Clinical Pharmacokinetics

, Volume 41, Issue 5, pp 329–342 | Cite as

How Important Are Gender Differences in Pharmacokinetics?

Leading Article

Abstract

Gender-related differences in pharmacokinetics have frequently been considered as potentially important determinants for the clinical effectiveness of drug therapy. The mechanistic processes underlying gender-specific pharmacokinetics can be divided into molecular and physiological factors.

Major molecular factors involved in drug disposition include drug transporters and drug-metabolising enzymes. Men seem to have a higher activity relative to women for the cytochrome P450 (CYP) isoenzymes CYP1A2 and potentially CYP2E1, for the drug efflux transporter P-glycoprotein, and for some isoforms of glucuronosyltransferases and sulfotransferases. Women were suggested to have a higher CYP2D6 activity. No major gender-specific differences seem to exist for CYP2C19 and CYP3A. The often-described higher hepatic clearance in women compared with men for substrates of CYP3A and P-glycoprotein, such as erythromycin and verapamil, may be explained by increased intrahepatocellular substrate availability due to lower hepatic P-glycoprotein activity in women relative to men.

Physiological factors resulting in gender-related pharmacokinetic differences include the generally lower bodyweight and organ size, higher percentage of body fat, lower glomerular filtration rate and different gastric motility in women compared with men.

Although gender disparity in pharmacokinetics has been identified for numerous drugs, differences are generally only subtle. For a few drugs, e.g. verapamil, β-blockers and selective serotonin reuptake inhibitors, gender-related differences in pharmacokinetics have been shown to result in different pharmacological responses, but their clinical relevance remains unproven. In contrast, gender differences of clinical importance have clearly been identified for pharmacodynamic processes such as QTc prolongation, and intensive future research efforts are needed to assess the full scope and impact of pharmacodynamic gender disparity on applied pharmacotherapy.

Notes

Acknowledgements

The authors did not receive any funding in the preparation of this manuscript. There are no conflicts of interest directly relevant to the contents of this article.

References

  1. 1.
    Beierle I, Meibohm B, Derendorf H. Gender differences inpharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther 1999; 37(11): 529–47PubMedGoogle Scholar
  2. 2.
    Thurmann PA, Hompesch BC. Influence of gender on the pharmacokinetics and pharmacodynamics of drugs. Int J Clin Pharmacol Ther 1998; 36(11): 586–90PubMedGoogle Scholar
  3. 3.
    Pollock BG. Gender differences in psychotropic drug metabolism. Psychopharmacol Bull 1997; 33(2): 235–41PubMedGoogle Scholar
  4. 4.
    Gleiter CH, Gundert Remy U. Gender differences in pharmacokinetics. Eur J Drug Metab Pharmacokinet 1996; 21(2): 123–8PubMedCrossRefGoogle Scholar
  5. 5.
    Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995; 50(2): 222–39PubMedCrossRefGoogle Scholar
  6. 6.
    Fletcher CV, Acosta EP, Strykowski JM. Gender differences in human pharmacokinetics and pharmacodynamics. J Adolesc Health 1994; 15(8): 619–29PubMedCrossRefGoogle Scholar
  7. 7.
    Yonkers KA, Kando JC, Cole JO, et al. Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication. Am J Psychiatry 1992; 149(5): 587–95PubMedGoogle Scholar
  8. 8.
    Bonate PL. Gender-related differences in xenobiotic metabolism. J Clin Pharmacol 1991; 31(8): 684–90PubMedGoogle Scholar
  9. 9.
    Wizemann T, Pardue M, editors. Exploring the biological contributions to human health: does sex matter? Institute of Medicine. Washington (DC): National Academy Press; 2001Google Scholar
  10. 10.
    Kashuba AD, Nafziger AN. Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet 1998; 34(3): 203–18PubMedCrossRefGoogle Scholar
  11. 11.
    Loebstein R, Lalkin A, Koren G. Pharmacokinetic changes during pregnancy and their clinical relevance. Clin Pharmacokinet 1997; 33(5): 328–43PubMedCrossRefGoogle Scholar
  12. 12.
    D’Arcy PF. Drug interactions with oral contraceptives. Drug Intell Clin Pharm 1986; 20(5): 353–62PubMedGoogle Scholar
  13. 13.
    Back DJ, Orme ML. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990; 18(6): 472–84PubMedCrossRefGoogle Scholar
  14. 14.
    Kim JS, Nafziger AN. Is it sex or is it gender? Clin Pharmacol Ther 2000; 68(1): 1–3PubMedCrossRefGoogle Scholar
  15. 15.
    Fromm MF. P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 2000; 38(2): 69–74PubMedGoogle Scholar
  16. 16.
    Ambudkar SV, Dey S, Hrycyna CA, et al. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999; 39: 361–98PubMedCrossRefGoogle Scholar
  17. 17.
    Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 1995; 275(2): 1011–8PubMedGoogle Scholar
  18. 18.
    Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal P-glycoprotein (mdrl) in interpatient variation in the oral bio-availability of cyclosporine. Clin Pharmacol Ther 1997; 62(3): 248–60PubMedCrossRefGoogle Scholar
  19. 19.
    Benet LZ, Izumi T, Zhang Y, et al. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J Controlled Release 1999; 62(1–2): 25–31CrossRefGoogle Scholar
  20. 20.
    Steiner H, Polliack A, Kimchi-Sarfaty C, et al. Differences in rhodamine-123 efflux in B-type chronic lymphocytic leukemia suggest possible gender and stage variations in drug-resistance gene activity. Ann Hematol 1998; 76(5): 189–94PubMedCrossRefGoogle Scholar
  21. 21.
    Filipits M, Stranzl T, Pohl G, et al. MRP expression in acute myeloid leukemia. An update. Adv Exp Med Biol 1999; 457: 141–50PubMedCrossRefGoogle Scholar
  22. 22.
    Takebayashi Y, Akiyama S, Natsugoe S, et al. The expression of multidrug resistance protein in human gastrointestinal tract carcinomas. Cancer 1998; 82(4): 661–6PubMedCrossRefGoogle Scholar
  23. 23.
    Simon FR, Fortune J, Iwahashi M, et al. Characterization of the mechanisms involved in the gender differences in hepatic taurocholate uptake. Am J Physiol 1999; 276(2 Pt 1): G556–65Google Scholar
  24. 24.
    Urakami Y, Okuda M, Saito H, et al. Hormonal regulation of organic cation transporter OCT2 expression in rat kidney. FEBS Lett 2000; 473(2): 173–6PubMedCrossRefGoogle Scholar
  25. 25.
    Urakami Y, Nakamura N, Takahashi K, et al. Gender differences in expression of organic cation transporter OCT2 in rat kidney. FEBS Lett 1999; 461(3): 339–42PubMedCrossRefGoogle Scholar
  26. 26.
    Smith G, Stubbins MJ, Harries LW, et al. Molecular genetics of the human cytochrome P450 monooxygenase superfamily. Xenobiotica 1998; 28(12): 1129–65PubMedCrossRefGoogle Scholar
  27. 27.
    Kashuba AD, Bertino JS Jr., Kearns GL, et al. Quantitaten of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping. Clin Pharmacol Ther 1998; 63(5): 540–51PubMedCrossRefGoogle Scholar
  28. 28.
    Greenblatt DJ, Abernethy DR, Locniskar A, et al. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 1984; 61(1): 27–35PubMedGoogle Scholar
  29. 29.
    Holazo AA, Winkler MB, Patel IH. Effects of age, gender and oral contraceptives on intramuscular midazolam pharmacokinetics. J Clin Pharmacol 1988; 28(11): 1040–5PubMedGoogle Scholar
  30. 30.
    Thummel KE, O’Shea D, Paine MF, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 1996; 59(5): 491–502PubMedCrossRefGoogle Scholar
  31. 31.
    Tamminga WJ, Werner J, Oosterhuis B, et al. CYP2D6 and CYP2C19 activity in a large population of Dutch healthy volunteers: indications for oral contraceptive-related gender differences. Eur J Clin Pharmacol 1999; 55(3): 177–84PubMedCrossRefGoogle Scholar
  32. 32.
    Labbe L, Sirois C, Pilote S, et al. Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates. Pharmacogenetics 2000; 10(5): 425–38PubMedCrossRefGoogle Scholar
  33. 33.
    Hagg S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol 2001; 51(2): 169–73PubMedCrossRefGoogle Scholar
  34. 34.
    Bock KW, Schrenk D, Forster A, et al. The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes. Pharmacogenetics 1994; 4(4): 209–18PubMedCrossRefGoogle Scholar
  35. 35.
    Relling MV, Lin JS, Ayers GD, et al. Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther 1992; 52(6): 643–58PubMedCrossRefGoogle Scholar
  36. 36.
    Ou-Yang DS, Huang SL, Wang W, et al. Phenotypic polymorphism and gender-related differences of CYP1A2 activity in a Chinese population. Br J Clin Pharmacol 2000; 49(2): 145–51PubMedCrossRefGoogle Scholar
  37. 37.
    Bartoli A, Xiaodong S, Gatti G, et al. The influence of ethnic factors and gender on CYP1A2-mediated drug disposition: a comparative study in Caucasian and Chinese subjects using phenacetin as a marker substrate. Ther Drug Monit 1996; 18(5): 586–91PubMedCrossRefGoogle Scholar
  38. 38.
    Takanashi K, Tainaka H, Kobayashi K, et al. CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics 2000; 10(2): 95–104PubMedCrossRefGoogle Scholar
  39. 39.
    Karim A, Noveck R, McMahon FG, et al. Oxaprozin and piroxicam, nonsteroidal antiinflammatory drugs with long half-lives: effect of protein-binding differences on steady-state pharmacokinetics. J Clin Pharmacol 1997; 37(4): 267–78PubMedGoogle Scholar
  40. 40.
    Brunner HR. The new angiotensin II receptor antagonist, irbesartan: pharmacokinetic and pharmacodynamic considerations. Am J Hypertens 1997; 10(12 Pt 2): 311S–7SPubMedCrossRefGoogle Scholar
  41. 41.
    Wilkinson GR, Guengerich FP, Branch RA. Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 1989; 43(1): 53–76PubMedCrossRefGoogle Scholar
  42. 42.
    Laine K, Tybring G, Bertilsson L. No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. Clin Pharmacol Ther 2000; 68(2): 151–9PubMedCrossRefGoogle Scholar
  43. 43.
    Koop DR, Tierney DJ. Multiple mechanisms in the regulation of ethanol-inducible cytochrome P450IIE1. Bioessays 1990; 12(9): 429–35PubMedCrossRefGoogle Scholar
  44. 44.
    Lucas D, Menez C, Girre C, et al. Cytochrome P450 2E1 genotype and chlorzoxazone metabolism in healthy and alcoholic Caucasian subjects. Pharmacogenetics 1995; 5(5): 298–304PubMedCrossRefGoogle Scholar
  45. 45.
    Kim RB, O’Shea D. Interindividual variability of chlorzoxazone 6-hydroxylation in men and women and its relationship to CYP2E1 genetic polymorphisms. Clin Pharmacol Ther 1995; 57(6): 645–55PubMedCrossRefGoogle Scholar
  46. 46.
    Miners JO, Attwood J, Birkett DJ. Influence of sex and oral contraceptive steroids on paracetamol metabolism. Br J Clin Pharmacol 1983; 16(5): 503–9PubMedCrossRefGoogle Scholar
  47. 47.
    Court MH, Duan SX, von Moltke LL, et al. Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther 2001; 299(3): 998–1006PubMedGoogle Scholar
  48. 48.
    Macdonald JI, Herman RJ, Verbeeck RK. Sex-difference and the effects of smoking and oral contraceptive steroids on the kinetics of diflunisal. Eur J Clin Pharmacol 1990; 38(2): 175–9PubMedGoogle Scholar
  49. 49.
    Morissette P, Albert C, Busque S, et al. In vivo higher glucuronidation of mycophenolic acid in male than in female recipients of a cadaveric kidney allograft and under immunosuppressive therapy with mycophenolate mofetil. Ther Drug Monit 2001; 23(5): 520–5PubMedCrossRefGoogle Scholar
  50. 50.
    Pacifici GM, Evangelisti L, Giuliani L, et al. Zidovudine glucuronidation in human liver: interindividual variability. Int J Clin Pharmacol Ther 1996; 34(8): 329–34PubMedGoogle Scholar
  51. 51.
    Aksoy IA, Sochorova V, Weinshilboum RM. Human liver dehydroepiandrosterone sulfotransferase: nature and extent of individual variation. Clin Pharmacol Ther 1993; 54(5): 498–506PubMedCrossRefGoogle Scholar
  52. 52.
    Marazziti D, Palego L, Rossi A, et al. Gender-related seasonality of human platelet phenolsulfotransferase activity. Neuropsychobiology 1998; 38(1): 1–5PubMedCrossRefGoogle Scholar
  53. 53.
    Brittelli A, De Santi C, Raunio H, et al. Interethnic and interindividual variabilities of platelet sulfotransferases activity in Italians and Finns. Eur J Clin Pharmacol 1999; 55(9): 691–5PubMedCrossRefGoogle Scholar
  54. 54.
    Floderus Y, Ross SB, Wetterberg L. Erythrocyte catechol-O-methyltransferase activity in a Swedish population. Clin Genet 1981; 19(5): 389–92PubMedCrossRefGoogle Scholar
  55. 55.
    Fahndrich E, Coper H, Christ W, et al. Erythrocyte COMT-activity in patients with affective disorders. Acta Psychiatr Scand 1980; 61(5): 427–37PubMedCrossRefGoogle Scholar
  56. 56.
    Boudikova B, Szumlanski C, Maidak B, et al. Human liver catechol-O-methyltransferase pharmacogenetics. Clin Pharmacol Ther 1990; 48(4): 381–9PubMedCrossRefGoogle Scholar
  57. 57.
    McLeod HL, Fang L, Luo X, et al. Ethnic differences in erythrocyte catechol-O-methyltransferase activity in black and white Americans. J Pharmacol Exp Ther 1994; 270(1): 26–9PubMedGoogle Scholar
  58. 58.
    Klemetsdal B, Tollefsen E, Loennechen T, et al. Interethnic difference in thiopurine methyltransferase activity. Clin Pharmacol Ther 1992; 51(1): 24–31PubMedCrossRefGoogle Scholar
  59. 59.
    McLeod HL, Lin JS, Scott EP, et al. Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 1994; 55(1): 15–20PubMedCrossRefGoogle Scholar
  60. 60.
    Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286(5439): 487–91PubMedCrossRefGoogle Scholar
  61. 61.
    de Wildt SN, Kearns GL, Leeder JS, et al. Cytochrome P450 3 A: ontogeny and drug disposition. Clin Pharmacokinet 1999; 37(6): 485–505PubMedCrossRefGoogle Scholar
  62. 62.
    Lew KH, Ludwig EA, Milad MA, et al. Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1993; 54(4): 402–14PubMedCrossRefGoogle Scholar
  63. 63.
    Krecic-Shepard ME, Park K, Barnas C, et al. Race and sex influence clearance of nifedipine: results of a population study. Clin Pharmacol Ther 2000; 68(2): 130–42PubMedCrossRefGoogle Scholar
  64. 64.
    Kahan BD, Kramer WG, Wideman CA, et al. Analysis of pharmacokinetic profiles in 232 renal and 87 cardiac allograft recipients treated with cyclosporine. Transplant Proc 1986; 18(6 Suppl. 5): 115–9PubMedGoogle Scholar
  65. 65.
    Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol 1992; 44(2): 275–83PubMedCrossRefGoogle Scholar
  66. 66.
    Schinkel AH, Wagenaar E, van Deemter L, et al. Absence of the mdrla P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995; 96(4): 1698–705PubMedCrossRefGoogle Scholar
  67. 67.
    Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P4503A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13(3): 129–34PubMedCrossRefGoogle Scholar
  68. 68.
    Kim RB, Wandel C, Leake B, et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 1999; 16(3): 408–14PubMedCrossRefGoogle Scholar
  69. 69.
    Lan LB, Dalton JT, Schuetz EG. Mdrl limits CYP3A metabolism in vivo. Mol Pharmacol 2000; 58(4): 863–9PubMedGoogle Scholar
  70. 70.
    Kinirons MT, O’Shea D, Kim RB, et al. Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin Pharmacol Ther 1999; 66(3): 224–31PubMedCrossRefGoogle Scholar
  71. 71.
    Kivisto KT, Kroemer HK. Use of probe drugs as predictors of drug metabolism in humans. J Clin Pharmacol 1997; 37(1 Suppl.): 40S–8SPubMedGoogle Scholar
  72. 72.
    Rivory LP, Slaviero KA, Hoskins JM, et al. The erythromycin breath test for the prediction of drug clearance. Clin Pharmacokinet 2001; 40(3): 151–8PubMedCrossRefGoogle Scholar
  73. 73.
    Hunt CM, Westerkam WR, Stave GM, et al. Hepatic cytochrome P-4503A (CYP3A) activity in the elderly. Mech Ageing Dev 1992; 64(1–2): 189–99PubMedCrossRefGoogle Scholar
  74. 74.
    Watkins PB, Turgeon DK, Saenger P, et al. Comparison of urinary 6-beta-cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity. Clin Pharmacol Ther 1992; 52(3): 265–73PubMedCrossRefGoogle Scholar
  75. 75.
    Watkins PB. Noninvasive tests of CYP3A enzymes. Pharmacogenetics 1994; 4(4): 171–84PubMedCrossRefGoogle Scholar
  76. 76.
    Krecic-Shepard ME, Barnas CR, Slimko J, et al. Faster clearance of sustained release verapamil in men versus women: continuing observations on sex-specific differences after oral administration of verapamil. Clin Pharmacol Ther 2000; 68(3): 286–92PubMedCrossRefGoogle Scholar
  77. 77.
    Chiou WL, Jeong HY, Wu TC, et al. Use of the erythromycin breath test for in vivo assessments of cytochrome P4503A activity and dosage individualization. Clin Pharmacol Ther 2001; 70(4): 305–10PubMedGoogle Scholar
  78. 78.
    Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270(1): 414–23PubMedGoogle Scholar
  79. 79.
    Schmucker DL, Woodhouse KW, Wang RK, et al. Effects of age and gender on in vitro properties of human liver microsomal monooxygenases. Clin Pharmacol Ther 1990; 48(4): 365–74PubMedCrossRefGoogle Scholar
  80. 80.
    Gorski JC, Jones DR, Haehner-Daniels BD, et al. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin Pharmacol Ther 1998; 64(2): 133–43PubMedCrossRefGoogle Scholar
  81. 81.
    Wrighton SA, Brian WR, Sari MA, et al. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Mol Pharmacol 1990; 38(2): 207–13PubMedGoogle Scholar
  82. 82.
    Gorski JC, Hall SD, Jones DR, et al. Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily. Biochem Pharmacol 1994; 47(9): 1643–53PubMedCrossRefGoogle Scholar
  83. 83.
    Schuetz JD, Beach DL, Guzelian PS. Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics 1994; 4(1): 11–20PubMedCrossRefGoogle Scholar
  84. 84.
    Wacher VJ, Silverman JA, Zhang Y, et al. Role of P-glycoprotein and cytochrome P4503A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci 1998; 87(11): 1322–30PubMedCrossRefGoogle Scholar
  85. 85.
    Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27(4): 383–91PubMedCrossRefGoogle Scholar
  86. 86.
    Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998; 18(1): 84–112PubMedGoogle Scholar
  87. 87.
    May DG, Porter J, Wilkinson GR, et al. Frequency distribution of dapsone N-hydroxylase, a putative probe for P4503A4 activity, in a white population. Clin Pharmacol Ther 1994; 55(5): 492–500PubMedCrossRefGoogle Scholar
  88. 88.
    McCune JS, Lindley C, Decker JL, et al. Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan. J Clin Pharmacol 2001; 41(7): 723–31PubMedCrossRefGoogle Scholar
  89. 89.
    Landi MT, Sinha R, Lang NP, et al. Human cytochrome P4501A2. Chapter 16. IARC Sci Publ 1999; 148: 173–95PubMedGoogle Scholar
  90. 90.
    Eiermann B, Engel G, Johansson I, et al. The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Br J Clin Pharmacol 1997; 44(5): 439–46PubMedCrossRefGoogle Scholar
  91. 91.
    Fang J, Coutts RT, McKenna KF, et al. Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine. Naunyn Schmiedebergs Arch Pharmacol 1998; 358(5): 592–9PubMedCrossRefGoogle Scholar
  92. 92.
    Bertilsson L, Carrillo JA, Dahl ML, et al. Clozapine disposition ovaries with CYP1A2 activity determined by a caffeine test. Br J Clin Pharmacol 1994; 38(5): 471–3PubMedCrossRefGoogle Scholar
  93. 93.
    Lane HY, Chang YC, Chang WH, et al. Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry 1999; 60(1): 36–40PubMedCrossRefGoogle Scholar
  94. 94.
    Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45(6): 525–38PubMedCrossRefGoogle Scholar
  95. 95.
    Xie HG, Huang SL, Xu ZH, et al. Evidence for the effect of gender on activity of (S)-mephenytoin 4’-hydroxylase (CYP2C19) in a Chinese population. Pharmacogenetics 1997; 7(2): 115–9PubMedCrossRefGoogle Scholar
  96. 96.
    Hooper WD, Qing MS. The influence of age and gender on the stereoselective metabolism and pharmacokinetics of mephobarbital in humans. Clin Pharmacol Ther 1990; 48(6): 633–40PubMedCrossRefGoogle Scholar
  97. 97.
    Tanaka E, Terada M, Misawa S. Cytochrome P450 2E1: its clinical and toxicological role. J Clin Pharm Ther 2000; 25(3): 165–75PubMedCrossRefGoogle Scholar
  98. 98.
    Lu Z, Zhang R, Diasio RB. Population characteristics of hepatic dihydropyrimidine dehydrogenase activity, a key metabolic enzyme in 5-fluorouracil chemotherapy. Clin Pharmacol Ther 1995; 58(5): 512–22PubMedCrossRefGoogle Scholar
  99. 99.
    Port RE, Daniel B, Ding RW, et al. Relative importance of dose, body surface area, sex, and age for 5-fluorouracil clearance. Oncology 1991; 48(4): 277–81PubMedCrossRefGoogle Scholar
  100. 100.
    Milano G, Etienne MC, Cassuto-Viguier E, et al. Influence of sex and age on fluorouracil clearance. J Clin Oncol 1992; 10(7): 1171–5PubMedGoogle Scholar
  101. 101.
    de Wildt SN, Kearns GL, Leeder JS, et al. Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet 1999; 36(6): 439–52PubMedCrossRefGoogle Scholar
  102. 102.
    Xie T, Ho SL, Ramsden D. Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol Pharmacol 1999; 56(1): 31–8PubMedGoogle Scholar
  103. 103.
    Kishino S, Nomura A, Di ZS, et al. Alpha-1-acid glycoprotein concentration and the protein binding of disopyramide in healthy subjects. J Clin Pharmacol 1995; 35(5): 510–4PubMedGoogle Scholar
  104. 104.
    Routledge PA, Stargel WW, Kitchell BB, et al. Sex-related differences in the plasma protein binding of lignocaine and diazepam. Br J Clin Pharmacol 1981; 11(3): 245–50PubMedCrossRefGoogle Scholar
  105. 105.
    Gilmore DA, Gal J, Gerber JG, et al. Age and gender influence the stereoselective pharmacokinetics of propranolol. J Pharmacol Exp Ther 1992; 261(3): 1181–6PubMedGoogle Scholar
  106. 106.
    Kristensen CB. Imipramine serum protein binding in healthy subjects. Clin Pharmacol Ther 1983; 34(5): 689–94PubMedCrossRefGoogle Scholar
  107. 107.
    Rolan PE. Plasma protein binding displacement interactions-why are they still regarded as clinically important? Br J Clin Pharmacol 1994; 37(2): 125–8PubMedCrossRefGoogle Scholar
  108. 108.
    Greenblatt DJ, Sellers EM, Shader RI. Drug therapy: drug disposition in old age. N Engl J Med 1982; 306(18): 1081–8PubMedCrossRefGoogle Scholar
  109. 109.
    Ducharme MP, Slaughter RL, Edwards DJ. Vancomycin pharmacokinetics in a patient population: effect of age, gender, and body weight. Ther Drug Monit 1994; 16(5): 513–8PubMedCrossRefGoogle Scholar
  110. 110.
    Efthymiopoulos C, Bramer SL, Maroli A. Effect of age and gender on the pharmacokinetics of grepafloxacin. Clin Pharmacokinet 1997; 33 Suppl. 1: 9–17PubMedCrossRefGoogle Scholar
  111. 111.
    Reigner BG, Welker HA. Factors influencing elimination and distribution of fleroxacin: metaanalysis of individual data from 10 pharmacokinetic studies. Antimicrob Agents Chem-other 1996; 40(3): 575–80Google Scholar
  112. 112.
    Sowinski KM, Abel SR, Clark WR, et al. Effect of gender on the pharmacokinetics of ofloxacin. Pharmacotherapy 1999; 19(4): 442–6PubMedCrossRefGoogle Scholar
  113. 113.
    Kando JC, Yonkers KA, Cole JO. Gender as a risk factor for adverse events to medications. Drugs 1995; 50(1): 1–6PubMedCrossRefGoogle Scholar
  114. 114.
    Mesnil F, Mentre F, Dubruc C, et al. Population pharmacokinetic analysis of mizolastine and validation from sparse data on patients using the nonparametric maximum likelihood method. J Pharmacokinet Biopharm 1998; 26(2): 133–61PubMedGoogle Scholar
  115. 115.
    Levey A, Madaio M, Perrone R. Laboratory assessment of renal disease: clearance, urinanalysis, and renal biopsy. In: Brenner B, Rector FJ, editors. The kidney. 4th ed. Philadelphia (PA): WB Saunders Company, 1991: 919–68Google Scholar
  116. 116.
    Wright CE, Sisson TL, Ichhpurani AK, et al. Steady-state pharmacokinetic properties of pramipexole in healthy volunteers. J Clin Pharmacol 1997; 37(6): 520–5PubMedGoogle Scholar
  117. 117.
    Yukawa E, Honda T, Ohdo S, et al. Population-based investigation of relative clearance of digoxin in Japanese patients by multiple trough screen analysis: an update. J Clin Pharmacol 1997; 37(2): 92–100PubMedGoogle Scholar
  118. 118.
    Yukawa E, Mine H, Higuchi S, et al. Digoxin population pharmacokinetics from routine clinical data: role of patient characteristics for estimating dosing regimens. J Pharm Pharmacol 1992; 44(9): 761–5PubMedCrossRefGoogle Scholar
  119. 119.
    Corey A, Bao J, Bryson P, et al. Effect on age and gender on azimilide pharmacokinetics after a single oral dose of azimilide dihydrochloride. J Clin Pharmacol 1997; 37: 946–53PubMedGoogle Scholar
  120. 120.
    Marathe PH, Greene DS, Kollia GD, et al. The effects of age and gender on single dose pharmacokinetics of avitriptan administered to healthy volunteers. J Clin Pharmacol 1997; 37: 937–45PubMedGoogle Scholar
  121. 121.
    Marathe PH, Greene DS, Lee JS, et al. Assessment of effect of food, gender, and intra-subject variability in the pharmacokinetics of avitriptan. Biopharm Drug Dispos 1998; 19(3): 153–7PubMedCrossRefGoogle Scholar
  122. 122.
    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(5): 545–52PubMedCrossRefGoogle Scholar
  123. 123.
    Krecic-Shepard ME, Barnas CR, Slimko J, et al. Gender-specific effects on verapamil pharmacokinetics and pharmacodynamics in humans. J Clin Pharmacol 2000; 40(3): 219–30PubMedCrossRefGoogle Scholar
  124. 124.
    Schwartz JB, Capili H, Wainer IW. Verapamil stereoisomers during racemic verapamil administration: effects of aging and comparisons to administration of individual stereoisomers. Clin Pharmacol Ther 1994; 56(4): 368–76PubMedCrossRefGoogle Scholar
  125. 125.
    Gupta SK, Atkinson L, Tu T, et al. Age and gender related changes in stereoselective pharmacokinetics and pharmacodynamics of verapamil and norverapamil. Br J Clin Pharmacol 1995; 40(4): 325–31PubMedCrossRefGoogle Scholar
  126. 126.
    Walle UK, Fagan TC, Topmiller MJ, et al. The influence of gender and sex steroid hormones on the plasma binding of propranolol enantiomers. Br J Clin Pharmacol 1994; 37(1): 21–5PubMedCrossRefGoogle Scholar
  127. 127.
    Luzier AB, Killian A, Wilton JH, et al. Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 1999; 66(6): 594–601PubMedGoogle Scholar
  128. 128.
    Johnson JA, Akers WS, Herring VL, et al. Gender differences in labetalol kinetics: importance of determining stereoisomer kinetics for racemic drugs. Pharmacotherapy 2000; 20(6): 622–8PubMedCrossRefGoogle Scholar
  129. 129.
    Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors: an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 1997; 32 Suppl. 1: 1–21PubMedCrossRefGoogle Scholar
  130. 130.
    Hartter S, Wetzel H, Hammes E, et al. Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients. Psychopharmacology (Beri) 1993; 110(3): 302–8CrossRefGoogle Scholar
  131. 131.
    Hartter S, Wetzel H, Hammes E, et al. Nonlinear pharmacokinetics of fluvoxamine and gender differences. Ther Drug Monit 1998; 20(4): 446–9PubMedCrossRefGoogle Scholar
  132. 132.
    Ronfeld RA, Tremaine LM, Wilner KD. Pharmacokinetics of sertraline and its N-demethyl metabolite in elderly and young male and female volunteers. Clin Pharmacokinet 1997; 32 Suppl. 1: 22–30CrossRefGoogle Scholar
  133. 133.
    US Department of Health and Human Services Food and Drug Administration. Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs. Fed Regist 1993; 58(139): 39406–16Google Scholar
  134. 134.
    FDAMA Women and Minorities Working Group Report. Rock-ville (MD): US Department of Health and Human Services, Food and Drug Administration, 1998 Jul 20Google Scholar
  135. 135.
    US Department of Health and Human Services Food and Drug Administration. Investigational new drug applications: amendment to clinical hold regulations for products intended for life-threatening diseases and conditions. Fed Regist 2000; 65(106): 34963–71Google Scholar
  136. 136.
    Oliva A. Efficacy of tirilazad mesylate in aneurysmal subarachnoid hemorrhage. In: FDA. Peripheral and central nervous system drugs advisory committee meeting; Gaithersburg (MD); FDA: 1999 Apr 29Google Scholar
  137. 137.
    Kassell NF, Haley EC Jr., Apperson-Hansen C, et al. Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg 1996; 84(2): 221–8PubMedCrossRefGoogle Scholar
  138. 138.
    Fleishaker JC, Pearson PG, Wienkers LC, et al. Biotransformation of tirilazad in human: 4. Effect of finasteride on tirilazad clearance and reduced metabolite formation. J Pharmacol Exp Ther 1998; 287(2): 591–7PubMedGoogle Scholar
  139. 139.
    Wienkers LC, Steenwyk RC, Hauer MJ, et al. Biotransformation of tirilazad in human: 3. Tirilazad A-ring reduction by human liver microsomal 5alpha-reductase type 1 and type 2. J Pharmacol Exp Ther 1998; 287(2): 583–90PubMedGoogle Scholar
  140. 140.
    Wienkers LC, Steenwyk RC, Pearson PG. Biotransformation of tirilazad in humans: 1. Cytochrome P450 3A mediated hydroxylation of tirilazad mesylate in human liver chromosomes. J Pharmacol Exp Ther 1996; 56: 389–97Google Scholar
  141. 141.
    Fleishaker JC, Pearson LK, Peters GR. Gender does not affect the degree of induction of tirilazad clearance by phenobarbital. Eur J Clin Pharmacol 1996; 50(1–2): 139–45PubMedCrossRefGoogle Scholar
  142. 142.
    Fleishaker JC, Peters GR, Cathcart KS, et al. Evaluation of the pharmacokinetics and tolerability of tirilazad mesylate, a 21-aminosteroid free radical scavenger: II. Multiple-dose administration. J Clin Pharmacol 1993; 33(2): 182–90PubMedGoogle Scholar
  143. 143.
    Fleishaker JC, Peters GR, Cathcart KS. Evaluation of the pharmacokinetics and tolerability of tirilazad mesylate, a 21-aminosteroid free radical scavenger: I. Single-dose administration. J Clin Pharmacol 1993; 33(2): 175–81PubMedGoogle Scholar
  144. 144.
    Fleishaker JC, Hulst LK, Peters GR. Multiple-dose tolerability and pharmacokinetics of tirilazad mesylate at doses of up to 10 mg/kg/day administered over 5–10 days in healthy volunteers. Int J Clin Pharmacol Ther 1994; 32(5): 223–30PubMedGoogle Scholar
  145. 145.
    Fleishaker JC, Hulst LK, Peters GR. Lack of a pharmacokinetic/pharmacodynamic interaction between nimodipine and tirilazad mesylate in healthy volunteers. J Clin Pharmacol 1994; 34(8): 837–41PubMedGoogle Scholar
  146. 146.
    Fleishaker JC, Hulst LK, Peters GR. The effect of phenytoin on the pharmacokinetics of tirilazad mesylate in healthy male volunteers. Clin Pharmacol Ther 1994; 56(4): 389–97PubMedCrossRefGoogle Scholar
  147. 147.
    Hulst LK, Fleishaker JC, Peters GR, et al. Effect of age and gender on tirilazad pharmacokinetics in humans. Clin Pharmacol Ther 1994; 55(4): 378–84PubMedCrossRefGoogle Scholar
  148. 148.
    Fleishaker JC, Pearson LK, Pearson PG, et al. Hormonal effects on tirilazad clearance in women: assessment of the role of CYP3A. J Clin Pharmacol 1999; 39(3): 260–7PubMedGoogle Scholar
  149. 149.
    Fleishaker JC, Fiedler-Kelly J, Grasela TH. Population pharmacokinetics of tirilazad: effects of weight, gender, concomitant phenytoin, and subarachnoid hemorrhage. Pharm Res 1999; 16(4): 575–83PubMedCrossRefGoogle Scholar
  150. 150.
    Ratain MJ, Mick R, Janisch L, et al. Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender. Pharmacogenetics 1996; 6(1): 93–101PubMedCrossRefGoogle Scholar
  151. 151.
    CDER Report to the Nation. Rockville (MD): US Department of Health and Human Services, Food and Drug Administration, 2000Google Scholar
  152. 152.
    Levy G. Predicting effective drug concentrations for individual patients: determinants of pharmacodynamic variability. Clin Pharmacokinet 1998; 34(4): 323–33PubMedCrossRefGoogle Scholar
  153. 153.
    Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsade de pointes associated with cardiovascular drugs. JAMA 1993; 270(21): 2590–6PubMedCrossRefGoogle Scholar
  154. 154.
    Benton RE, Sale M, Flockhart DA, et al. Greater quinidineinduced QTc interval prolongation in women. Clin Pharmacol Ther 2000; 67(4): 413–8PubMedCrossRefGoogle Scholar
  155. 155.
    Frackiewicz EJ, Sramek JJ, Herrera JM, et al. Ethnicity and antipsychotic response. Ann Pharmacother 1997; 31(11): 1360–9PubMedGoogle Scholar
  156. 156.
    Walker JS, Carmody JJ. Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen. Anesth Analg 1998; 86(6): 1257–62PubMedGoogle Scholar
  157. 157.
    Schwartz JB. Gender differences in response to drugs: pain medications. J Gend Specif Med 1999; 2(5): 28–30PubMedGoogle Scholar
  158. 158.
    Sarton E, Olofsen E, Romberg R, et al. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology 2000; 93(5): 1245–54PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Bernd Meibohm
    • 1
  • Ingrid Beierle
    • 2
  • Hartmut Derendorf
    • 3
  1. 1.Department of Pharmaceutical SciencesCollege of Pharmacy, University of TennesseeMemphisUSA
  2. 2.Department of Clinical PharmacyCollege of Pharmacy, University of TennesseeMemphisUSA
  3. 3.Department of PharmaceuticsCollege of Pharmacy, University of FloridaGainesvilleUSA

Personalised recommendations