生物等效性和生物利用度杂志

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Metabolic Disposition of [Women 14 C] Ulipristal Acetate in Healthy Premenopausal

Oliver Pohl, John Kendrick and Jean-Pierre Gotteland

Introduction: Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for the treatment of benign gynaecological conditions such as uterine myoma. The disposition of [ 14 C] UPA was determined in five healthy premenopausal women after administration of a single oral dose of 20 mg (59 μCi). Materials and Methods: The single dose study allocated 5 healthy women of reproductive age to receive a single radio labelled dose of 20 mg (59 μCi) UPA. After dosing, blood, plasma, urine and faecal samples were collected for up to 11 days and analysed for concentrations of radioactivity. UPA metabolite profiles in plasma were determined by high-performance liquid chromatography with radioactivity flow detection; metabolite structures were confirmed by liquid chromatography-mass spectrometry. Results: UPA was rapidly absorbed, exhibiting a mean peak plasma concentration of 141 ng/mL at 0.7 hours post-dose. Plasma radioactivity maxima were observed 0.9 hours post-dose at 281ng equivalents/mL. The total mean recovery of the radioactive dose in excreta was 78.8%, with the majority recovered in faeces (72.5%) and only a small fraction (6.4%) in urine. UPA was extensively metabolised. Radio-chromatograms of plasma revealed that oxidative demethylation was the major metabolic pathway, most likely via cytochrome P450 isoenzyme3A4. At peak plasma radioactivity, the majority of circulating radioactivity was constituted by parent (58.0%), N-monodemethylated UPA (PGL4002 (20.5%)) and N-didemethylated UPA (PGL4004) eluting together with PGL4002+2H (8.3%). Unchanged UPA was not present in faeces, but PGL4002, hydroxylated PGL4004 and UPA +2H, UPA +2O -2H, as well as acetylated or glucuronidated UPA were identified. Conclusion: After oral administration in healthy premenopausal women, UPA was rapidly absorbed, extensively metabolized via oxidative demethylation, and excreted predominantly in faeces.