Pharmacokinetics and metabolism of the anti-oestrogen droloxifene in female human subjects

1. Single oral doses of a solution formulation of 14 C-droloxifene citrate (141?mg) appeared to be rapidly and well absorbed in four post-menopausal female subjects. Peak plasma concentrations (C max) of total 14 C (1260 ng eq. ml -1), droloxifene (196 ng ml -1) and the major metabolite droloxifene glucuronide (851ng eq. ml -1) occurred at 0.9-1.1h (T max) and declined bi-exponentially with terminal half-lives of 45.0, 31.6 and 32.0h respectively. The mean AUCs of droloxifene and the major metabolite were 21 and 37% respectively that of total 14 C. 2. Total 14 C was excreted slowly, mainly in the faeces. Mean totals of 6.6 and 90.3% of the dose were excreted in the urine and faeces respectively during 11 days. The data were consistent with biliary excretion and enterohepatic circulation of the major metabolite, droloxifene glucuronide. 3. GC-MS showed that the major 14 C-components in 0-24-h urine were droloxifene (mean 0.4% dose) and its glucuronide (2.3% dose), and in faeces were droloxifene (60.2% dose) and N- desmethyldroloxifene (4.2% dose). Other components in faeces corresponded chromatographically to reference standards, droloxifene N -oxide (1.9% dose), side-chain hydroxylated droloxifene (dimethylamine moiety of droloxifene side-chain replaced by hydroxyl, 1.3% dose) and droloxifene glucuronide (10.7% dose). The latter was resistant to enzymic hydrolysis by the β -glucuronidase used. 4. Intersubject variability in the pharmacokinetics of droloxifene in this study was relatively low (CV < 20% for AUC and half-life).