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Pharmacokinetics of oestrone-3-O-sulphamate
M I Hidalgo Aragones1, A Purohit, D Parish
1Unit of Metabolic Medicine, St. Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, U.K.
Abstract:
The sulphatase pathway is thought to be the major route of oestrogen synthesis in breast tumours in postmenopausal women. There is currently considerable interest in developing a potent steroid sulphatase inhibitor to block oestrogen synthesis by this route. One of the most potent inhibitors discovered so far is oestrone-3-O-sulphamate (EMATE) which is active in vivo. In this study we report the preparation of a formulation for the administration of EMATE by the oral route. A method, using high-performance liquid chromatography (HPLC), was also established 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 EMATE concentrations were related to the dose of drug administered orally over the 10-40 mg/kg range. To examine the pharmacokinetics of EMATE, the compound (40 mg/kg, single dose) was administered either orally (in the formulation) or i.v. (in propylene glycol) with plasma samples 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 1 h similar to that after oral administration. The clearance of EMATE from plasma 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 obtained for any metabolism of EMATE to oestrone. Rat liver sulphatase activity was almost completely inhibited (>99%) within 30 min of oral or i.v. administration of EMATE.
Insights
Oestrone-3-O-sulphamate (EMATE) is a potent steroid sulphatase inhibitor. This study developed an oral formulation and HPLC assay for EMATE, demonstrating its rapid absorption and significant inhibition of sulphatase activity in rats.
Area of Science:
- Endocrinology
- Pharmacology
- Medicinal Chemistry
Background:
- The sulphatase pathway is a key route for oestrogen synthesis in postmenopausal breast tumours.
- Developing potent steroid sulphatase inhibitors is crucial for blocking this pathway.
- Oestrone-3-O-sulphamate (EMATE) is a highly potent in vivo active inhibitor.
Purpose of the Study:
- To prepare an oral formulation for EMATE administration.
- To establish a high-performance liquid chromatography (HPLC) method for quantifying EMATE in rat plasma.
- To investigate the pharmacokinetics and sulphatase inhibitory activity of orally administered EMATE in rats.
Main Methods:
- Preparation of an oral EMATE formulation.
- Development and validation of an HPLC assay for rat plasma EMATE measurement.
- Pharmacokinetic studies involving oral and intravenous administration of EMATE in rats, with plasma sampling up to 6 hours.
- Assessment of rat liver sulphatase activity inhibition.
Main Results:
- EMATE was successfully formulated for oral administration and detected in rat plasma post-administration using HPLC.
- Plasma EMATE concentrations showed a dose-dependent relationship (10-40 mg/kg) after oral dosing.
- Oral EMATE exhibited rapid absorption (peak at 30 min) and bi-phasic elimination (half-lives of 30 min and 4.5 h).
- EMATE administration led to near-complete inhibition (>99%) of rat liver sulphatase activity within 30 minutes.
- Minimal evidence of EMATE metabolism to oestrone was observed.
Conclusions:
- An effective oral formulation and pharmacokinetic assay for EMATE were developed.
- EMATE demonstrates favorable pharmacokinetic properties and potent, rapid sulphatase inhibition in vivo.
- These findings support EMATE's potential as a therapeutic agent for hormone-dependent conditions.