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Differential Kinetics of Phenytoin in Elderly Patients

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Abstract

The elderly have a relatively high risk of developing adverse drug reactions. Phenytoin continues to be a preferred drug for treating generalised tonic-clonic seizures in the elderly and simple partial seizures that generalise. Phenytoin is eliminated almost entirely by hepatic oxidation. The principle enzymes responsible are cytochrome P450 (CYP)2C9 and CYP2C19. CYP2C9 is saturated by therapeutic doses of phenytoin, and at steady state both enzymes are probably operant in most people. The nonlinear pharmacokinetics of phenytoin make it a difficult drug for which to establish safe and effective administration regimens. An important area of inquiry is whether the differential disposition kinetics of phenytoin in the elderly render its administration an even more difficult challenge. Moreover, since the elderly are generally subject to more polypharmacy than younger adults, are they, as a result, subject to either more frequent or more severe drug interactions with phenytoin than younger adults? In order to examine these issues we were interested in learning the extent to which old age might affect the plasma protein binding of phenytoin, its hepatic metabolism and, ultimately, its pharmacokinetic profile.

With regard to the latter we looked carefully at the methods that have been used to characterise the disposition kinetics of phenytoin in general, and in the elderly, in particular. There are many conflicting findings with regard to the effect of age on the disposition kinetics of phenytoin. However, the strategies used for estimating kinetic parameters for phenytoin [viz the maximum rate of metabolism/elimination (Vmax) and the Michaelis-Menton constant (Km)] exhibit deficiencies that could account for some of the disparate findings. Certainly, more careful prospective studies focusing on the effects of age on phenytoin disposition kinetics are warranted. However, in light of the information currently available, no special attention need be paid to the initiation of phenytoin administration in elderly patients who are taking multiple anticonvulsants. On the other hand, for the elderly receiving phenytoin monotherapy, the initiation of phenytoin administration should occur at lower doses than would be customary for younger adults, and phenytoin blood concentrations should be appropriately monitored in order to evaluate individual Vmax and Km values for informed dosage adjustments.

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References

  1. Lindley C, Tully M, Paramsothy V, et al. Inappropriate medication is a major cause of adverse drug reactions in elderly patients. Age Ageing 1992; 21: 294–300

    PubMed  CAS  Google Scholar 

  2. Cadieux R. Drug interactions in the elderly: how multiple drug use increases risk exponentially. Postgrad Med 1989; 86: 179–86

    PubMed  CAS  Google Scholar 

  3. Pourmand R. Seizures and epilepsy in older patients: evaluation and management. Geriatrics 1996; 51: 39–52

    PubMed  CAS  Google Scholar 

  4. Stolarek IH, Brodie AF, Brodie MJ. Management of seizures in the elderly: a survey of UK geriatricians. J R Soc Med 1995; 88: 686–9

    PubMed  CAS  Google Scholar 

  5. Doecke CJ, Veronese ME, Pond SM, et al. Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes. Br J Clin Pharmacol 1991; 31: 125–30

    PubMed  CAS  Google Scholar 

  6. Levy RH. Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia 1995; 36:Suppl. 5: S8–13

    PubMed  Google Scholar 

  7. Glazko AJ. Diphenylhydantoin metabolism. Drug Metab Dispos 1973; 5: 711–4

    Google Scholar 

  8. Fritz S, Lindner W, Roots I, et al. Stereochemistry of aromatic phenytoin hydroxylation in various drug hydroxylation phenotypes in humans. J Pharmacol Exp Ther 1987; 241: 615–22

    PubMed  CAS  Google Scholar 

  9. Srivastava P, Yun CH, Beaune P, et al. Separation of human liver microsomal tolbutamide hydroxylase and (S)-mephenytoin 4′-hydroxylase cytochrome P-450 enzymes. Mol Pharmacol 1991; 40: 69–79

    PubMed  CAS  Google Scholar 

  10. Richardson TH, Johnson EF. The CYP2C subfamily. In: Ioannides C, editor. Cytochromes P450: metabolic and toxicological aspects. Boca Raton (FL): CRC Press, 1996: 161–81

    Google Scholar 

  11. Veronese M, Doecke C, Mackenzie P, et al. Site-directed mutation studies of human liver cytochrome P-450 isoenzymes in the CYP2C subfamily. Biochem J 1993; 289: 533–8

    PubMed  CAS  Google Scholar 

  12. Veronese M, Mackenzie P, Doecke C, et al. Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9. Biochem Biophys Res Commun 1991; 175: 1112–8

    PubMed  CAS  Google Scholar 

  13. Tassaneeyakl W, Veronese M, Birkett D, et al. Co-regulation of phenytoin and tolbutamide metabolism in humans. Br J Clin Pharmacol 1992; 34: 494–8

    Google Scholar 

  14. Bajpai M, Roskos L, Shen D, et al. Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos 1996; 24: 1401–3

    PubMed  CAS  Google Scholar 

  15. Inoue K, Yamazaki H, Imiya K, et al. Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl-hydroxylation and S-mephenytoin 4′-hydroxylation activities in livers of Japanese and Caucasian populations. Pharmacogenetics 1997; 7: 103–13

    PubMed  CAS  Google Scholar 

  16. Meyer U, Zanger U. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol 1997; 37: 269–96

    PubMed  CAS  Google Scholar 

  17. Odani A, Hashimoto Y, Otsuki Y, et al. Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy. Clin Pharmacol Ther 1997; 62: 287–92

    PubMed  CAS  Google Scholar 

  18. Durnas C, Loi CM, Cusack BJ. Hepatic drug metabolism and aging. Clin Pharmacokinet 1990; 19: 359–89

    PubMed  CAS  Google Scholar 

  19. LeCouteur D, McLean A. The aging liver: drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet 1998; 34: 359–73

    CAS  Google Scholar 

  20. Wood A, Vestal R, Wilkinson G, et al. Effect of aging and cigarette smoking on antipyrine and indocyanine green elimination. Clin Pharmacol Ther 1979; 26: 16–20

    PubMed  CAS  Google Scholar 

  21. Wynne H, Cope L, Mutch E, et al. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology 1989; 9: 297–301

    PubMed  CAS  Google Scholar 

  22. Tsujimoto G, Hashimoto K, Hoffman BB. Pharmacokinetic and pharmacodynamic principles of drug therapy in old age: Pt 1. Int J Clin Pharmacol Ther Toxicol 1989; 27: 13–26

    PubMed  CAS  Google Scholar 

  23. Kampmann J, Sinding J, Moller-Jorgensen I. Effect of age on liver function. Geriatrics 1975; 30: 91–5

    PubMed  CAS  Google Scholar 

  24. Birnbaum L. Pharmacokinetic basis of age-related changes in sensitivity to toxicants. Annu Rev Pharmacol 1991; 31: 101–28

    CAS  Google Scholar 

  25. Kamataki T, Maeda K, Shimado M, et al. Age related alteration in the activities of drug-metabolizing enzymes and contents of sex-specific forms of cytochrome P450 in liver microsomes from male and female rats. J Pharmacol Exp Ther 1985; 233: 222–8

    PubMed  CAS  Google Scholar 

  26. Sotaniemi E, Arranto A, Pelkonen O, et al. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther 1997; 61: 331–9

    PubMed  CAS  Google Scholar 

  27. Kinirons M, Crome P. Clinical pharmacokinetic considerations in the elderly: an update. Clin Pharmacokinet 1997; 33: 302–12

    PubMed  CAS  Google Scholar 

  28. Hunt C, Westerkam W, Stave G. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol 1992; 44: 275–83

    PubMed  CAS  Google Scholar 

  29. Vestal R. Aging and determinants of hepatic drug clearance. Hepatology 1989; 9: 331–4

    PubMed  CAS  Google Scholar 

  30. LeConteur D. The physiology of the aging liver. Brisbane: The University of Queensland, 1994

    Google Scholar 

  31. Posner J, Danhof M, Teunissen M, et al. The disposition of antipyrine and its metabolites in young and elderly healthy volunteers. Br J Clin Pharmacol 1987; 24: 51–5

    PubMed  CAS  Google Scholar 

  32. Richens A. A study of the pharmacokinetics of phenytoin (di-phenylhydantoin) in epileptic patients, and the development of a nomogram for making dose increments. Epilepsia 1975; 16: 627–46

    PubMed  CAS  Google Scholar 

  33. Bohinsky RC. Modern concepts in biochemistry. 2nd ed. Boston (MA): Allyn and Bacon, Inc., 1976

    Google Scholar 

  34. Wilkinson GN. Statistical estimations in enzyme kinetics. Biochem J 1961; 80: 324–32

    PubMed  CAS  Google Scholar 

  35. Grasela TH, Sheiner LB, Rambeck B, et al. Steady-state pharmacokinetics of phenytoin from routinely collected patient data. Clin Pharmacokinet 1983; 8: 355–64

    PubMed  CAS  Google Scholar 

  36. Roe DJ, Karol MD. Averaging pharmacokinetic parameter estimates from experimental studies: statistical theory and application. J Pharm Sci 1997; 86: 621–40

    PubMed  CAS  Google Scholar 

  37. Mawer GE, Mullen PW, Rodgers M, et al. Phenytoin dose adjustment in epileptic patients. Br J Clin Pharmacol 1974; 1: 163–8

    PubMed  CAS  Google Scholar 

  38. Murphy JE, Bruni J, Stewart RB. Clinical utility of six methods of predicting phenytoin doses and plasma concentrations. Am J Hosp Pharm 1981; 38: 348–54

    PubMed  CAS  Google Scholar 

  39. Hudson S, Farquhar D, Thompson D, et al. Phenytoin dosage individualization-five methods compared in elderly. J Clin Pharm Ther 1990; 15: 25–34

    PubMed  CAS  Google Scholar 

  40. Ismail R, Rahman AFA, Chand P. Pharmacokinetics of phenytoin in routine clinic patients in Malaysia. J Clin Pharm Ther 1994; 19: 245–8

    PubMed  CAS  Google Scholar 

  41. Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetic parameters. I. Michaelis-Menten model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm 1980; 8: 553–71

    PubMed  CAS  Google Scholar 

  42. Yukawa E, Higuchi S, Aoyama T. Population pharmacokinetics of phenytoin from routine clinical data in Japan: an update. Chem Pharm Bull 1990; 38: 1973–6

    PubMed  CAS  Google Scholar 

  43. Odani A, Hashimoto Y, Takayanagi K, et al. Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model. Biol Pharm Bull 1996; 19(3): 444–8

    PubMed  CAS  Google Scholar 

  44. Chan E, Ti TY, Lee HS. Population pharmacokinetics of phenytoin in Singapore Chinese. Eur J Clin Pharmacol 1990; 39(2): 177–81

    PubMed  CAS  Google Scholar 

  45. Hashimoto Y, Koue T, Otsuki Y, et al. Simulation for population analysis of Michaelis-Menten elimination kinetics. J Pharmacokinet Biopharm 1995; 23(2): 205–16

    PubMed  CAS  Google Scholar 

  46. Vozeh S, Muir K, Sheiner L, et al. Predicting individual phenytoin dosage. J Pharmacokinet Biopharm 1981; 9: 131–46

    PubMed  CAS  Google Scholar 

  47. Schumitzky A. The nonparametric maximum likelihood approach to pharmacokinetic population analysis. In: Proceedings of the 1993 Western Simulation Multiconference: simulation for healthcare; 1993 Jan 17–20: La Jolla (CA). San Diego (CA): Society for Computer Simulation International, 1993: 95–100

    Google Scholar 

  48. Mallet A. Amaximum likelihood estimation method for random coefficient regression models. Biometrika 1986; 73: 645–56

    Google Scholar 

  49. Schumitzky A. Nonparametric EM algorithms for estimating prior distributions. Appl Math Comput 1991; 45: 143–57

    Google Scholar 

  50. Houghton GW, Richens A, Leighton M. Effect of age, height, weight and sex on serum phenytoin concentration in epileptic patients. Br J Clin Pharmacol 1975; 2: 251–6

    PubMed  CAS  Google Scholar 

  51. Crowley J, Cusack B, Jue S, et al. Aging and drug interactions: II. Effect of phenytoin and smoking on the oxidation of theophylline and Cortisol in healthy men. J Pharmacol Exp Ther 1988; 245: 513–23

    PubMed  CAS  Google Scholar 

  52. Bach B, Hansen J, Kampmann J, et al. Disposition of antipyrine and phenytoin correlated with age and liver volume in man. Clin Pharmacokinet 1981; 6: 389–96

    PubMed  CAS  Google Scholar 

  53. Bauer L, Blouin R. Age and phenytoin kinetics in adult epileptics. Clin Pharmacol Ther 1982; 31: 301–4

    PubMed  CAS  Google Scholar 

  54. Quintana E, Maiques J, Ibanez E, et al. Parametros farmacocineticos de fenitoina en monoterapia en una poblacion geriatrica. Hosp Pharm 1995; 19: 24–5

    Google Scholar 

  55. Ludden TM, Allen JP, Valutsky WA, et al. Individualization of phenytoin dosage regimens. Clin Pharmacol Ther 1977; 31: 301–4

    Google Scholar 

  56. Verbeeck RK, Cardinal JA, Wallace SM. Effect of age and sex on the plasma binding of acidic and basic drugs. Eur J Clin Pharmacol 1984; 27: 91–7

    PubMed  CAS  Google Scholar 

  57. Estruch JA, Galdames DP, Martinetti AK, et al. Phenytoin pharmacokinetics in young and old adults [in Spanish]. Rev Med Chil 1992; 120: 1106–9

    PubMed  CAS  Google Scholar 

  58. Schmidt-Nielsen K. Energy metabolism, body size, and problems of scaling. Fed Proc 1970; 9: 1524–32

    Google Scholar 

  59. Klausen B, Toubro S, Astrup A. Age and sex effects on energy expenditure. Am J Clin Nutr 1997; 65: 895–907

    PubMed  CAS  Google Scholar 

  60. Driessen O, Treuren L, Meijer JWA, et al. Distribution of drugs over whole blood: II. The transport function of whole blood for phenytoin. Ther Drug Monit 1989; 11: 390–400

    PubMed  CAS  Google Scholar 

  61. Kramer RL, Richens A. Two dimensional immunoelectrophoresis of human serum proteins for the investigation of protein binding of drugs. Br J Pharmacol 1972; 45: 184P–5

    PubMed  CAS  Google Scholar 

  62. Pike E, Kierulf P, Skuterud B, et al. Drug binding in sera deficient in lipoproteins, albumin, or orosomucoid. Br J Clin Pharmacol 1983; 16: 233–9

    PubMed  CAS  Google Scholar 

  63. Lunde PKM, Rane A, Yaffe SJ, et al. Plasma protein binding of diphenylhydantoin in man: interaction with other drugs and the effects of temperature and plasma dilution. Clin Pharmacol Ther 1970; 11: 846–55

    PubMed  CAS  Google Scholar 

  64. Patterson M, Heazelwood R, Smithurst B, et al. Plasma protein binding of phenytoin in the aged: in vivo studies. Br J Clin Pharmacol 1982; 13: 423–5

    PubMed  CAS  Google Scholar 

  65. Bender AD, Post A, Meier JP, et al. Plasma protein binding of drugs as function of age in adult human subjects. J Pharm Sci 1975; 64: 1711–3

    PubMed  CAS  Google Scholar 

  66. Reidenburg N, Drayer D. Alteration of drug-protein binding in renal disease. Clin Pharmacokinet 1984; 9Suppl. 1: 18–26

    Google Scholar 

  67. Dasgupta A. Increased free phenytoin concentrations in predialysis serum compared to postdialysis serum in patients with uremia treated with hemodialysis: role of uremic compounds. Am J Clin Pathol 1992; 98: 19–25

    PubMed  CAS  Google Scholar 

  68. Olsen GD, Bennett WM, Porter GA. Morphine and phenytoin binding to plasma proteins in renal and hepatic failure. Clin Pharmacol Ther 1975; 17: 677–84

    PubMed  CAS  Google Scholar 

  69. Kober A, Jenner A, Sjöholm I. Differentiated effects of liver cirrhosis on the albumin binding sites for diazepam, salicylic acid and warfarin. Biochem Pharmacol 1978; 27: 2729–35

    PubMed  CAS  Google Scholar 

  70. Williams R, Blaschke TF, Meffin P, et al. Influence of acute viral hepatitis on disposition and plasma binding of tolbutamide. Clin Pharmacol Ther 1977; 21: 301–9

    PubMed  CAS  Google Scholar 

  71. Lai C, Moore P, Quon CY. Binding of fosphenytoin, phosphate ester pro drug of phenytoin, to human serum proteins and competitive binding with carbamazepine, diazepam, phenobarbital, phenylbutazone, phenytoin, valproic acid or warfarin. Res Commun Mol Pathol Pharmacol 1995; 88: 51–62

    PubMed  CAS  Google Scholar 

  72. Hayes MJ, Langman MJS, Short AH. Changes in drug metabolism with increasing age: 2. Phenytoin clearance and protein binding. Br J Clin Pharmacol 1975; 2: 73–9

    PubMed  CAS  Google Scholar 

  73. Winter ME, Tozer TN. Phenytoin. In: Evans WE, Schentag JJ, Jusko WK, editors. Applied pharmacokinetics: principles of therapeutic drug monitoring. Vancouver (WA): Applied Therapeutics, Inc., 1992: 25–1–44

    Google Scholar 

  74. Mattson RH, Cramer J, Williamson PD, et al. Valproic acid in epilepsy: clinical and pharmacological effects. Ann Neurol 1978; 3: 20–5

    PubMed  CAS  Google Scholar 

  75. Kober A, Olsson Y, Sjöholm I. Binding of drugs to human serum albumin XIV: the theoretical basis for the interaction between phenytoin and valproate. Mol Pharmacol 1980; 18: 237–42

    PubMed  CAS  Google Scholar 

  76. Haidukewych D, Rodin E, Zielinski J. Derivation and evaluation of an equation for prediction of free phenytoin concentration in patients co-medicated with valproic acid. Ther Drug Monit 1989; 11: 134–9

    PubMed  CAS  Google Scholar 

  77. Lai ML, Huang JD. Dual effect of valproic acid on the pharmacokinetics of phenytoin. Biopharm Drug Dispos 1993; 14: 365–70

    PubMed  CAS  Google Scholar 

  78. Kutt H, Verebely K. Metabolism of diphenylhydantoin by rat liver microsomes: I. Characteristics of the reaction. Biochem Pharmacol 1970; 19: 675–86

    PubMed  CAS  Google Scholar 

  79. Brennan R, Dehejia H, Kutt H, et al. Diphenylhydantoin intoxication attendant to slow inactivation of isoniazid. Neurology 1970; 20: 687–93

    PubMed  CAS  Google Scholar 

  80. Miller R, Porter J, Greenblatt DJ. Clinical importance of the interaction of phenytoin and isoniazid. Chest 1979; 75: 356–8

    PubMed  CAS  Google Scholar 

  81. Zand R, Nelson S, Slattery J, et al. Inhibition and induction of cytochrome P4502El-catalyzed oxidation by isoniazid in humans. Clin Pharmacol Ther 1993; 54: 142–9

    PubMed  CAS  Google Scholar 

  82. Hansen J, Kampmann J, Siersbaek-Nielson K, et al. The effect of different sulfonamides on phenytoin metabolism in man. Acta Med Scand 1979; 624 Suppl.: 106–10

    CAS  Google Scholar 

  83. Brian W, Srivastava P, Umbenhauer D, et al. Expression of a human liver cytochrome P-450 protein with tolbutamide hydroxylase activity in Saccaromyces cerevisiae. Biochemistry 1989; 28(12): 4993–9

    PubMed  CAS  Google Scholar 

  84. Miners J, Smith K, Robson R, et al. Tolbutamide hydroxylation by human liver microsomes: kinetic characterisation and relationship to other cytochrome P-450 dependent xenobiotic oxidations. Biochem Pharmacol 1988; 37: 1137–44

    PubMed  CAS  Google Scholar 

  85. Jones B, Hawksworth G, Home V, et al. Putative active site model for CP2C9 (tolbutamide hydroxylase). In: Lechner M, editor. Cytochrome P450 biochemistry biophysics and molecular biology. Paris: John Libbey Eurotext, 1994: 523–5

    Google Scholar 

  86. Zielinski J, Haidukewych D, Leheta B. Carbamazepine-phenytoin interaction: elevation of plasma phenytoin concentrations due to carbamazepine comedication. Ther Drug Monit 1985; 7: 51–3

    PubMed  CAS  Google Scholar 

  87. Kerr B, Thumel K, Wurden C, et al. Human liver carbamazepine metabolism: role of CYP3A4 and CYP2C8 in 10-11-epoxide formation. Biochem Pharmacol 1994; 47: 1969–79

    PubMed  CAS  Google Scholar 

  88. Zielinski J, Haidukewych D. Dual effects of carbamazepine-phenytoin interaction. Ther Drug Monit 1987; 9: 21–3

    PubMed  CAS  Google Scholar 

  89. Fleishaker JC, Pearson LK, Peters GR. Phenytoin causes a rapid increase in 6-beta-hydroxycortisol urinary excretion in humans: a putative measure of CYP3A induction. J Pharm Sci 1995; 84: 292–4

    PubMed  CAS  Google Scholar 

  90. Backman J, Olkkola K, Ojala M, et al. Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin. Epilepsia 1996; 37: 253–7

    PubMed  CAS  Google Scholar 

  91. Nolan Jr P, Erstad B, Hoyer G, et al. Steady-state interaction between amiodarone and phenytoin in normal subjects. Am J Cardiol 1990; 65: 1252–7

    PubMed  CAS  Google Scholar 

  92. Fabre G, Julian B, Saint-Aubert B, et al. Evidence for CYP3-mediated N-deethylation of amiodarone in human liver mi-crosomal fractions. Drug Metab Dispos 1993; 21: 978–85

    PubMed  CAS  Google Scholar 

  93. Ha H, Candinas R, Stieger B, et al. Interaction between amiodarone and lidocaine. J Cardiovasc Pharmacol 1996; 28: 533–9

    PubMed  CAS  Google Scholar 

  94. Frigo G, Lecchini S, Caravaggi M, et al. Reduction in phenytoin clearance caused by cimetidine. Eur J Clin Pharmacol 1983; 25: 135–7

    PubMed  CAS  Google Scholar 

  95. Bartle W, Walker S, Shapero T. Dose-dependent effect of cimetidine on phenytoin kinetics. Clin Pharmacol Ther 1983; 33: 649–55

    PubMed  CAS  Google Scholar 

  96. Nation R, Evans A, Milne R. Pharmacokinetic drug interactions with phenytoin: Pt I. Clin Pharmacokinet 1990; 18: 37–60

    PubMed  CAS  Google Scholar 

  97. Knodell R, Browne D, Gwozdz G, et al. Differential inhibition of individual human liver cytochromes P-450 by cimetidine. Gastroenterology 1991; 101: 1680–91

    PubMed  CAS  Google Scholar 

  98. Sadeque AJM, Fisher MB, Korzekwa KR, et al. Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene valproic acid. J Pharmacol Exp Ther 1997; 283(2): 698–703

    PubMed  CAS  Google Scholar 

  99. Prichard P, Walt R, Kithingman G, et al. Oral phenytoin pharmacokinetics during omeprazole therapy. Br J Clin Pharmacol 1987; 24: 543–5

    PubMed  CAS  Google Scholar 

  100. Yamazaki H, Inoue K, Shaw P, et al. Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of contents of these two forms in individual human samples J Pharmacol Exp Ther 1997; 283: 434–42

    PubMed  CAS  Google Scholar 

  101. Ieiri I, Mamiya K, Urae A, et al. Stereoselective 4′-hydroxylation of phenytoin: relationship to (S)-mephenytoin polymorphism in Japanese. Br J Clin Pharmacol 1997; 43: 441–5

    PubMed  CAS  Google Scholar 

  102. von Moltke L, Greenblatt D, Shader R. Clinical pharmacokinetics of antidepressants in the elderly: therapeutic implications. Clin Pharmacokinet 1993; 24: 141–60

    Google Scholar 

  103. Beers M. Explicit criteria for determining inappropriate medication use by the elderly: an update. Arch Intern Med 1997; 157: 1531–6

    PubMed  CAS  Google Scholar 

  104. Shader R, Greenblatt D, von Moltke L. Fluoxetine inhibition of phenytoin metabolism. J Clin Psychopharmacol 1994; 14: 375–6

    PubMed  CAS  Google Scholar 

  105. Richelson E. Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs. Mayo Clin Proc 1997; 7: 835–47

    Google Scholar 

  106. Schmider J, Greenblatt D, von Moltke L, et al. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylation. Br J Clin Pharmacol 1997; 44: 495–8

    PubMed  CAS  Google Scholar 

  107. Haselberger M, Freedman L, Tolbert S. Elevated serum phenytoin concentrations associated with coadministration of sertraline. J Clin Psychopharmacol 1997; 17: 107–9

    PubMed  CAS  Google Scholar 

  108. Rapeport W, Muirhead D, Williams S, et al. Absence of effect of sertraline on the pharmacokinetics and pharmacodynamics of phenytoin. J Clin Psychiatry 1996; 57(1 Suppl.): 24–8

    PubMed  CAS  Google Scholar 

  109. Touchette M, Chandrasekar P, Milad M, et al. Contrasting effects of fluconazole and ketoconazole on phenytoin and testosterone disposition in man. Br J Clin Pharmacol 1992; 34: 75–8

    PubMed  CAS  Google Scholar 

  110. Blum R, Wilton J, Hilligoss D, et al. Effect of fluconazole on the disposition of phenytoin. Clin Pharmacol Ther 1991; 49: 420–5

    PubMed  CAS  Google Scholar 

  111. Rindone J, Bryan G. Phenytoin toxicity associated with ticlopidine administration [letter]. Arch Intern Med 1996; 156:1113

    PubMed  CAS  Google Scholar 

  112. Riva R, Cerullo A, Albani F, et al. Ticlopidine impairs phenytoin clearance: a case report. Neurology 1996; 46: 1172–3

    PubMed  CAS  Google Scholar 

  113. Donahue S, Abernethy D. Ticlopidine inhibition of steady state phenytoin metabolism in humans [abstract]. Clin Pharmacol Ther 1998; 63: 183

    Google Scholar 

  114. Donahue S, Flockhart D, Abernethy D, et al. Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. Clin Pharmacol Ther 1997; 62: 572–7

    PubMed  CAS  Google Scholar 

  115. Conney A. Pharmacological implications of microsomal enzyme induction. Pharmacol Rev 1967; 19: 317–65

    PubMed  CAS  Google Scholar 

  116. Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 1997; 29: 413–580

    PubMed  CAS  Google Scholar 

  117. Browne T, Szabo G, Evans J, et al. Phenobarbital does not alter phenytoin steady-state serum concentration or pharmacokinetics. Neurology 1988; 38: 639–42

    PubMed  CAS  Google Scholar 

  118. Yoshida N, Oda Y, Nishi S, et al. Effect of barbiturate therapy on phenytoin pharmacokinetics. Crit Care Med 1993; 21: 1514–22

    PubMed  CAS  Google Scholar 

  119. Kutt H. Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 1984; 25(2 Suppl.): S118–31

    PubMed  Google Scholar 

  120. Bachmann K, Jauregui L. Use of single sample clearance estimates of cytochrome P450 substrates to characterize hepatic CYP status in vivo. Xenobiotica 1993; 23: 307–15

    PubMed  CAS  Google Scholar 

  121. Kay L, Kampmann J, Svendsen T, et al. Influence of rifampicin and isoniazid on the kinetics of phenytoin. Br J Clin Pharmacol 1985; 20: 323–6

    PubMed  CAS  Google Scholar 

  122. Loi CM, Parker B, Cusack BJ, et al. Aging and drug interactions: III. Individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism in heathy male and female nonsmokers. J Pharmacol Exp Ther 1997; 280: 627–37

    PubMed  CAS  Google Scholar 

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  1. Department of Pharmacology, College of Pharmacy, The University of Toledo, 2801 W. Bancroft St, Toledo, Ohio, 43606-3390, USA

    Kenneth A. Bachmann & Robert J. Belloto Jr

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Bachmann, K.A., Belloto, R.J. Differential Kinetics of Phenytoin in Elderly Patients. Drugs Aging 15, 235–250 (1999). https://doi.org/10.2165/00002512-199915030-00006

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  • DOI: https://doi.org/10.2165/00002512-199915030-00006

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