Clinical Pharmacokinetics

, Volume 40, Issue 10, pp 753–772 | Cite as

Pharmacokinetic and Pharmacodynamic Drug Interactions in the Treatment of Attention-Deficit Hyperactivity Disorder

Review Article Drug Interactions


The psychostimulants methylphenidate, amphetamine and pemoline are among the most common medications used today in child and adolescent psychiatry for the treatment of patients with attention-deficit hyperactivity disorder. Frequently, these medications are used in combination with other medications on a short or long term basis. The present review examines psychostimulant pharmacology, summarises reported drug-drug interactions and explores underlying pharmacokinetic and pharmacodynamic considerations for interactions. A computerised search was undertaken using Medline (1966 to 2000) and Current Contents to provide the literature base for reports of drug-drug interactions involving psycho-stimulants. These leads were further cross-referenced for completeness of the survey.

Methylphenidate appears to be more often implicated in pharmacokinetic interactions suggestive of possible metabolic inhibition, although the mechanisms still remain unclear. Amphetamine was more often involved in apparent pharmaco-dynamic interactions and could potentially be influenced by medications affecting cytochrome P450 (CYP) 2D6. No published reports of drug interactions involving pemoline were found.

The α2-adrenergic agonists clonidine and guanfacine have been implicated in several interactions. Perhaps best documented is their antagonism by tricyclic antidepressants and phenothiazines. In additional, concurrent β-blocker use, or abrupt discontinuation, can lead to hypertensive response.

Although there are few published well-controlled interaction studies with psycho-stimulants and α2-adrenergic agonists, it appears that these agents may be safely coadministered. The interactions of monoamine oxidase inhibitors with psycho-stimulants represent one of the few strict contraindications.


  1. 1.
    Cantwell DP. Attention deficit disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1996; 35: 978–87PubMedGoogle Scholar
  2. 2.
    Dulcan M, and 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 Suppl. 10: 85S–121SPubMedGoogle Scholar
  3. 3.
    Tannock R. Attention deficit hyperactivity disorder: advances in cognitive, neurobiological, and genetic research. J Child Psychol Psychiatry 1998; 39: 65–99PubMedGoogle Scholar
  4. 4.
    Spencer T, Biederman J, Wilens T. Attention-deficit/hyperactivity disorder and comorbidity. Pediatr Clin North Am 1999; 46: 915–27PubMedGoogle Scholar
  5. 5.
    Elia J, Ambrosini PJ, Rapoport JL. Treatment of attention-deficit-hyperactivity disorder. N Engl J Med 1999; 340: 780–8PubMedGoogle Scholar
  6. 6.
    Goldman LS, Genel M, Bezman RJ, et al. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA 1998; 279: 1100–7PubMedGoogle Scholar
  7. 7.
    Bonn D. Methylphenidate: US and European views converging? [editorial]. Lancet 1996; 348: 255Google Scholar
  8. 8.
    Spencer T, Biederman J, Wilens T, et al. Pharmacotherapy of attention-deficit hyperactivity across the life cycle. J Am Acad Child Adolesc Psychiatry 1996; 35: 409–32PubMedGoogle Scholar
  9. 9.
    Faraone SV, Biederman J. Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 1998; 44: 951–8PubMedGoogle Scholar
  10. 10.
    Winsberg BG, Comings DE. Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J Am Acad Child Adolesc Psychiatry 1999; 38: 1474–7PubMedGoogle Scholar
  11. 11.
    Silver LB. Alternative (nonstimulant) medications in the treatment of attention-deficit/hyperactivity disorder in children. Pediatr Clin North Am 1999; 46: 965–75PubMedGoogle Scholar
  12. 12.
    Bradley C. Behavior of chidren receiving benzedrine. Am J Psychiatry 1937; 94: 577–85Google Scholar
  13. 13.
    McArdle P, O’Brien G, Kolvin I. Hyperactivity: presence and relationship with conduct disorder. J Child Psychol Psychiatry 1995; 36: 279–303PubMedGoogle Scholar
  14. 14.
    Connor DF, Ozbayrak KR, Kusiak K, et al. Combined pharmacotherapy in children and adolescents in a residential treatment center. J Am Acad Child Adolesc Psychiatry 1997; 36: 248–54PubMedGoogle Scholar
  15. 15.
    Wilens TE, Spencer T, Biederman J, et al. Combined pharmacotherapy: an emerging trend in pediatric psychopharmacology. J Am Acad Child Adolesc Psychiatry 1995; 34: 110–2PubMedGoogle Scholar
  16. 16.
    Markowitz JS, Morrison SD, DeVane CL. Drug interactions with psychostimulants. Int Clin Psychopharmacol 1999; 14: 1–18PubMedGoogle Scholar
  17. 17.
    Elia J, Ambrosini PL, Rapoport JL. Treatment of attention-deficit hyperactivity disorder. N Engl J Med 1999; 340: 780–8PubMedGoogle Scholar
  18. 18.
    Patrick KS, Mueller RA, Gualtieri CT, et al. Pharmacokinetics and actions of methylphenidate, In: Meltzer HY, editor. Psychopharmacology: the third generation of progress. New York: Raven Press, 1987: 1387–95Google Scholar
  19. 19.
    Lin SN, Andrenyak DM, Moody DE, et al. Enantioselective gas chromatographic-negative ion chemical ionization mass spectrometry for methylphenidate in human plasma. J Anal Toxicol 1999; 23: 524–30PubMedGoogle Scholar
  20. 20.
    Patrick KS, Markowitz JS. Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder: a review. Hum Psychopharmacol 1997; 12: 527–46Google Scholar
  21. 21.
    Patrick KS, Ellington KR, Breese GR, et al. Gas chromatographic-mass spectrometric analysis of methylphenidate and p-hydroxymethylphenidate using deuterated internal standards. J Chromatogr B Biomed Appl 1985; 343: 329–38Google Scholar
  22. 22.
    Swanson JM, Lerner M, Williams L. The more frequent diagnosis of attention deficit-hyperactivity disorder [letter]. N Engl J Med 1995; 333: 944PubMedGoogle Scholar
  23. 23.
    Patrick KS, Caldwell RW, Ferris RM, et al. Pharmacology of the enantiomers of threo-methylphenidate. J Pharmacol Exp Ther 1987; 241: 152–8PubMedGoogle Scholar
  24. 24.
    Froimowitz M, Patrick KS, Cody V. Conformation analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT. Pharm Res 1995; 12: 1430–3PubMedGoogle Scholar
  25. 25.
    Volkow ND, Ding Y, Fowler JS, et al. Is methylphenidate like cocaine? Arch Gen Psychiatry 1995; 52: 456–63PubMedGoogle Scholar
  26. 26.
    Seeman P, Madras BK. Anti-hyperactivity medication: methylphenidate and amphetamine. Mol Psychiatry 1998; 3: 386–96PubMedGoogle Scholar
  27. 27.
    Hitri A, Hurd YL, Wyatt RJ, et al. Molecular, functional and biochemical characteristics of the dopamine transporter: regional differences and clinical relevance. Clin Neuropharmacol 1994; 17: 1–22PubMedGoogle Scholar
  28. 28.
    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: 561–8PubMedGoogle Scholar
  29. 29.
    Aoyama T, Sasaki T, Kotaki J, et al. Pharmacokinetics and pharmacodynamics of (+)-threo-methylphenidate enantiomer in patients with hypersomnia. Clin Pharm Ther 1994; 55: 270–6Google Scholar
  30. 30.
    Eckerman DA, Moy SS, Perkins AN, et al. Enantioselective behavioral effects of threo-methylphenidate in rats. Pharmacol Biochem Behav 1991; 40: 875–80PubMedGoogle Scholar
  31. 31.
    Magill-Lewis J. Psychotropics and kids. Drug Top 2000; Jul 3: 35-42Google Scholar
  32. 32.
    Patrick KS, Kilts CD, Breese GR. Synthesis and pharmacology of hydroxylated metabolites of methylphenidate. J Med Chem 1981; 29: 1237–40Google Scholar
  33. 33.
    Chan Y-P, Swanson JM, Soldin SS, et al. Methylphenidate hydrochloride given with or before breakfast: II. Effects on plasma concentration of methylphenidate and ritalinic acid. Pediatrics 1983; 72: 56–9Google Scholar
  34. 34.
    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: 381–4PubMedGoogle Scholar
  35. 35.
    Srinivas NR, Hubbard JW, Korchiniski ED, et al. Enantioselective pharmacokinetics of dl-threo-methylphenidate in humans. Pharm Res 1993; 286: 880–1Google Scholar
  36. 36.
    Redalieu E, Bartlet MF, Waldes LM, et al. A study of methylphenidate in man with respect to its major metabolite. Drug Metab Dispos 1982; 10: 708–9PubMedGoogle Scholar
  37. 37.
    Wargin W, Patrick K, Kilts C, et al. Pharmacokinetics of methylphenidate in man, rat and monkey. J Pharmacol Exp Ther 1983; 226 382–6PubMedGoogle Scholar
  38. 38.
    Modi NB, Lindemulder G, Gupta SK. Single-and multiple-dose pharmacokinetics of oral once-a-day osmotic controlled-release OROS7 (methylphenidate HCl) formulation. J Clin Pharmacol 2000; 40: 379–88PubMedGoogle Scholar
  39. 39.
    Modi NB, Wang B, Noveck RJ, et al. Dose-proportional and stereospecific pharmacokinetics of methylphenidate delivered using an osmotic controlled-release oral delivery system. J Clin Pharmacol 2000; 40: 1141–9PubMedGoogle Scholar
  40. 40.
    Barlett MF, Egger HP. Disposition an metabolism of methylphenidate in dog and man. Fed Proc 1972; 31: 537Google Scholar
  41. 41.
    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: 535–47PubMedGoogle Scholar
  42. 42.
    Lim HK, Hubbard J, Midha KK. Development of enantioselective gas chromatographic quantitation assay for dl-threo-methylphenidate in biological fluids. J Chromatogr 1986; 378: 109–23PubMedGoogle Scholar
  43. 43.
    Wong NY, King SP, Laughton WB, et al. Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in combination in healthy male volunteers. J Clin Pharmacol 1998; 38: 276–82PubMedGoogle Scholar
  44. 44.
    Ramos L, Bakhtiar K, Majumdar T, et al. Liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry enantiomeric separation of dl-threo-methylphenidate, (Ritalin®) using a macrocyclic antibiotic as the chiral selector. Rapid Commun Mass Spectrom 1999; 13: 2054–62PubMedGoogle Scholar
  45. 45.
    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: 115–8PubMedGoogle Scholar
  46. 46.
    Markowitz JS, Logan BK, Diamond F, et al. Detection of the novel metabolite ethylphenidate following methylphenidate overdose with alcohol co-ingestion. J Clin Psychopharmacol 1999; 19: 362–6PubMedGoogle Scholar
  47. 47.
    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; 25: 620–4Google Scholar
  48. 48.
    Brzezinski MR, Abraham TL, Stone CL, et al. Purification and characterization of a human liver cocaine carboxylesterase that catalyzes the production of benzoylecgonine and the formation of cocaethylene from alcohol and cocaine. Biochem Pharmacol 1994; 48: 1747–55PubMedGoogle Scholar
  49. 49.
    Lockridge O. Genetic variants of human serum cholinesterase influence metabolism of the muscle relaxant succinylcholine. Pharmacol Ther 1990; 47: 35–60PubMedGoogle Scholar
  50. 50.
    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: 537–41PubMedGoogle Scholar
  51. 51.
    DeVane CL, Markowitz JS, Carson SW, et al. Single dose methylphenidate pharmacokinetics in CYP 2D6 extensive and poor metabolizers. J Clin Psychopharmacol 2000; 20: 347–9PubMedGoogle Scholar
  52. 52.
    Pelham WE, Greenslade KE, Vodde-Hamilton M, et al. Relative efficacy of long-acting stimulants on children with attention deficit-hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dexamfetamine, and pemoline. Pediatrics 1990; 86: 226–37PubMedGoogle Scholar
  53. 53.
    Pelham WE, Aronoff HR, Midlam JK, et al. A comparison of Ritalin and Adderall: efficacy and time-course in children with attention-deficit/hyperactivity disorder. Pediatrics 1999; 103: E431–4Google Scholar
  54. 54.
    Arnold LE, Huestis RD, Smeltzer DJ, et al. Levamphetamine vs. dextroamphetamine in minimal brain dysfunction. Arch Gen Psychiatry 1976; 33: 292–301PubMedGoogle Scholar
  55. 55.
    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: 429–35PubMedGoogle Scholar
  56. 56.
    Janowsky DS, Davis JM. Methylphenidate, dextroamphetamine and levamphetamine. Arch Gen Psychiatry 1976; 33: 304–8PubMedGoogle Scholar
  57. 57.
    Wan SH, Martin SB, Azarnoff DL. Kinetics salivary excretion of amphetamine isomers, and effect of urinary pH. Clin Pharmacol Ther 1978; 23: 585–9PubMedGoogle Scholar
  58. 58.
    Hutchaleelaha A, Sukbuntherng J, Chow H-H, et al. Disposition kinetics of d- and l-amphetamine following intravenous administration of racemic amphetamine to rats. Drug Metab Dispos 1994; 22: 406–11PubMedGoogle Scholar
  59. 59.
    Seiden LS, Sabol KE, Ricaurte GA. Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 1993; 32: 639–77Google Scholar
  60. 60.
    Thornberg JE, Moore KE. Dopamine and norepinephrine uptake by rat brain synaptosomes: relative potencies of l and d amphetamine and amantidine. Res Commun Chem Pathol Pharmacol 1973; 5: 81–9Google Scholar
  61. 61.
    Dring LG, Smith RL, Williams RT. The metabolic fate of amphetamine in man and other species. Biochem J 1970; 116: 425–35PubMedGoogle Scholar
  62. 62.
    Patrick, KS. Effect of metabolism on the response to dopamine agonists and antagonists. Am J Pharm Educ 1989; 53: 163–8Google Scholar
  63. 63.
    Bach MV, Coutts RT, Baker GB. Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkyl-amphetamines and their 4-methoxylated derivatives. Xenobiotica 1999; 29: 719–32PubMedGoogle Scholar
  64. 64.
    Wu D, Otton SV, Inaba T, et al. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol 1997; 53: 1605–12PubMedGoogle Scholar
  65. 65.
    Moody DE, Ruangyuttikarn W, Law MY. Quinidine inhibits in vivo metabolism of amphetamine in rats: impact upon correlation between GC/MS and immunoassay findings in rat urine. J Anal Toxicol 1990; 14: 311–7PubMedGoogle Scholar
  66. 66.
    Tomkins DM, Otton SV, Joharchi N, et al. Effect of CYP2D1 inhibition on the behavioral effects of D-amphetamine. Behav Pharmacol 1997; 8: 223–35PubMedGoogle Scholar
  67. 67.
    Cashman JR, Xiong YN, Xu L, et al. N-Oxidation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (Form 3): role in bioactivation and detoxification. J Pharmacol Exp Ther 1999; 288: 1251–60PubMedGoogle Scholar
  68. 68.
    Andriola MR. Efficacy and safety of methylphenidate and pemoline in children with attention deficit hyperactivity disorder. Curr Ther Res Clin Exp 2000; 61: 208–15Google Scholar
  69. 69.
    Nehra A, Mullick R, Ishak KG, et. al. Pemoline-associated hepatic injury. Gastroenterology 1990; 99: 1517–9PubMedGoogle Scholar
  70. 70.
    Vermeulen NPE, Teunissen MWE, Breimer DD. Pharmacokinetics of pemoline in plasma, saliva, and urine following oral administration. Br J Pharmacol 1979; 8: 459–63Google Scholar
  71. 71.
    Sallee FR, Stiller RL, Perel JM, et al. Oral pemoline kinetics in hyperactive children. Clin Pharmacol Ther 1985; 37: 606–9PubMedGoogle Scholar
  72. 72.
    Skejelbo E, Brosen K, Hallas J, et al. The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 1991; 49: 18–23Google Scholar
  73. 73.
    Lemoine A, Gautier JC, Azoulay D, et al. Major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver. Mol Pharmacol 1993; 43: 827–32PubMedGoogle Scholar
  74. 74.
    Perel JM, Black N, Wharton RN, et al. Inhibition of imipramine metabolism by methylphenidate [abstract]. Fed Proc 1969; 28: 418Google Scholar
  75. 75.
    Wharton RN, Perel JM, Dayton PG, et al. A potential clinical use of methylphenidate with tricyclic antidepressants. Am J Psychiatry 1971; 127: 55–61Google Scholar
  76. 76.
    Zeidenberg P, Perel JM, Kanzler M, et al. Clinical and metabolic studies with imipramine in man. Am J Psychiatry 1971; 127: 57–62Google Scholar
  77. 77.
    Cooper TB, Thomas GM. Concomitant imipramine and methylphenidate administration: a case report. Am J Psychiatry 1973; 130: 72Google Scholar
  78. 78.
    Drimmer EJ, Gitlin MJ, Gwirtsman HE. Desipramine and methylphenidate combination treatment for depression: case report. Am J Psychiatry 1983; 140: 241–2PubMedGoogle Scholar
  79. 79.
    Pataki CS, Carlson GA, Kelly KL, et al. Side effects of methylphenidate and desipramine alone and in combination in children. J Am Acad Child Adolesc Psychiatry 1993; 32: 1065–72PubMedGoogle Scholar
  80. 80.
    Flemenbaum A. Hypertensive episodes after adding methylphenidate (Ritalin) to tricyclic antidepressants. Psychosomatics 1972; 13: 265–8PubMedGoogle Scholar
  81. 81.
    Burke MS, Josephson A, Lightsey A. Combined methylphenidate and imipramine complication. J Am Acad Child Adolesc Psychiatry 1995; 34: 403–4PubMedGoogle Scholar
  82. 82.
    Markowitz JS, Patrick KS. Polypharmacy interactions [letter]. J Am Acad Child Adolesc Psychiatry 1996; 35: 842PubMedGoogle Scholar
  83. 83.
    Gwirtsman HE, Szuba MO, Toren L, et al. The antidepressant response to tricyclics is accelerated with the adjunctive use of methylphenidate. Psychopharmacol Bull 1994; 30: 157–64PubMedGoogle Scholar
  84. 84.
    Grob CS, Coyle JT. Suspected adverse methylphenidate-imipramine interactions in children. J Dev Behav Pediatr 1986; 7: 265–7PubMedGoogle Scholar
  85. 85.
    Cohen LG, Prince J, Biederman J, et al. Absence of effect of stimulants on the pharmacokinetics of desipramine in children. Pharmacotherapy 1999; 19: 746–52PubMedGoogle Scholar
  86. 86.
    Feighner JP, Herbstein J, Damlouji N. Combined MAOI, TCA, and direct stimulant therapy of treatment-resistant depression. J Clin Psychiatry 1985; 46: 206–9PubMedGoogle Scholar
  87. 87.
    Sherman M, Hauser GC, Glover BH. Toxic reactions to tranylcypromine. Am J Psychiatry 1964; 120: 1019–21PubMedGoogle Scholar
  88. 88.
    Zeck P. The dangers of some antidepressant drugs. Med J Aust 1961; 2: 607–8Google Scholar
  89. 89.
    Lloyd JTA, Walker DRH. Death after combined dextroamphetamine and phenelzine. BMJ 1965; 2: 168–9PubMedGoogle Scholar
  90. 90.
    Kirsko I, Lewis E, Johnson JE. Severe hyperexia due to tranylcypromine-amphetamine toxicity. Ann Intern Med 1969; 70: 559–64Google Scholar
  91. 91.
    Fawcett J, Kravitz HM, Zajecka JM, et al. CNS stimulant potentiation of monoamine oxidase inhibitors in the treatment of depression. J Clin Psychopharmacol 1991; 11: 127–32PubMedGoogle Scholar
  92. 92.
    DeVane CL, Sallee FR. Serotonin selective reuptake inhibitors in child and adolescent psychopharmacology: a review of published experience. J Clin Psychiatry 1996; 57: 55–66PubMedGoogle Scholar
  93. 93.
    Labellarte MJ, Walkup JT, Riddle MA. The new antidepressants-selective serotonin reuptake inhibitors. Pediatr Clin North Am 1998; 45: 1137–55PubMedGoogle Scholar
  94. 94.
    DeVane CL. Metabolism and pharmacokinetics of serotonin selective reuptake inhibitors. Cell Mol Neurobiol 1999; 19: 443–66PubMedGoogle Scholar
  95. 95.
    McGlohn SE, Bostwick JM. Sertraline with methylphenidate in an ICU patient. Psychosomatics 1995; 36: 584–5PubMedGoogle Scholar
  96. 96.
    Feeney DJ, Klykylo WM. Medication-induced seizures. J Am Acad Child Adolesc Psychiatry 1997; 36: 1018–9PubMedGoogle Scholar
  97. 97.
    Gammon GD, Brown TE. Fluoxetine and methylphenidate combination for treatment of attention deficit disorder and comorbid depressive disorder. J Child Adolesc Psychopharmacol 1993; 3: 1–10PubMedGoogle Scholar
  98. 98.
    Findling RI. Open-label treatment of comorbid depression and attentional disorders with co-administration of serotonin reuptake inhibitors and psychostimulants in children, adolescents, and adults: a case series. J Child Adolesc Psychopharmacol 1996; 16: 165–75Google Scholar
  99. 99.
    Stoll AL, Pillay SS, Diamond L, et al Methylphenidate augmentation of serotonin selective reuptake inhibitors: a case series. J Clin Psychiatry 1996; 57: 72–6PubMedGoogle Scholar
  100. 100.
    Linet LS. Treatment of a refractory depression with a combination of fluoxetine and d-amphetamine. Am J Psychiatry 1989; 146: 803–4PubMedGoogle Scholar
  101. 101.
    Gupta S, Ghaly N, Dewan M. Augmenting fluoxetine with dextroamphetamine to treat refractory depression. Hosp Commun Psychiatry 1992; 43: 281–3Google Scholar
  102. 102.
    Sills TL, Greenshaw AJ, Baker GB, et al. The potentiating effect of sertraline and fluoxetine on amphetamine-induced locomotor activity is not mediated by serotonin. Psychopharmacology 1999; 143: 426–32PubMedGoogle Scholar
  103. 103.
    Sills TL, Greenshaw AJ, Baker GB, et al. Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus acumbens dopamine release: possible pharmacokinetic interaction. Psychopharmacology 1999; 141: 421–7PubMedGoogle Scholar
  104. 104.
    Sills TL, Greenshaw AJ, Baker GB, et al. Subchronic fluoxetine treatment induces a transient potentiation of amphetamine-induced hyperlocomotion: possible pharmacokinetic interaction. Behav Pharmacol 2000; 11: 109–16PubMedGoogle Scholar
  105. 105.
    Garrettson LK, Perel JM, Dayton PG. Methylphenidate interaction with both anticonvulsants and ethyl biscoumacetate. JAMA 1969; 207: 2053–6PubMedGoogle Scholar
  106. 106.
    Ghofrani M. Possible phenytoin-methylphenidate interaction. Dev Med Child Neurol 1988; 30: 266–8Google Scholar
  107. 107.
    Mirkin BL, Wright F. Drug interaction: effects of methylphenidate on the disposition of diphenylhydantoin in man. Neurology 1971; 21: 1123–8PubMedGoogle Scholar
  108. 108.
    Kupferberg HJ, Jeffery W, Huninghake DB. Effect of methylphenidate on plasma anticonvulsant levels. Clin Pharmacol Ther 1972; 13: 201–4PubMedGoogle Scholar
  109. 109.
    Gross-Tsur V, Manor O, van der Meere J, et al. Epilepsy and attention deficit disorder: is methylphenidate safe and effective? J Pediatr 1997; 130: 40–4PubMedGoogle Scholar
  110. 110.
    Gara L, Roberts W. Adverse response to methylphenidate in combination with valproic acid. J Child Adolesc Psychopharmacol 2000; 10: 39–43PubMedGoogle Scholar
  111. 111.
    Behar D, Schaller J, Spreat S. Extreme reduction of methylphenidate levels by carbamazepine. J Am Acad Child Adolesc Psychiatry 1998; 37: 1128–9PubMedGoogle Scholar
  112. 112.
    Schaller JL, Behar D. Carbamazepine and methylphenidate in ADHD. J Am Acad Child Adolesc Psychiatry 1999; 38: 112–3PubMedGoogle Scholar
  113. 113.
    Gross-Tsur V. Carbamazepine andmethylphenidate. J Am Acad Child Adolesc Psychiatry 1999; 38: 637PubMedGoogle Scholar
  114. 114.
    Janowsky DS, Davis JM. Methylphenidate, dextroamphetamine, and levoamphetamine: effects on schizophrenic symptoms. Arch Gen Psychiatry 1976; 33: 304–8PubMedGoogle Scholar
  115. 115.
    Wald D, Ebstein RP, Belmaker R. Haloperidol and lithium blocking of the mood response to intravenous methylphenidate. Psychopharmacology 1978; 57: 83–7PubMedGoogle Scholar
  116. 116.
    Levy F, Hobbes G. The action of stimulant medication in attention deficit disorder with hyperactivity: dopaminergic, noradrenergic, or both? J Am Acad Child Adolesc Psychiatry 1988; 27: 802–5PubMedGoogle Scholar
  117. 117.
    Levy F, Hobbes G. Does haloperidol block methylphenidate? Motivation or attention? Psychopharmacology 1996; 126: 70–4PubMedGoogle Scholar
  118. 118.
    Silverstone T, Fincham J, Wells B, et al. The effect of the dopamine receptor blocking drug pimozide on the stimulant and anorectic actions of dextroamphetamine in man. Neuropsychopharmacology 1980; 19: 1235–7Google Scholar
  119. 119.
    Gittleman-Klein R, Klein DF, Katz S, et al. Comparative effects of methylphenidate and thioridazine in hyperkinetic children. Arch Gen Psychiatry 1976; 33: 1217–31Google Scholar
  120. 120.
    Newcorn JH, Schulz K, Harrison M, et al. α2 adrenergic agonists: neurochemistry, efficacy, and clinical guidelines for use in children. Pediatr Clin North Am 1998; 45: 1099–122PubMedGoogle Scholar
  121. 121.
    Popper CW. Combining methylphenidate and clonidine: pharmacologic questions and news reports about sudden death. J Child Adolesc Psychopharmacol 1995; 5: 157–66Google Scholar
  122. 122.
    Fenichel RR. Combining methylphenidate and clonidine: the role of post-marketing surveillance. J Child Adolesc Psycopharmacol 1995; 5: 155–6Google Scholar
  123. 123.
    Connor DF, Barkley RA, Davis HT. Apilot study of methylphenidate, clonidine, or the combination in ADHD comorbid with aggressive oppositional defiant or conduct disorder. Clin Pediatr 2000; 39: 15–25Google Scholar
  124. 124.
    Swanson JM, Flockhart D, Udrea D, et al. Clonidine in the treatment of ADHD: questions about safety and efficacy. J Child Adolesc Psychopharmacol 1995; 5: 301–4Google Scholar
  125. 125.
    Hunt RD, Cohen DJ, Anderson G, et al. Possible changes in noradrenergic receptor sensitivity following methylphenidate treatment: growth hormone and MHPG response to clonidine in children with attention deficit disorder with hyperactivity. Life Sci 1984; 35: 885–97PubMedGoogle Scholar
  126. 126.
    Gulati OD, Dave BT, Gokhale SD, et al. Antagonism of adrenergic neuron blockade in hypertensive subjects. Clin Pharmacol Ther 1966; 7: 510–4PubMedGoogle Scholar
  127. 127.
    Gokhale SD, Gulati OD, Udwadia BP. Antagonism of the adrenergic neurone blocking action of guanethidine by certain antidepressant and antihistamine drugs. Arch Int Pharmacodyn Ther 1966; 160: 321–9PubMedGoogle Scholar
  128. 128.
    Wender P. Concurrent therapy with d-amphetamine and adrenergic drugs. Am J Psychiatry 1986; 143: 259–60PubMedGoogle Scholar
  129. 129.
    Day MD. Effect of sympathomimetic amines on the blocking action of guanethidine, bretylium and xylocholine. Br J Pharmacol 1962; 18: 421–39Google Scholar
  130. 130.
    Hague DE, Smith ME, Ryan JR, et al. The effect of methylphenidate and prolintane on the metabolism of ethylbiscoumacetate. Clin Pharmacol Ther 1971; 12: 259–62PubMedGoogle Scholar
  131. 131.
    Bellward G, Read, III JM, Garrettson LK. Further studies of the inhibition of drug metabolism by methylphenidate [abstract]. Fed Proc 1969; 28: 418Google Scholar
  132. 132.
    Hunningshake D. Studies of the inhibition of drug metabolism by methylphenidate [abstract]. Fed Proc 1970; 29: 345Google Scholar
  133. 133.
    Dayton PG, Johnson LD, Wilson CH, et al. Inhibition of the metabolism of phenylbutazone by methylphenidate in man [abstract]. Pharmacologist 1969: 11: 272Google Scholar
  134. 134.
    Beckett AH, Rowland M. Urinary excretion kinetics of amphetamine in man. J Pharm Pharmacol 1965; 17: 628–39PubMedGoogle Scholar
  135. 135.
    Clarke’s isolation and identification of drugs. Moffat AC, editor. 2nd ed. London: Pharmaceutical Press, 1986: 349-50Google Scholar
  136. 136.
    Beckett AH, Rowland M, Turner P. Influence of urinary pH on excretion of amphetamine [letter]. Lancet 1965; I: 303Google Scholar
  137. 137.
    Siegel S, Lachman L, Malspeis L. A kinetic study of the hydrolysis of methyl dl-α-phenyl-2-piperidylacetate. J Am Pharm Assoc 1959; 48: 431–9Google Scholar
  138. 138.
    Levine B, Caplan YH, Kauffman G. Fatality resulting from methylphenidate overdose. J Anal Toxicol 1986; 10: 209–10PubMedGoogle Scholar
  139. 139.
    Shore PA, Brodie BB, Hogben CAM. The gastric secretion of drugs: a pH partition hypothesis. J Pharmacol Exp Ther 1957; 119: 361–9PubMedGoogle Scholar
  140. 140.
    Langer SZ, Cavero I, Massinham R. Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents. Hypertension 1980; 3: 372–82Google Scholar
  141. 141.
    Van Zwieten PA. Antihypertensive drugs interacting with α- and β-adrenoceptors: a review of basic pharmacology. Drugs 1988; 6: 6–19Google Scholar
  142. 142.
    Sorkin EM, Heel RC. Guanfacine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of hypertension. Drugs 1986; 31: 301–36PubMedGoogle Scholar
  143. 143.
    Briant RH, Reid JL, Dollery CT. Interaction between clonidine and desipramine in man. BMJ 1973; I: 522–3Google Scholar
  144. 144.
    Hui KK. Hypertensive crisis induced by interaction of clonidine with imipramine. J Am Geriatr Soc 1983; 31: 164–5PubMedGoogle Scholar
  145. 145.
    Van Zwieten PA. Interactions between centrally acting antihypertensive drugs and tricyclic antidepressants. Arch Int Pharmacodyn 1975; 214: 12–30PubMedGoogle Scholar
  146. 146.
    Buckley M, Feely J. Antagonism of antihypertensive effects of guanfacine by tricyclic antidepressants [letter]. Lancet 1991; 337: 1173–4PubMedGoogle Scholar
  147. 147.
    Markowitz JS, Wells GG, Carson WH. Interactions between antipsychotic and antihypertensive drugs. Ann Pharmacother 1995; 29: 603–9PubMedGoogle Scholar
  148. 148.
    Bailey RR, Neale TJ. Rapid clonidine withdrawal with blood pressure overshoot exaggerated by beta-blockade. BMJ 1976; I: 944–3Google Scholar
  149. 149.
    Strauss FG, Franklin SS, Lewin AJ, et al. Withdrawal of anti-hypertensive therapy. Hypertensive crisis in renovascular hypertension. JAMA 1977; 238: 1734–6PubMedGoogle Scholar
  150. 150.
    Vernon C, Sakula A. fatal rebound hypertension after abrupt withdrawal of clonidine and propranolol. Br J Clin Pract 1979; 33: 112PubMedGoogle Scholar
  151. 151.
    Warren SE, Ebert E, Swerdlin AH, et al. Clonidine and propranolol paradoxical hypertension [letter]. Arch Intern Med 1979; 139: 253PubMedGoogle Scholar
  152. 152.
    Jounela AJ, Lilja M. Interaction between beta-blockers and clonidine. Ann Clin Res 1984; 16: 181–2PubMedGoogle Scholar
  153. 153.
    Gilbert RD, Kahn D, Cassidy M. Interaction between clonidine and cyclosporine A. Nephron 1995; 71: 105PubMedGoogle Scholar
  154. 154.
    Silverman JA. P-Glycoprotein. In: Levy RH, Thummel KE, Trager WF, et al., editors. Metabolic drug interactions. Philadelphia: Lippincott Williams and Wilkins, 2000Google Scholar
  155. 155.
    Wu CY, Benet LZ, Hebert MF, et al. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin Pharmacol Ther 1995; 58: 492–7PubMedGoogle Scholar
  156. 156.
    Jaffe R, Livshits T, Bursztyn M. Adverse interaction between clonidine and verapamil. Ann Pharmacother 1994; 28: 881–3PubMedGoogle Scholar
  157. 157.
    Tracy TS, Korzekwa KR, Gonzalez FJ, et al. Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil. Br J Clin Pharmacol 1999; 47: 545–52PubMedGoogle Scholar
  158. 158.
    Ambrosini PJ, Sheikh RM. Increased plasma valproate concentrations when coadministered with guanfacine. J Child Adolesc Psychopharmacol 1998; 8: 143–7PubMedGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesInstitute of Psychiatry, Medical University of South CarolinaCharlestonUSA

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