcher JW. Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics. J Clin Pharmacol 2002;42:1219–27.PubMedGoogle Scholar

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© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • John S. Markowitz
    • 1
  • Kennerly S. Patrick
    • 1
  1. 1.Department of Pharmaceutical Sciences, College of PharmacyMedical University of South CarolinaCharleston

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