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Clinical Pharmacokinetics

, Volume 9, Issue 3, pp 189–202 | Cite as

Sex-Related Differences in Drug Disposition in Man

  • Keith Wilson
Review Article

Summary

Sex-related differences in the disposition of some analgesics, anxiolytics and hypnotics have recently been reported. With certain benzodiazepines, sex has been shown to be a more important determinant of variability in drug disposition than age, while with other benzodiazepines an age-related decline in clearance was more pronounced in men than women. In young healthy adults these sex-related differences in drug disposition were related to the phase of the menstrual cycle, oral contraceptive steroid administration, and variations in plasma concentrations of albumin, α1-acid glycoprotein, free fatty acids and sex hormones. While none of the sex-related differences so far reported necessitates the modification of a therapeutic dosage regimen, it is prudent that future protocols for pharmacokinetic studies should regard age, sex, the menstrual cycle and oral contraceptive steroids as potential sources of variability.

Keywords

Clinical Pharmacology Menstrual Cycle Plasma Protein Binding Antipyrine Drug Disposition 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Abel, J.G.; Sellers, E.M.; Naranjo, C.A.; Shaw, J.; Kadar, D. and Romach, M.K.: Inter- and intra-subject variation in diazepam free fraction. Clinical Pharmacology and Therapeutics 26: 247–255 (1979).PubMedGoogle Scholar
  2. Abernethy, D.R. and Greenblatt, D.J.: Impairment of antipyrine metabolism by low-dose oral contraceptive steroids. Clinical Pharmacology and Therapeutics 29: 106–110 (1981).PubMedCrossRefGoogle Scholar
  3. Abshagen, U.; Spörl-Radun, S. and Marinow, J.: Steady state kinetics of bezafibrate and Clofibrate in healthy female volunteers. European Journal of Clinical Pharmacology 17: 305–308 (1980).PubMedCrossRefGoogle Scholar
  4. Allen, M.D.; Greenblatt, D.J.; Harmatz, J.S. and Shader, R.I.: Desmethyldiazepam kinetics in the elderly after oral prazepam. Clinical Pharmacology and Therapeutics 28: 196–202 (1980).PubMedCrossRefGoogle Scholar
  5. Bäckström, T. and Jorpes, P.: Serum Phenytoin, phenobarbital, carbamazepine, albumin, and plasma estradiol progesterone concentrations during the menstrual cycle in women with epilepsy. Acta Neurologica Scandinavica 58: 63–71 (1979).Google Scholar
  6. Benford, D.J.; Bridges, J.W.; Boobis, A.R.; Kahn, G.C.; Brodie, M.J. and Davies, D.S.: The selective oxidation of cytochrome P450 dependent microsomal hydroxylases in human and rat liver microsomes. Biochemical Pharmacology 30: 1702–1703 (1981).PubMedCrossRefGoogle Scholar
  7. Bennett, B.M.; Twiddy, D.A.S.; Moffat, J.A.; Armstrong, P.W. and Marks, G.S.: Sex-related difference in the metabolism of isosorbide dinitrate following incubation in human blood. Biochemical Pharmacology 32: 3729–3734 (1983).PubMedCrossRefGoogle Scholar
  8. Berlin, C.M. and Vesell, E.S.: Antipyrine disposition in milk and saliva of lactating women. Clinical Pharmacology and Therapeutics 31: 38–44 (1982).PubMedCrossRefGoogle Scholar
  9. Bickel, M.H.: Binding of ehlorpromazine and Imipramine to red cells, albumin, lipoproteins and other blood components. Journal of Pharmacy and Pharmacology 27: 733–738 (1975).PubMedCrossRefGoogle Scholar
  10. Bjorntorp, P.; Bengtsson, C.; Blohme, G.; Jonsson, A.; Sjostrom, L.; Tibblin, E.; Tibblin, G. and Wilhelmsen, L.: Adipose tissue tat cell size and number in relation to metabolism in randomly selected middle-aged men and women. Metabolism 20: 927–935 (1971).PubMedCrossRefGoogle Scholar
  11. Booth, M.; Hunt, J.N.; Miles, J.M. and Murray, F.A.: Comparison of gastric emptying and secretion in men and women with reference to prevalence of duodenal ulcer on each sex. Lancet 1: 657–659 (1957).CrossRefGoogle Scholar
  12. Bower, S.: Plasma protein binding of fentanyl. Journal of Pharmacy and Pharmacology 33: 507–514 (1981).PubMedCrossRefGoogle Scholar
  13. Carter, D.E.; Bressler, R.; Hughes, M.R.; Haussler, M.R.; Christian, C.D. and Heine, M.W.: Effect of oral contraceptives on plasma clearance. Clinical Pharmacology and Therapeutics 18: 700–707 (1975).PubMedGoogle Scholar
  14. Carter, D.E.; Goldman, J.M.; Bressler, R.; Huxtable, R.J.; Christian, C.D. and Heine, M.W.: Effect of oral contraceptives on drug metabolism. Clinical Pharmacology and Therapeutics 15: 22–31 (1973).Google Scholar
  15. Clark, A.F.; Calandra, R.S. and Bird, C.E.: Binding of testosterone and 5α-dihydrotestosterone to plasma proteins in humans. Clinical Biochemistry 4: 89–96 (1971).CrossRefGoogle Scholar
  16. Colby, H.D.; Gaskin, J.H. and Kitay, J.I.: Effects of anterior pituitary hormones on hepatic corticosterone metabolism in rats. Steroids 24: 679–686 (1974).PubMedCrossRefGoogle Scholar
  17. Crawford, J.S. and Rudofsky, S.: Some alterations in the pattern of drug metabolism associated with pregnancy, oral contraceptives and the newlyborn. British Journal of Anaesthesia 38: 446–454 (1966).PubMedCrossRefGoogle Scholar
  18. Danef, C.: Effect of hypophysectomy and pituitary implants at puberty on the sexual differentiation of testosterone metabolism in rat liver. Endocrinology 94: 1577–1582 (1974).CrossRefGoogle Scholar
  19. Danhof, M.; Verbeek, R.M.A.; Van Boxtel, C.J.; Boeijinga, J.K. and Briemer, D.D.: Differential effects of enzyme induction on antipyrinc metabolite formation. British Journal of Clinical Pharmacology 13: 379–386 (1982).PubMedCrossRefGoogle Scholar
  20. Davison, J.S.; Davison, M.C. and Hay, D.M.: Gastric emptying time in late pregnancy and labour. Journal of Obstetrics and Gynaecology of the British Commonwealth 77: 37–41 (1970).PubMedCrossRefGoogle Scholar
  21. Divoll, M.; Greenblatt, D.J.; Harmatz, J.S. and Shader, R.I.: Effect of age and gender on disposition of temazepam. Journal of Pharmaceutical Sciences 70: 1104–1107 (1981).PubMedCrossRefGoogle Scholar
  22. Divoll, M. and Grcenblatt, D.J.: Effect of age and sex on lorazepam protein binding. Journal of Pharmacy and Pharmacology 34: 122–123 (1982).PubMedCrossRefGoogle Scholar
  23. Field, B.; Lu, C. and Hepner, G.W.: Inhibition of hepatic drug metabolism by norethindrone. Clinical Pharmacology and Therapeutics 25: 196–198 (1979).PubMedGoogle Scholar
  24. Findlay, J.W.A.; Wyek, J.V.; Smith, P.G.; Butz, R.F.; Hinton, M.L.; Blum, M.R. and Sehroeder, D.H.: Pharmacokinetics of bupropion, a novel antidepressant agent, following oral administration to healthy subjects. European Journal of Clinical Pharmacology 21: 127–135 (1981).PubMedCrossRefGoogle Scholar
  25. Fishman, J.; Bradlow, H.L.; Schneider, J.; Anderson, K.E. and Kappas, A.: A study of differences of estradiol metabolism between men and women by means of an in vivo radiometric analysis. Transactions of the Association of American Physicians 93: 295–304 (1980).PubMedGoogle Scholar
  26. Fraser, H.S.; Mucklow, J.C.; Bulpitt, C.J.; Khan, C.; Mould, G. and Dollery, C.T.: Environmental effects on antipyrine half-life in man. Clinical Pharmacology and Therapeutics 22: 799–808 (1977).PubMedGoogle Scholar
  27. Giles, H.G.; Sellers, E.M.; Naranjo, C.A.; Frecker, R.C. and Greenblatt, D.J.: Disposition of intravenous diazepam in young men and women. European Journal of Clinical Pharmacology 20: 207–213 (1981).PubMedCrossRefGoogle Scholar
  28. Giudieelli, J.F. and Tillement, J.P.: Influence of sex on drug kinetics in man. Clinical Pharmacokinetics 2: 157–166 (1977).CrossRefGoogle Scholar
  29. Gleichmann, W.; Bachmann, G.W.; Dengler, H.J. and Dudeek, J.: Effects of hormonal contraceptives and pregnancy on serum protein pattern. European Journal of Clinical Pharmacology 5: 212–225 (1973).CrossRefGoogle Scholar
  30. Goble, F.C.; Sex as a factor in metabolism, toxicity and efficacy of pharmacodynamic and chemotherapeutic agents; in Garattini et al. (Eds) Advances in Pharmacology and Chemotherapy. Vol. 13. pp. 174–252 (Academic Press, New York 1975).Google Scholar
  31. Gordon, G.C.; Altman, K.; Southern, A.L. and Olivo, J.: Human hepatic testosterone A-ring reductase activity: Effect of medroxyprogesterone acetate. Journal of Clinical Endocrinology and Metabolism 32: 457–461 (1971).PubMedCrossRefGoogle Scholar
  32. Grahnén, A.; von-Bahr, C.; Lindström, B. and Rosen, A.: Bio-availability and pharmacokinetics of Cimetidine. European Journal of Clinical Pharmacology 16: 335–340 (1979).PubMedCrossRefGoogle Scholar
  33. Greenblatt, D.J.; Allen, M.D.; Harmatz, J.S. and Shader, R.I.: Diazepam disposition determinants. Clinical Pharmacology and Therapeutics 27: 301–302 (1980a).PubMedCrossRefGoogle Scholar
  34. Greenblatt, D.J.; Divoll, M.; Abernethy, D.R. and Harmatz, J.S.: Antipyrine kinetics in the elderly: Prediction of age-related changes on benzodiazepine oxidising capacity. Journal of Pharmacology and Experimental Therapeutics 220: 120–126 (1982).PubMedGoogle Scholar
  35. Greenblatt, D.J.; Divoll, M.; Harmatz, J.S. and Shader, R.I.: Oxazepam kinetics: Effects of age and sex. Journal of Pharmacology and Experimental Therapeutics 215: 86–91 (1980b).PubMedGoogle Scholar
  36. Greenblatt, D.J.; Harmatz, J.S. and Shader, R.I.: Sex differences in diazepam protein binding in patients with renal insufficiency. Pharmacology 16: 26–29 (1978a).PubMedCrossRefGoogle Scholar
  37. Greenblatt, D.J.; Harmatz, J.S. and Shader, R.I.: Factors influencing diazepam pharmacokinetics: Age, sex and liver disease. International Journal of Clinical Pharmacology 16: 177–179 (1978b).Google Scholar
  38. Greenblatt, D.J.; Shader, R.I.; Franke, K.; MacLaughlin, D.S.; Ransil, B.J. and Koch-Weser, J.: Kinetics of intravenous chlordiazepoxide: Sex differences in drug distribution. Clinical Pharmacology and Therapeutics 22: 893–903 (1977).PubMedGoogle Scholar
  39. Grossman, M.I.; Kirsner, J.B. and Gillespie, I.A.: Basal and Histalog-stimulated gastric secretion in control subjects and in patients with peptic ulcer or gastric cancer. Gastroenterology 45: 14–26 (1963).PubMedGoogle Scholar
  40. Gustafsson, J.-A. and Stenberg, Å.: Irreversible androgenic programming at birth of microsomal and soluble rat liver enzymes active on 4-androstene-3.17-dione and 5α-androstane-3α. 17β-diol. Journal of Biological Chemistry 249: 711–718 (1974).PubMedGoogle Scholar
  41. Herz, R.; Koelz, H.R.; Haemmerli, V.P., Benes, I. and Blum, A.L.: Inhibition of hepatic demethylation of aminopyrine by oral contraceptive steroids in humans. European Journal of Clinical Investigation 8: 27–30 (1978).PubMedCrossRefGoogle Scholar
  42. Homeida, M.; Halliwell, M. and Branch, R.A.: Effects of an oral contraceptive on hepatic size and antipyrine metabolism in premenopausal women. Clinical Pharmacology and Therapeutics 24: 228–232 (1978).PubMedGoogle Scholar
  43. Honda, K.: Continuous low dose contraception with norethisterone acetate; in Hasegawa et al. (Eds) Fertility and Sterility (Excerpta Medica, Amsterdam 1973).Google Scholar
  44. Jack, D.B.; Quarterman, C.P.; Zaman, R. and Kendall, M.J.: Variability of beta-blocker pharmacokinetics in young volunteers. European Journal of Clinical Pharmacology 23: 37–42 (1982).PubMedCrossRefGoogle Scholar
  45. Joehemsen, R.; Van der Graaff, M.; Boeijinga, J.K. and Breimer, D.D.: Influence of sex, menstrual cycle and oral contraceptives on the disposition of nitrazepam. British Journal of Clinical Pharmacology 13: 319–324 (1982).CrossRefGoogle Scholar
  46. Jones, B.M. and Jones, M.K.: Alcohol effects in women during the menstrual cycle. Annals of the New York Academy of Sciences 273: 576–587 (1976).PubMedCrossRefGoogle Scholar
  47. Juchau, M.R. and Fouts, J.R.: Effects of norethynodrel and progesterone on hepatic drug-metabolizing enzyme systems. Biochemical Pharmacology 15: 891–898 (1966).CrossRefGoogle Scholar
  48. Juhlin, I.: Problems in diagnosis, treatment and control of gonorrhoeal infections. Acta Dermato-Venerologica 45: 231–241 (1965).Google Scholar
  49. Kato, R.: Sex-related differences in drug metabolism. Drug Metabolism Reviews 3: 1–32 (1974).PubMedCrossRefGoogle Scholar
  50. Kellermann, G.; Luyten-Kellermann, M.; Horning, M.G. and Stafford, M.: Elimination of antipyrine and benzo(a)pyrene metabolism in cultured human lymphocytes. Clinical Pharmacology and Therapeutics 20: 72–80 (1976).PubMedGoogle Scholar
  51. Kim, H. and Kalkhoff, R.K.: Sex steroid influence on triglyceride metabolism. Journal of Clinical Investigation 56: 858–896 (1975).CrossRefGoogle Scholar
  52. Knutti, R.; Rothweiler, H. and Schlatter, Ch.: Effect of pregnancy on the pharmacokinetics of caffeine. European Journal of Clinical Pharmacology 21: 121–126 (1981).PubMedCrossRefGoogle Scholar
  53. Kolmodin, B.; Azarnoff, D.L. and Sjöqvist, F.: Effect of environmental factors on drug metabolism: Decreased plasma half-life of antipyrine in workers exposed to chlorinated hydrocarbon insecticides. Clinical Pharmacology and Therapeutics 101: 638–642 (1969).Google Scholar
  54. Kristensen, C.B.: Imipramine serum protein binding in healthy subjects. Clinical Pharmacology and Therapeutics 34: 689–694 (1983).PubMedCrossRefGoogle Scholar
  55. Laurell, C.; Kullandcr, S. and Thorell, J.: Plasma protein changes induced by sequential type of contraceptive steroid pills. Clinica Chimica Acta 25: 294–296 (1969).CrossRefGoogle Scholar
  56. Lax, E.R.; Ghraf, R.; Schriefers, H.; Herrmann, M. and Petutschnigk, D.: Regulation of the activities of the enzymes involved in the metabolism of steroid hormones in rat liver. The effect of administration of pituitary hormones and gon-adotrophin preparations in hypophysectomised rats. Acta Endocrinologica (Copenhagen) 82: 774–784 (1976).Google Scholar
  57. MacLeod, S.M.; Giles, H.G.; Bengert, B.; Liu, F.F. and Sellers, E.M.: Age- and gender-related differences in diazepam pharmacokinetics. Journal of Clinical Pharmacology 19: 15–19 (1979).PubMedGoogle Scholar
  58. Miaskiewicz, S.L.; Shively, C.A. and Vesell, E.S.: Sex differences in absorption kinetics of sodium salicylate. Clinical Pharmacology and Therapeutics 31: 30–37 (1982).PubMedCrossRefGoogle Scholar
  59. Miners, J.O.; Attwood, J. and Birkett, D.J.: Influence of sex and oral contraceptive steroids on paracetamol metabolism. British Journal of Clinical Pharmacology 16: 503–509 (1983).PubMedCrossRefGoogle Scholar
  60. Mode, A.; Norstedt, G.; Simic, B.; Eneroth, P. and Gustafsson, J.-A.: Continuous infusion of growth hormone feminizes hepatic steroid metabolism in the rat. Endocrinology 108: 2103–2106 (1981).PubMedCrossRefGoogle Scholar
  61. Mucklow, J.C.; Fraser, H.S.; Bulpitt, C.J.; Kahn, C.; Mould, G. and Dollery, C.T.: Environmental factors affecting paracetamol metabolism in London factory and office workers. British Journal of Clinical Pharmacology 10: 67–74 (1980).PubMedCrossRefGoogle Scholar
  62. Nilsen, O.G. and Jacobsen, S.: The binding of quinidine to protein fractions of normal human sera. Biochemical Pharmacology 24: 995–998 (1975).PubMedCrossRefGoogle Scholar
  63. Novak, L.P.: Ageing total body potassium, fat free mass and cell mass in males and females between the ages 18 and 85 years. Journal of Gerontology 27: 438–443 (1972).PubMedCrossRefGoogle Scholar
  64. Ochs, H.R.; Greenblatt, D.J.; Divoll, M.; Abernethy, D.R.; Feyerabend, H. and Dengler, H.J.: Diazepam kinetics in relation to age and sex. Pharmacology 23: 24–30 (1981).PubMedCrossRefGoogle Scholar
  65. Oram, M; Wilson, K. and Burnett, D.: The influence of oral contraceptives on the metabolism of methaqualone in man. British Journal of Clinical Pharmacology 14: 341–345 (1982).PubMedCrossRefGoogle Scholar
  66. O’Malley, K.; Crooks, J.; Duke, E. and Stevenson, I.H.: Effects of age and sex on human drug metabolism. British Medical Journal 3: 607–609 (1971).PubMedCrossRefGoogle Scholar
  67. O’Malley, K.; Stevenson, I.H. and Alexander., W.: Increased antipyrine half-life in women taking oral contraceptives. Scottish Medical Journal 15: 454–456 (1970).PubMedGoogle Scholar
  68. O’Malley, K.; Stevenson, I.H. and Crooks, J.: Impairment of human drug metabolism by oral contraceptive steroids. Clinical Pharmacology and Therapeutics 13: 552–557 (1972).PubMedGoogle Scholar
  69. Perucca, E. and Crema, A.: Plasma protein binding of drugs in pregnancy. Clinical Pharmacokinetics 7: 336–352 (1982).PubMedCrossRefGoogle Scholar
  70. Proven, G. and Canetti, G.: Les taux di rifampicine dans le serum de l’homme. Revue de la Tuberculose (Paris) 32: 707–716 (1968).Google Scholar
  71. Rey, E.; d’Athis, Ph.; Gineux, P.; dc Lautare, D.E.; Turquats, J.M.; Chavinie, J. and Olive, G.: Pharmacokinetics of clorazepate in pregnant and non-pregnant women. European Journal of Clinical Pharmacokinetics 15: 175–180 (1979).CrossRefGoogle Scholar
  72. Riester, E.F.; Pantuck, E.J.; Pantuck, C.B.; Passananti, G.T.; Vesell, E.S. and Conney, A.H.: Antipyrine metabolism during the menstrual cycle. Clinical Pharmacology and Therapeutics 28: 384–391 (1980).PubMedCrossRefGoogle Scholar
  73. Rinehart, W.: Minipill — a limited alternative for certain women. Population Report (A) 3: 53–67 (1975).Google Scholar
  74. Roberts, R.K.; Desmond, P.V.; Wilkinson, G.R. and Schenker, S.: Disposition of chlordiazepoxide: Sex differences and effects of oral contraceptives. Clinical Pharmacology and Therapeutics 25: 826–831 (1979).PubMedGoogle Scholar
  75. Routledge, P.A.; Stargel, W.W.; Kitchell, B.B., Barchowsky, A. and Shand, D.G.: Sex-related differences in plasma protein binding of lignocaine and diazepam. British Journal of Clinical Pharmacology 11: 245–250 (1981).PubMedCrossRefGoogle Scholar
  76. Rumbaugh, H.C. and Colby, H.D.: Growth hormone the pituitary feminising factor mediating the actions of estradiol on hepatic drug and steroid metabolism? Endocrinology 107: 719–724 (1980).PubMedCrossRefGoogle Scholar
  77. Setchell, K.D.R.; Lawson, A.M.; Mitchell, F.L.; Adlercreutz, H.; Kirk, D.N. and Axelson, M.: Lignans in man and in animal species. Nature 287: 740–742 (1980).PubMedCrossRefGoogle Scholar
  78. Scotti, R.: Sex differences in blood levels of some antibiotics. Chemotherapy 18: 205–211 (1973).PubMedCrossRefGoogle Scholar
  79. Shirasu, Y.: Grantham, P.H.; Weisburger, E.K. and Weisburger, J.H.: Effects of adrenocorticotrophic hormone and growth hormone on the metabolism of N-hydroxy-N-2-fluorenylacetamide and on physiological parameters. Cancer Research 27: 81–87 (1967).PubMedGoogle Scholar
  80. Skett, P.; Eneroth, P.; Gustafsson, J.-Å.; Sonnenschein, C.; Stenberg, A. and Åhlén, A.: Evidence for an unidentified factor from the pituitary gland which affects the steroid metabolism in isolated hepatocytes and hepatoma cells of the rat. Molecular and Cellular Endocrinology 10: 249–262 (1978).PubMedCrossRefGoogle Scholar
  81. Skett, P. and Gustafsson J.-Å.: Hypothalamo-pituitary regulation of liver function. Medical Biology 57: 374–389 (1979).PubMedGoogle Scholar
  82. Skett, P. and Young, C.: The effect of pituitary hormones on hepatic drug metabolism; in Gustafsson (Ed.) Biochemistry, Biophysics and Regulation of Cytochrome P450. pp. 195–198 (Elscvier North Holland Biomedical Press, Amsterdam 1980).Google Scholar
  83. Skett, P. and Young, C.: The effects of pituitary hormones on hepatic drug metabolism in the rat. Acta Endocrinologica 100: 421–426 (1982).PubMedGoogle Scholar
  84. Smart, G.A. and Brown, S.S.: Preparative ultra-centrifugation of small samples of plasma and the protein binding of methaqualone. Analytical Biochemistry 35: 518–522 (1970).CrossRefGoogle Scholar
  85. Song, C.S.; Merkatz, I.R.; Rifkind, A.B.; Gillett, P.R. and Kappas, A.: The influence of pregnancy and oral contraceptive steroids on 1he concentration of plasma proteins. American Journal of Obstetrics and Gynecology 108: 277–231 (1970).Google Scholar
  86. Stitch, S.R.; Toumba, J.K.; Groen, M.B.; Funke, D.W.; Leemhuis, J.; Vink, J. and Woods, G.F.: Excretion, isolation and structure of a new phenolic constituent of female urine. Nature 287: 738–740 (1980).PubMedCrossRefGoogle Scholar
  87. Teunissen, M.W.E.; Srivastava, A.K. and Breimer, D.D.: Influence of sex and oral contraceptive steroids on antipyrine metabolite formation. Clinical Pharmacology and Therapeutics 32: 240–246 (1982).PubMedCrossRefGoogle Scholar
  88. Tsutsumi, E.; Inaba, T.; Mahon, W.A. and Kalow, W.: The displacing effect of a fatty acid on the binding of diazepam to human serum albumin. Biochemical Pharmacology 24: 1361–1362 (1975).PubMedCrossRefGoogle Scholar
  89. Toverud, E.L.; Boobis, A.R.; Brody, M.J.; Murray, S.; Bennett, P.N.; Whitmarsh, V. and Davies, D.S.: Differential induction of antipyrine metabolism by rifampicine. European Journal of Clinical Pharmacology 21: 155–160 (1981).PubMedCrossRefGoogle Scholar
  90. Vermculen, A. and Verdonk, L.: Studies on the binding of lestesterone in human plasma. Steroids 11: 609–611 (1968).CrossRefGoogle Scholar
  91. Vesell, E.S.: On the significance of host factors that affect drug disposition. Clinical Pharmacology and Therapeutics 31: 1–7 (1982).PubMedCrossRefGoogle Scholar
  92. Vesell, E.S. and Page, J.G.: Genetic control of drug levels in man: Phenylbutazone. Science 159: 1479–1480 (1968).PubMedCrossRefGoogle Scholar
  93. Vukovich, R.A.; Brannick, L.H.; Sugerman, A.A. and Neiss, E.S.: Sex differences in the intramuscular absorption and bioavailability of cephradine. Clinical Pharmacology and Therapeutics 18: 215–220 (1975).PubMedGoogle Scholar
  94. Willis, J.V.; Kendall, M.J.; Flinn, R.M.; Thornhill, D.P. and Welling, P.G.: The pharmacokinetics of dielofenac sodium following intravenous and oral administration. European Journal of Clinical Pharmacology 16: 405–410 (1979).PubMedCrossRefGoogle Scholar
  95. Wilson, K.; Oram, M.; Horth, C.E. and Burnett, D.: The influence of the menstrual cycle on the metabolism and clearance of methaqualone. British Journal of Clinical Pharmacology 14: 333–339 (1982).PubMedCrossRefGoogle Scholar
  96. Wilson, K.; Reynolds, C.N. and Burnett, D.: Inter- and intra-individual variation in the metabolism of methaqualone in man after a single oral dose. European Journal of Clinical Pharmacology 13: 291–297 (1978).PubMedCrossRefGoogle Scholar
  97. Wójeicki, J.; GawroĔska-Szklarz, B., Kazimierczyk, J.; Baskiewicz, Z. and RaczyĔski, A.: Comparative pharmacokineties of paracetamol in men and women considering follicular and lutcal phases. Arzneimittel-Forschung 29: 350–352 (1979).Google Scholar
  98. Wood, M. and Wood, A.J.J.: Changes in plasma drug binding and α1-acid glycoprotein in mother and newborn infant. Clinical Pharmacology and Therapeutics 29: 522–526 (1981).PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press Limited 1984

Authors and Affiliations

  • Keith Wilson
    • 1
    • 2
  1. 1.School of Natural SciencesThe Hatfield PolytechnicHatfield, HertsEngland
  2. 2.Biological SciencesThe Hatfield PolytechnicHatfieldEngland

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