The influence of a graded dose schedule of aminoglutethimide on the disposition of the optical enantiomers of warfarin in patients with breast cancer.

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. together 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.