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Hepatic and Endocrine Effects of Azole Antifungal Agents

  • Michael H. Tarbit
  • William R. Robertson
  • Ann Lambert
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 96)

Abstract

The group of drugs known collectively as the azoles, comprising a number of 1-substituted imidazole and triazole compounds, undoubtedly represents the modern approach to both topical and systemic treatment of fungal disease. The first generation of azole antifungals, lipophilic imidazole compounds such as clotrimazole, econazole and miconazole, exhibited poor systemic availability following oral administration, due to both poor absorption and ex-tensive first-pass metabolism. Their use has consequently been essentially limited to topical treatment of superficial fungal infections. Ketoconazole, a more polar imidazole introduced into therapy in the late 1970s (Thienpont et al. 1979), represented a breakthrough in the treatment of antifungal disease since it was the first imidazole agent with good oral bioavailability in humans (Heel et al. 1982). Consequently, it was introduced for the treatment of both superficial and systemic fungal infections by oral administration. The subsequent extensive systemic use of ketoconazole resulted in the appearance of two major classes of side effect: drug-related idiosyncratic hepatitis and decreased plasma concentrations of steroid hormones. In addition, and some-what less serious in impact, the drug has also been shown to interfere with the metabolism of a number of co-administered drugs.

Keywords

Antifungal Agent Hydroxysteroid Dehydrogenase Adrenal Steroidogenesis Azole Antifungal Agent Testicular Steroidogenesis 
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. Allolio B, Stuttmann R, Winkelmann W (1986) Missing effect of etomidate on testosterone secretion in man. Klin Wochenschr 15: 86–88CrossRefGoogle Scholar
  2. Anderson JE, Blaschke TF (1986) Ketoconazole inhibits cyclosporin metabolism in vivo in mice. J Pharmacol Exp Ther 236: 671–674PubMedGoogle Scholar
  3. Angeli A, Frairia R (1985) Ketoconazole therapy in Cushing’s disease. Lancet I: 821Google Scholar
  4. Awouters FHL, Niemeegers CJF (1983) In vivo study of the possible inhibition and induction of microsomal enzymes by the antimycotic R51211.Google Scholar
  5. Janssen Pharma- ceutica Preclinical Research Report R51211/4Google Scholar
  6. Ayub M, Levell MJ (1987) Inhibition of testicular 17a-hydroxylase and 17,20-lyase but not 3 (3-hydroxysteroid dehyrogenase-isomerase or 17(3-hydroxysteroid oxidoreductase by ketoconazole and other imidazole drugs. J Steroid Biochem 28: 521–531PubMedCrossRefGoogle Scholar
  7. Back DJ, Tjia JF (1985) Inhibition of tolbutamide metabolism by substituted imidazole drugs in vivo: evidence for structure activity relationship. Br J Pharmacol 85: 121–126PubMedGoogle Scholar
  8. Ballard SA (1988) Interaction of azole antifungal agents with mouse hepatic microsomal cytochromes P-450. PhD Thesis. University of Kent, Canterbury, UKGoogle Scholar
  9. Ballard SA, Tarbit MH, Burnet FR, Lodola A (1987) Selective interaction of two N- substituted imidazole antifungal compounds with cytochromes P-450 catalysing ethoxyresorufin O-de-ethylation. Biochem Soc Trans 15: 1116–1117Google Scholar
  10. Ballard SA, Lodola A, Tarbit MH (1988) A comparative study of 1-substituted imidazole and 1,2,4-triazole antifungal compounds as inhibitors of testosterone hydroxylations catalysed by mouse hepatic microsomal cytochrome P-450. Biochem Pharmacol 37: 4643–4651PubMedCrossRefGoogle Scholar
  11. Best TR, Jenkins JK, Murphy FY, Nicks SA, Bussell KL, Nesely DL (1987) Persistent adrenal insufficiency secondary to low-dose ketoconazole therapy. Am J Med 82: 676–680PubMedCrossRefGoogle Scholar
  12. Bhasin S, Sikka S, Fielder T, Sod-Moriah U, Levine HB, Swerdloff RS, Rajfer J (1986) Hormonal effects of ketoconazole in vivo in the male rat: mechanism of action. Endocrinology 118: 1229–1232PubMedCrossRefGoogle Scholar
  13. Black SD, Coon MJ (1986) Comparative structures of P-450 cytochromes. In: Ortiz de Montellano P (ed) Cytochrome P-450, structure, mechanism and biochemistry. Plenum, New York, p 161Google Scholar
  14. Blyden GT, Abernethy DR, Greenblatt DJ (1986) Ketoconazole does not impair antipyrine clearance in humans. Int J Clin Pharmacol Ther Toxicol 24: 225–226PubMedGoogle Scholar
  15. Boobis AR, Brodie MJ, Kahn GC, Toverud GL, Blair IA, Murray S, Davies DS (1981) Comparison of the in vivo and in vitro rates of formation of the three main oxidative metabolites of antipyrine in man. Br J Clin Pharmacol 12: 771–777PubMedGoogle Scholar
  16. Brass C, Galgiani JN, Blaschke TF, Defelice R, O’Reilly RA, Stevens DA (1982) Disposition of ketoconazole, an oral antifungal, in humans. Antimicrob Agents Chemother 21: 151–158PubMedGoogle Scholar
  17. Britton H, Shehab Z, Lightner E, New M, Chow D (1988) Adrenal response in children receiving high doses of ketoconazole for systemic coccidiomycosis. J Pediatr 112: 488–492PubMedCrossRefGoogle Scholar
  18. Brown MW, Maldonado AL, Meredith CG, Speeg KV (1985) Effect of ketoconazole on hepatic oxidative drug metabolism. Clin Pharmacol Ther 37: 290–297PubMedCrossRefGoogle Scholar
  19. Burgess MA, Bodey GP (1972) Clotrimazole (Bay b5097): in vitro and clinical pharmacology studies. Antimicrob Agents Chemother 2: 423–426PubMedGoogle Scholar
  20. Burrin JM, Yeo TH, Ashby MJ, Bloom SR (1986) Effect of ketoconazole on adreno- corticotrophic hormone secretion in vitro and in vivo. J Endocrinol 108: 37–41PubMedCrossRefGoogle Scholar
  21. Carvalho D, Pignatelli D, Resende C (1985) Ketoconazole for hirsutism. Lancet ii: 560Google Scholar
  22. Conney AH (1986) Induction of cytochrome P-450 enzymes: the first Bernard B. Brodie Lecture. Life Sciences 39: 2493–2518PubMedCrossRefGoogle Scholar
  23. Contreras P, Altieri E, Liberman C, Gal A, Rojas A, Ibarra A, Ravanal M, Serum-Ferre M (1985a) Adrenal rest tumor of the liver causing Cushing’s syndrome treatment with ketoconazole preceding an apparent surgical cure. J Clin Endo¬crinol Metab 60: 21–28CrossRefGoogle Scholar
  24. Contreras P, Rojas A, Costamaillere L, Michelsen H, Pumarino H, Artega E (1985b) Endocrine effects of ketoconazole administration in 10 patients with Cushings syndrome. Proceedings of the 67th Annual Meeting of the Endocrine Society, Baltimore MD, p 112 (Abstract 550)Google Scholar
  25. Daneshmend TK, Warnock DW, Eve MD, Johnson EM, Parker G, Richardson MD, Roberts CJC (1983) Multiple dose pharmacokinetics of ketoconazole and their effects on antipyrine kinetics in man. J Antimicrob Chemother 12: 185–188PubMedCrossRefGoogle Scholar
  26. De Coster R, Beerens D, Dom J, Willemsens G (1984) Endocrinological effects of single daily ketoconazole administration in male beagle dogs. Acta Endocrinol 107: 275–281PubMedGoogle Scholar
  27. De Coster R, Caers I, Haelterman C, Debroye M (1985) Effect of a single administration of ketoconazole on total and physiologically free plasma testosterone and 17β-oestradiol levels in healthy male volunteers. Eur J Clin Pharmacol 29: 489–493PubMedCrossRefGoogle Scholar
  28. De Coster R, Haelterman C, Beerens D (1986) Effects of ketoconazole on the LH-RH induced testosterone biosynthesis in male beagle dogs. Ann Med Vet 130:431– 438Google Scholar
  29. De Coster R, Coene MC, Haelterman C, Beerens D, Goeminne N (1987) Effects of high-dose ketoconazole treatment on adrenal mineralocorticoid biosynthesis in dogs and rats. Acta Endocrinol 115: 423–431PubMedGoogle Scholar
  30. DeFelice R, Johnson DG, Galgiani JN (1981) Gynecomastia with ketoconazole. Antimicrob Agents Chemother 19: 1073–1074PubMedGoogle Scholar
  31. Deresinski SC, Galgiani JN, Stevens DA (1977) Miconazole treatment of human coccidioidomycosis: status report. In: Ajello L (ed) Coccidioidomycosis: current clinical and diagnostic status. Proceedings of the Third International Coccidioidomycosis Symposium, Tucson, Arizona 1976. Symposia Specialists, Miami, pp 257–292Google Scholar
  32. Dieperink H, Moller J (1982) Ketoconazole and cyclosporine. Lancet II: 1217PubMedCrossRefGoogle Scholar
  33. D’Mello A, Satake M, Toda S, Takaya S, Ptachcinski RJ, Burckart GJ (1986) Cyclosporine-ketoconazole interaction in dogs. Pharm Res 3:Suppl 1545Google Scholar
  34. D’Mello AP, D’Souza MJ, Bates TR (1985) Pharmacokinetics of ketoconazole-antipyrine interaction. Lancet II: 209–210PubMedCrossRefGoogle Scholar
  35. Doenicke A, Löffler B, Kugler J, Suttmann H, Grote B (1982) Plasma concentration and E.E.G. after various regimens of etomidate. Br J Anaesthesia 54: 393–400CrossRefGoogle Scholar
  36. Engelhardt D, Dorr G, Jaspers CH, Knorr D (1985) Ketoconazole blocks Cortisol secretion in man by inhibition of adrenal llß-hydroxylase. Klin Wochenschr 63: 607–612PubMedCrossRefGoogle Scholar
  37. English HF, Santner SJ, Levine HB, Santen RJ (1986) Inhibition of testosterone production with ketoconazole alone and in combination with a gonadotropin releasing hormone analogue in the rat. Cancer Res 46: 38–42PubMedGoogle Scholar
  38. Estabrook RW, Werringloer J (1978) The measurement of difference spectra: application to the cytochromes of microsomes. Fleischer S, Packer L (eds) Methods in enzymology, vol LII. Academic, New York, pp 212–221Google Scholar
  39. Farwell AP, Devlin JT, Stewart J A (1988) Total suppression of Cortisol excretion by ketoconazole in the therapy of the ectopic adrenocorticotropic hormone syndrome. Am J Med 84: 1063–1066PubMedCrossRefGoogle Scholar
  40. Fellows IW, Bastow MD, Byrne AJ, Allison SP (1983) Adrenocortical suppression in multiply injured patients: a complication of etomidate treatment. Br Med J 287: 1835–1837CrossRefGoogle Scholar
  41. Ferguson RM, Sutherland DER, Simmons RL, Najarian JS (1982) Ketoconazole, cyclosporin metabolism and renal transplantation. Lancet ii: 882–883Google Scholar
  42. Glynn AM, Slaughter RL, Brass C, D’Ambrosio RD, Jusko WJ (1986) Effects of ketoconazole on methylprednisolone pharmacokinetics and Cortisol secretion. Clin Pharmacol Ther 39: 654–659PubMedCrossRefGoogle Scholar
  43. Grosso DS, Boyden TW, Pamenter RW, Johnson DG, Stevens DA, Galgiani JN (1983) Ketoconazole inhibition of testicular secretion of testosterone and displacement of steroid hormones from serum transport protein. Antimicrob Agents Chemother 23: 207–212PubMedGoogle Scholar
  44. Guengerich FP (1988) Cytochromes P-450. Comp Biochem Physiol 89: 1–4Google Scholar
  45. Hajek KK, Cook NI, Novak RF (1982) Mechanism of inhibition of microsomal drug metabolism by imidazole. J Pharm Exp Ther 223: 97–104Google Scholar
  46. Heel RC, Brogden RN, Carmine A, Morley PA, Speight TH, Avery GS (1982) Ketoconazole: a review of its therapeutic efficacy in superficial and systemic fungal infections. Drugs 23: 1–36PubMedCrossRefGoogle Scholar
  47. Heiberg JK, Svejgaard E (1981) Toxic hepatitis during ketoconazole treatment. Br Med J 283: 825–826CrossRefGoogle Scholar
  48. Henry HL (1985) Effect of ketoconazole and miconazole on 25-hydroxyvitamin D3 metabolism by cultured chick kidney cells. J Steroid Biochem 23: 991–994PubMedCrossRefGoogle Scholar
  49. Heusner JJ, Franklin MR (1985) Inhibition of the ‘non-classical’ antifolate trimetrexate [2,4-diamino-5-methyl-6-(3,4,5-trimethoxy anilino)methyl/quinazole] by drugs containing an imidazole moiety. Pharmacology 30: 266–272PubMedCrossRefGoogle Scholar
  50. Heykants J, Michiels M, Meuldermans W, Monbalin J, Lavrijsen K, Van Peer A, Levron JC, Woestenborghs R, Cauwenbergh G (1987) The pharmacokinetics of itraconazole in animals and man: an overview. In: Fromtling RA (ed) Recent trends in the discovery, development and evaluation of antifungal agents. JR Prous, Barcelona, pp 223–249Google Scholar
  51. Heyns W, Drochmans A, van der Schueren E, Verhoeven G (1985) Endocrine effects of high dose ketoconazole therapy in advanced prostate cancer. Acta Endocrinol 110: 276–283PubMedGoogle Scholar
  52. Holland FJ, Fishman L, Bailey JD, Fazekas ATA (1985) Ketoconazole in the management of precocious puberty not responsive to LHRH-analogue therapy. N Engl J Med 312: 1023–1028PubMedCrossRefGoogle Scholar
  53. Houston JB, Humphrey MJ, Matthew DE, Tarbit MH (1988) Comparison of two azole antifungal drugs, ketoconazole and fluconazole, as modifiers of rat hepatic monooxygenase activity. Biochem Pharmacol 37: 401–408PubMedCrossRefGoogle Scholar
  54. Howden CW, Kenyon CJ, Beastall GH, Reid JL (1986) Inhibition by omeprazole of adrenocortical response to ACTH: clinical studies and experiments on bovine adrenal cortex in vitro. Clin Sci 70: 99–102PubMedGoogle Scholar
  55. Kahl R, Friederici DE, Kahe GF, Ritter W, Krebs R (1980) Clotrimazole as an inhibitor of benzo(a)pyrene metabolite-DNA adduct formation in vitro and of microsomal mono-oxygenase activity. Drug Metab Dispos 8: 191–196PubMedGoogle Scholar
  56. Kan PB, Hirst MA, Feldman D (1985) Inhibition of steroidogenic cytochrome P-450 enzyme in rat testis by ketoconazole and related imidazole antifungal drugs. J Steroid Biochem 23: 1023–1029PubMedCrossRefGoogle Scholar
  57. Kapetanovic IM, Kupferberg HJ (1985) Inhibition of microsomal phenytoin metabolism by nafimidone and related imidazoles. Drug Metab Dispos 13: 430–437PubMedGoogle Scholar
  58. Kaul KL, Novak RF (1984) Induction of rabbit hepatic microsomal cytochrome P-450 by imidazole: enhanced metabolic activity and altered substrate specificity. Arch Biochem Biophys 235: 470–481PubMedCrossRefGoogle Scholar
  59. Kowal J (1983) The effect of ketoconazole on steroidogenesis in cultured mouse adrenal cortex tumour cells. Endocrinology 112: 1541–1543PubMedCrossRefGoogle Scholar
  60. Kraemer FB, Pont A (1986) Inhibition of cholesterol synthesis by ketoconazole. Am J Med 80: 616–622PubMedCrossRefGoogle Scholar
  61. Kumaki K, Sato M, Kon H, Nebert DW (1978) Correlation of type I, type II, and reverse type I difference spectra with absolute changes in spin state of hepatic microsomal cytochrome P-450 iron from five mammalian species. J Biol Chem 253: 1048–1058PubMedGoogle Scholar
  62. Kwan JTC, Foxall PJD, Davidson DGC, Bending MR, Eisinger AJ (1987) Interaction of cyclosporin and itraconazole. Lancet ii: 282Google Scholar
  63. Lake-Bakaar G, Scheuer PJ, Sherlock S (1987) Hepatic reactions associated with ketoconazole in the United Kingdom. Br Med J 294: 419–422CrossRefGoogle Scholar
  64. Lambert A, Mitchell R, Frost J, Ratcliffe JG, Robertson WR (1983) Direct in vitro inhibition of adrenal steroidogenesis by etomidate Lancet II: 1085–1086Google Scholar
  65. Lambert A, Frost J, Mitchell R, Wilson AV, Robertson WR (1984) On the site of the anti-adrenal steroidogenic effect of etomidate and megestrol acetate. Clin Endocrinol 21: 721–727CrossRefGoogle Scholar
  66. Lambert A, Mitchell R, Frost J, Robertson WR (1985a) A simple in vitro approach to the estimation of the biopotency of drugs affecting endocrine tissues. J Steroid Biochem 23: 235–238PubMedCrossRefGoogle Scholar
  67. Lambert A, Mitchell R, Robertson WR (1985b) The effect of propofol, thiopentone and etomidate on adrenal steroidogenesis in vitro. Br J Anaesthesia 57: 505–508CrossRefGoogle Scholar
  68. Lambert A, Mitchell R, Robertson WR (1985c) On the site of action of the anti- adrenal steroidogenic effect of cyproterone acetate. Biochem Pharmacol 34: 2091–2095PubMedCrossRefGoogle Scholar
  69. Lambert A, Frost J, Mitchell R, Robertson WR (1986a) On the assessment of the in vitro biopotency and site(s) of action of drugs affecting adrenal steroidogenesis. Ann Clin Biochem 23: 225–229PubMedGoogle Scholar
  70. Lambert A, Mitchell R, Robertson WR (1986b) The effect of ketoconazole on in vitro adrenal and testicular steroidogenesis. Biochem Pharmacol 35: 3999–4004PubMedCrossRefGoogle Scholar
  71. Lambert A, Mitchell R, Robertson WR (1987) The biopotency and site of action of drugs affecting testicular steroidogenesis. J Endocrinol 113: 457–461PubMedCrossRefGoogle Scholar
  72. Lamberts SWJ, Bons EG, Bruining HA, De Jong FH (1987) Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyra- pone on the secretion of Cortisol and its precursors by human adrenocortical cells. J Pharmacol Exp Ther 240: 259–264PubMedGoogle Scholar
  73. Lavrijsen K, Van Houdt J, Thijs D, Meuldermans W, Heykants J (1987) Interaction of miconazole, ketoconazole and itraconazole with rat liver microsomes. Xeno- biotica 17: 45–57Google Scholar
  74. Ledingham IMcA, Watt I (1983) Influence of sedation on mortality in critically ill multiple trauma patients. Lancet I: 1270Google Scholar
  75. Lewis JH, Zimmerman HJ, Benson Gd, Ishak KG (1984) Hepatic injury associated with ketoconazole therapy. Gastroenterology 86: 503–513PubMedGoogle Scholar
  76. Liebman K (1971) Studies on modifiers of microsomal drug oxidation. Chem Biol Interactions 3: 289–290CrossRefGoogle Scholar
  77. Liebman KC, Ortiz E (1973) New potent modifiers of liver microsomal drug metabolism: 1-arylimidazoles. Drug Metab Dispos 1: 1495–1499Google Scholar
  78. Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D (1983a) Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P-450-dependent enzymes. J Clin Invest 71: 1495–1499PubMedCrossRefGoogle Scholar
  79. Loose DS, Stover DP, Feldman D (1983b) Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells. J Clin Invest 72: 404–408PubMedCrossRefGoogle Scholar
  80. Mailman RB, Kulkarni AP, Baker RC, Hodgson E (1974) Cytochrome P-450 difference spectra: effect of chemical structure on type II spectra in mouse hepatic microsomes. Drug Metab Dispos 2: 301–307PubMedGoogle Scholar
  81. Malozowski S, Mericq V, Cassorla F (1986) Effects of ketoconazole on rat steroidogenic enzymatic activities. Res Commun Chem Pathol Pharmacol 52: 403–406PubMedGoogle Scholar
  82. Mason JI, Murry BA, Olcott M, Sheets JI (1985) Imidazole antimycotics: inhibitors of steroid aromatase. Biochem Pharmacol 34: 1087–1092PubMedCrossRefGoogle Scholar
  83. Meredith. CG, Maldonado AL, Speeg KV (1985) The effect of ketoconazole on hepatic oxidative drug metabolism in the rat in vivo and in vitro. Drug Metab Dispos 13: 156–162PubMedGoogle Scholar
  84. Mosca P, Bohazzi P, Novelli G, Jezequel AM, Orlandi F (1985) In vivo and in vitro inhibition of hepatic microsomal drug metabolism by ketoconazole. Br J Exp Pathol 66: 737–742PubMedGoogle Scholar
  85. Murray M, Wilkinson CF, Hetnarski K (1985) Cytochrome P-450 and monooxygenase activity in hepatic microsomes from N-phenylimidazole-treated rats. Toxicol Lett 25: 191–198PubMedCrossRefGoogle Scholar
  86. Namer M, Khater R, Frenay M, Boublil JL (1986) High dose of ketoconazole in the treatment of advanced breast cancers. Bull Cancer 73: 89PubMedGoogle Scholar
  87. Niemeegers CJE, Levron JCL, Awouters F, Janssen PAJ (1981) Inhibition and induction of microsomal enzymes in the rat. A comparative study of four antimycotics: miconazole, econazole, clotrimazole and ketoconazole. Arch Int Pharmacodyn Ther 251: 26–38Google Scholar
  88. Ortiz de Montellano P (1986) (ed) Cytochrome P-450: structure, mechanism and biochemistry. Plenum, New YorkGoogle Scholar
  89. Palmer ED, Cawthorne MA (1974) The effects of 1-alkylimidazoles on hepatic drug metabolising enzyme activity. Xenobiotica 4: 209–221PubMedCrossRefGoogle Scholar
  90. Pont A, Trachtenberg J (1984) Hormonal changes in patients on chronic high dose ketoconazole. Clin Res 32: 271AGoogle Scholar
  91. Pont A, Williams PL, Azhar S, Reitz RE, Bochra C, Smith ER, Stevens DA (1982a) Ketoconazole blocks testosterone synthesis. Arch Int Med 142: 2137–2140CrossRefGoogle Scholar
  92. Pont A, Williams PL, Loose DS, Feldman D, Reitz RE, Bochra C, Stevens DA (1982b) Ketoconazole blocks adrenal steroid synthesis. Ann Int Med 97: 370–372PubMedGoogle Scholar
  93. Pont A, Graybill JR, Craven PC, Galgiani JM, Dismukes WE, Reitz RE, Stevens DA (1984) High dose ketoconazole therapy and adrenal and testicular function in humans. Arch Int Med 144: 2150–2153CrossRefGoogle Scholar
  94. Purba HS, Back DJ (1986) Effect of fluconazole (UK-49,858) on antipyrine metabolism. Br J Clin Pharmacol 21: 603 PGoogle Scholar
  95. Rajfer J, Sikka SC, Xie HW, Swerdloff RS (1985) Effect of in vitro ketoconazole on steroid production in rat testis. Steroids 46: 867–881PubMedCrossRefGoogle Scholar
  96. Rajfer J, Sikka SC, Rivera F, Handelsman DJ (1986) Mechanism of inhibition of human testicular steroidogenesis by oral ketoconazole. J Clin Endocrinol Metab 63: 1193–1198PubMedCrossRefGoogle Scholar
  97. Razzouk C, Agazzi-Leonard E, Cumps J, Pondelet F, Mercier M, Roberfroid M (1978) Induction, modification and inhibition of rat liver microsomal benzo(a)- pyrene hydroxylase; correlation with the S-9-mediated mutagenicity of benzo(a)- pyrene. Biochem Biophys Res Commun 85: 1007–1016PubMedCrossRefGoogle Scholar
  98. Reader SCJ, Davison B, Ratcliffe JG, Robertson WR (1985) Measurement of low concentrations of bovine thyrotrophin by iodide uptake and organification in porcine thyrocytes. J Endocrinol 106: 13–20PubMedCrossRefGoogle Scholar
  99. Ritter JK, Franklin MR (1987) Induction and inhibition of rat hepatic drug metabolism by N-substituted imidazole drugs. Drug Metab Dispos 15: 335–343PubMedGoogle Scholar
  100. Robertson WR, Reader SCJ, Davison B, Frost J, Mitchell R, Kayte R, Lambert A (1985) on the biopotency and site of action of drugs affecting endocrine tissues with special reference to the anti-steroidogenic effect of anaesthetic agents. Postgrad Med J 61: 145–151Google Scholar
  101. Rochlitz CF, Damon LE, Russi MB, Geddes A, Cadman EC (1988) Cytotoxicity of ketoconazole in malignant cell lines. Cancer Chemother Pharmacol 21: 319–322PubMedCrossRefGoogle Scholar
  102. Rodrigues AD, Gibson GG, Ioannides C, Park DV (1987) Interactions of imidazole antifungal agents with purified cytochrome P-450 proteins. Biochem Pharmacol 36: 4277–4281PubMedCrossRefGoogle Scholar
  103. Rodrigues AD, Waddell PR, Ioannides C (1988) Inhibition of the rat hepatic mixed- function oxidases by in vivo administration of clotrimazole. Res Commun Chem Pathol Pharmacol 59: 403–406PubMedGoogle Scholar
  104. Rogerson TD, Wilkinson CF, Hetnarski K (1977) Steric factors in the inhibitory interaction of imidazoles with microsomal enzymes. Biochem Pharmacol 26: 1039–1042PubMedCrossRefGoogle Scholar
  105. Santen RJ, Vanden Bossche H, Symoens J, Brugmans J, De Coster R (1983) Site of action of low dose ketoconazole on androgen biosynthesis in men. J Clin Endocrinol Metab 57: 732–736PubMedCrossRefGoogle Scholar
  106. Schellens JHM, Van Der Wart JHF, Danhof M, Van Der Velde EA, Briemer DD (1988) Relationship between the metabolism of antipyrine, hexobarbital and theophylline in man as assessed by a ‘cocktail’ approach. Br J Clin Pharmacol 26: 373–384PubMedGoogle Scholar
  107. Schenkman JB, Remmer H, Estabrook RW (1967) Spectral studies of drug interaction with hepatic microsomal cytochrome. Mol Pharmacol 3: 113–123Google Scholar
  108. Schoene (1973) Unpublished data cited in: Bolt HM, Kappus H (1973) Effect of clotrimazole treatment on the demethylation of mestranol. Hormone Metab Res 5:234Google Scholar
  109. Schürmeyer T, Nieschlag E (1984) Effect of ketoconazole and other imidazole fungicides on testosterone biosynthesis. Acta Endocrinol (Copenh) 105: 275–280Google Scholar
  110. Schuster I (1985) The interaction of representative members from two classes of antimycotics—the azoles and the allylamines-with cytochromes P-450 in steroidogenic tissues and liver. Xenobiotica 15: 529–546PubMedCrossRefGoogle Scholar
  111. Schuster I (1988) Potential of allylamines to inhibit cytochrome P-450. In: Fromtling RA (ed) Recent trends in the discovery, development and evaluation of anti-fungal agents. JR Prous, Barcelona, pp 471–478Google Scholar
  112. Scott J, Drew R (1983) Interaction of imidazole drugs with hepatic cytochrome P-450 dependent enzymes. Clin Exp Pharm Pharmacol 10: 679–680Google Scholar
  113. Shaw JTB, Tarbit MH, Troke PF (1988) Cytochrome P-450 mediated sterol synthesis and metabolism: differences in sensitivity of fluconazole and other azoles. In: Fromtling RA (ed) Recent trends in the discovery, development and evaluation of antifungal agents. JR Prous, Barcelona, pp 125–140Google Scholar
  114. Shaw MA, Gumbleton M, Nicholls PJ (1987) Interaction of cyclosporin and itraconazole. Lancet ii: 637Google Scholar
  115. Sheets JJ, Mason JI (1984) Ketoconazole: a potent inhibitor of cytochrome P-450- dependent drug metabolism in rat liver. Drug Metab Dispos 12: 603–606PubMedGoogle Scholar
  116. Sheets JJ, Mason JI, Wise CA, Estabrook RW (1986) Inhibition of rat liver microsomal cytochrome P-450 steroid hydroxylase reactions by imidazole anti- mycotic agents. Biochem Pharmacol 35: 487–491PubMedCrossRefGoogle Scholar
  117. Shepherd FA, Hoffert B, Evans WK, Emery G, Trachtenberg J (1985) Ketoconazole. Use in the treatment of ectopic adrenocorticotrophic hormone and Cushing’s syndrome in small cell lung cancer. Arch Int Med 145: 863–864CrossRefGoogle Scholar
  118. Sikka SC, Swerdloff RS, Rajfer J (1985) In vitro inhibition of testosterone biosynthesis by ketoconazole. Endocrinology 116: 1920–1925PubMedCrossRefGoogle Scholar
  119. Smith AG (1984) Potentiation of oral anti-coagulants by ketoconazole. Br Med J 288: 188–189CrossRefGoogle Scholar
  120. Sonino N, Brownie AC (1987) Inhibition of aldosterone production by ketoconazole in vitro. Med Sci Res 15: 853–854Google Scholar
  121. Sonino N, Boscaro M, Merola G, Mantero F (1985) Prolonged treatment of Cushing’s disease by ketoconazole. J Clin Endocrinol Metab 61: 718–722PubMedCrossRefGoogle Scholar
  122. Tettenborn D (1974) Toxicity of clotrimazole. Postgrad Med J 50 (Suppl): 17PubMedGoogle Scholar
  123. Thienpont D, Van Cutsen J, Van Gerven F, Heeres J, Janssen PAJ (1979) Ketoconazole: a new broad spectrum orally active antimycotic. Experientia 35: 606–607PubMedCrossRefGoogle Scholar
  124. Thompson RG, Rawlins MD, James OFW, Wood P, Williams F (1988) The acute and subchronic effects of ketoconazole on hepatic microsomal monooxygenase in the rat. Biochem Pharmacol 37: 403–406CrossRefGoogle Scholar
  125. Trachtenberg J (1984) Ketoconazole therapy in advanced prostatic cancer. J Urol 132: 61–63PubMedGoogle Scholar
  126. Trachtenberg J, Pont A (1984) Ketoconazole therapy for advanced prostate cancer. Lancet ii: 433–435Google Scholar
  127. Trachtenberg J, Zadra J (1988) Steroid synthesis inhibition by ketoconazole: sites of action. Clin Invest Med 11: 1–5PubMedGoogle Scholar
  128. Trenk D, Brett W, Jahnchen E, Birnbaum D (1987) Time course of cyclosporin interaction. Lancet ii: 1335–1336Google Scholar
  129. Van Cauteren H, Heykants J, De Coster R, Cauwenbergh G (1987) Itraconazole: pharmacologic studies in animals and humans. Rev Inf Dis 9: S43–S45CrossRefGoogle Scholar
  130. Vanden Bossche H (1987) Itraconazole: a selective inhibitor of the cytochrome P-450 dependent ergosterol biosynthesis. In: Fromtling RA (ed) Recent trends in the discovery, development and evaluation of antifungal agents. JR Prous, Barcelona, pp 207–221Google Scholar
  131. Vanden Bossche H, Lauwers W, Willemsens G, Cools W (1985) The cytochrome P-450 dependent C17,20-lyase in subcellular fractions of the rat testis: differences in sensitivity to ketoconazole and itraconazole. In: Boobis AR, Caldwell J, De Matteis F, Elcombe CR (eds) Microsomes and drug oxidations. Taylor and Francis, London, pp 63–73Google Scholar
  132. Vanden Bossche H, Bellens D, Cools W, Gorrens J, Marichal P, Verhoeven H, Willemsens G, De Coster R, Beerens D, Haelterman C, Coene M-C, Lauwers W, Le Jeune L (1986) Cytochrome P-450: target for itraconazole. Drug Dev Res 8: 287–298CrossRefGoogle Scholar
  133. Vawda AI, Davies AG (1986) An investigation into the effect of ketoconazole on testicular function in Wistar rats. Acta Endocrinol (Copenh) 111: 246–251Google Scholar
  134. Watanabe H, Menzies JA (1985) Depression of ovarian estradiol–17(3 following single oral dose of ketoconazole. Res Commun Chem Pathol Pharmacol 48: 141–144PubMedGoogle Scholar
  135. Watanabe H, Menzies J A (1986) Effect of single dose ketoconazole on ovarian steroids. Res Commun Chem Pathol Pharmacol 54: 271–274PubMedGoogle Scholar
  136. Waxman DJ, Ko A, Walsh C (1983) Regioselectivity of androgen hydroxylations catalysed by cytochrome P-450 isozymes purified from phenobarbital-induced rat liver. J Biol Chem 258: 11937–11947PubMedGoogle Scholar
  137. Wenta H (1974) Clinical studies with oral clotrimazole. Postgrad Med J 50 (Suppl): 85CrossRefGoogle Scholar
  138. Wilkinson CF, Hetnarski K, Yellin TO (1972) Imidazole derivatives - a new class of microsomal enzyme inhibitors. Biochem Pharmacol 21: 3187–3192PubMedCrossRefGoogle Scholar
  139. Wilkinson CF, Hetnarski K, Cantwell GP, Di Carlo FJ (1974) Structure-activity relationships in the effects of 1-alkylimidazoles on microsomal oxidation in vitro and in vivo. Biochem Pharmacol 23: 2377–2386PubMedCrossRefGoogle Scholar
  140. Williams G, Kerle DJ, Ware H, Doble A, Dunlop H, Smith C, Allen J, Yeo T, Bloom SR (1986) Objective response to ketoconazole therapy in patients with relapsed prostatic cancer. Br J Urol 58: 45–51PubMedCrossRefGoogle Scholar
  141. Yamamoto TU, Urabe M, Okada H (1987) Inhibitory effect of miconazole on aromatase activity for androstenedione in human placental and ovarian preparations. Bosmoku Gijutsu 36: 1379–1385Google Scholar
  142. Yoshida Y, Aoyama Y (1986) Interaction of azole fungicides with yeast cytochrome P-450 which catalyzes lanosterol 14-demethylation. In: Iwata K, Vanden Bossche H (eds) In vitro and in vivo evaluation of antifungal agents. Elsevier, Amsterdam, pp 125–134Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • Michael H. Tarbit
  • William R. Robertson
  • Ann Lambert

There are no affiliations available

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