Summary
The pharmacokinetics of the optical enantiomers of warfarin (R-warfarin and S-warfarin) were investigated in patients treated for breast cancer with aminoglutethimide (AG). The patients received 125 mg AG b.i.d. (i.e., low-dosage regimen); 250 mg AG q.i.d. togetner with cortisone acetate (i.e. high-dosage regimen); or an escalating dose schedule was followed (i.e. low-dosage regimen followed by high-dosage regimen). The pharmacokinetics for R-warfarin and S-warfarin were determined before initiation of AG treatment and again after 2, 4 or 8 weeks of continuous AG treatment. The plasma clearance for both enantiomers showed a moderate increase (mean 41.2%) in patients receiving the low AG dose, whereas in patients treated according to the high-dosage regimen a marked increase (mean 90.8%) was observed. There was a corresponding reduction in warfarin half-life, and no alteration in distribution volume. These effects on the warfarin pharmacokinetics appeared after 14 days of AG treatment, and after this time point there was no further increase in warfarin clearance. Notably, the effect of AG on warfarin kinetics was the same for both enantiomeric forms of warfarin. These data show that there is a dose-response relationship between AG dose and induction of warfarin metabolism.
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References
American College of Clinical Pharmacology (1982) Manual of symbols, equations and definitions in pharmacokinetics. J Clin Pharmacol 22: 1s
Breckenridge A, Orme HL, Davies L, Thorgeirsson S, Davies DS (1973) Dose-dependent enzyme induction. Clin Pharmacol Ther 14: 514
Dowsett M, Jeffcoate SL, Santner S, Santen RJ, Stuart-Harris R, Smith DE (1985) Low-dose aminoglutethimide and aromatase inhibitors. Lancet 1: 175
Harris AL, Dowsett M, Smith IE, Jeffcate SL (1983) Endocrine effects of low dose aminoglutethimide alone in advanced postmenopausal breast cancer. Br J Cancer 47: 621
Harris AL, Cantwell BMJ, Sainsbury JR, Needham G, Evans RGB, Dawes PJDK, Wilson R, Farndon J (1986) Clinical effects of low-dose aminoglutethimide (AG) plus hydrocortisone (HC) in advanced breast cancer. Breast Cancer Res Treat (in press)
Hewick DS, McEwen J (1973) Plasma half-lives, plasma metabolites and anticoagulant efficacies of the enantiomers of warfarin in man. J Pharm Pharmacol 25: 458
Kelly JG, O'Malley K (1979) Clinical pharmacokinetics of oral anticoagulants. clin Pharmacokinet 4: 1
Kvinnsland S, Lønning PE, Dahl O (1984) Treatment of breast carcinoma with aminoglutethimide. Acta Radiol Oncol 23:421
Lewis RJ, Trager WF, Chan KK, Breckenridge A, Orme M, Roland M, Schaby W (1974) Warfarin. Stereochemical aspects of its metabolism and the interaction with phenylbutazone. J Clin Invest 53: 1607
Lønning PE, Kvinnsland S, Bakke OM (1984a) Effect of aminoglutethimide on antipyrine, theophylline, and digitoxin disposition in breast cancer. Clin Pharmacol Ther 36: 796
Lønning PE, Kvinnsland S, Jahren G (1984b) Aminoglutethimide and warfarin. A new important drug interaction. Cancer Chemother Pharmacol 12: 10
Lønning PE, Schanche JS, Kvinnsland S, Ueland PM (1985) Single-dose and steady-state pharmacokinetics of aminoglutethimide. Clin Pharmacokinet 10: 353
Murray FT, Santner S, Samojlik E, Santen RJ (1979) Serum aminoglutethimide levels: Studies of serum half-life, clearance and patient compliance. J Clin Pharmacol 19: 704
Murray RML, Pitt P (1985) Low-dose aminoglutethimide without steroid replacement in the treatment of postmenopausal women with advanced breast cancer. Eur J Cancer Clin Oncol 21: 19
Ohnhaus EE, Park BK (1979) Measurement of urinary 6-betahydroxycortisol excretion as an in vivo paramenter in the clinical assessment of the microsomal enzyme-inducing capacity of antipyrine, phenobarbitone and rifampicin. Eur J Clin Pharmacol 15: 139
O'Reilly R (1974) Interaction of sodium warfarin and rifampin. Ann Intern Med 81: 337
O'Reilly R (1976) The steroselective interaction of warfarin and metronidazole in man. N Engl J Med 295: 354
O'Reilly R, Aggeler PM, Leong LS (1963) Studies on the coumarin anticoagulant drugs. The pharmacodynamics of warfarin in man. J Clin Invest 42: 1542
O'Reilly R, Welling PG, Wagner JG (1971) Pharmacokinetics of warfarin following intravenous administration to man. Thromb Diath Haemorrh 25: 178
Park RK, Breckenridge AM (1981) Clinical implications of enzyme induction and enzyme inhibition. Clin Pharmacokinet 6: 1
Santen RJ, Lipton A, Kendall J (1974) Successful medical adrenalectomy with aminoglutethimide. Role of altered drug metabolism. JAMA 230: 1661
Santen RJ, Santner S, Davis B, Veldhuis J, Samojlik E, Ruby E (1978) Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma. J Clin Endocrinol Metab 47: 1257
Schanche JS, Lønning PE, Ueland PM, Kvinnsland S (1984) Determination of aminoglutethimide and N-acetylaminoglutethimide in humanplasma by reversed-phase liquid chromatography. Ther Drug Monit 6: 221
Stuart-Harris R, dowsett M, Bozek T, McKinna JA Gazet JC, Jeffcoate SL, Kurkura A, Carr L, Smith IE (1984) Lowdose aminoglutethimide in treatment of advanced breast cancer. Lancet 2: 604
Ueland PM, Kvalheim G, Lønning PE, Kvinnsland S (1985) Determination of warfarin in human plasma by high-performance liquid chromatography and photodiode array detector. Ther Drug Monit 7: 329
Vermeulen A, Paridaens R, Heuson JC (1983) Effect of aminoglutethimide on adrenal steroid secretion. Clin Endocrinol 19: 673
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This work was supported by grants from the Norwegian Cancer Society and the Norwegian Society for Fighting Cancer. The authors gratefully acknowledge the skillful technical assistance of Mr Hallvard Bergesen and Mrs Gry Kvalheim
PEL is a Research Fellow of the Norwegian Cancer Society
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Lønning, P.E., Ueland, P.M. & Kvinnsland, S. The influence of a graded dose schedule of aminoglutethimide on the disposition of the optical enantiomers of warfarin in patients with breast cancer. Cancer Chemother. Pharmacol. 17, 177–181 (1986). https://doi.org/10.1007/BF00306750
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DOI: https://doi.org/10.1007/BF00306750