PHARMACOKINETICS OF ESTRONE-3-O-SULFAMATE

The sulphatase pathway is thought to be the major route of oestrogen s ynthesis in breast tumours in postmenopausal women. There is currently considerable interest in developing a potent steroid sulphatase inhib itor to block oestrogen synthesis by this route. One of the most poten t inhibitors discovered so far is oestrone-3-O-sulphamate (EMATE) whic h is active in vivo. In this study we report the preparation of a form ulation for the administration of EMATE by the oral route. A method, u sing high-performance liquid chromatography (HPLC), was also establish ed to measure concentrations of EMATE in rat plasma after its oral or i.v. administration. Using the oral formulation and HPLC assay, EMATE was readily detected in rat plasma after oral administration. Plasma E MATE concentrations were related to the dose of drug administered oral ly over the 10-40 mg/kg range. To examine the pharmacokinetics of EMAT E, the compound (40 mg/kg, single dose) was administered either orally (in the formulation) or i.v. (in propylene glycol) with plasma sample s being collected for up to 6 h. After oral administration, EMATE was rapidly absorbed, with the peak plasma concentration being detected at 30 min, after which plasma concentrations rapidly decreased. After i. v. administration a plasma EMATE concentration was detected at Ih simi lar to that after oral administration. The clearance of EMATE from pla sma followed a bi-phasic curve, showing an initial half-life of 30 min , followed by a slower half-life of 4 h 30 min. Little evidence was ob tained for any metabolism of EMATE to oestrone. Rat liver sulphatase a ctivity was almost completely inhibited (>99%) within 30 min of oral o r i.v. administration of EMATE. Copyright (C) 1996 Elsevier Science Lt d.