Pharmacokinetics of oestrone-3-O-sulphamate: Journal of Steroid Biochemistry and Molecular Biology

M. I. H. Aragones, A. Purohit, D. Parish, U. G. Sahm, C. W. Pouton, B. V. L. Potter, M. J. Reed

Research output: Contribution to journalArticleResearchpeer-review

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 Ih 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. Copyright (C) 1996 Elsevier Science Ltd.
Original languageEnglish
Pages (from-to)611-617
Number of pages7
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume58
Publication statusPublished - 1996

Keywords

  • Animals Enzyme Inhibitors/administration & dosage/*pharmacokinetics Estrone/administration & dosage/*analogs & derivatives/pharmacokinetics Female Rats Rats, Wistar Sulfatases/*antagonists & inhibitors

Cite this

Aragones, M. I. H., Purohit, A., Parish, D., Sahm, U. G., Pouton, C. W., Potter, B. V. L., & Reed, M. J. (1996). Pharmacokinetics of oestrone-3-O-sulphamate: Journal of Steroid Biochemistry and Molecular Biology. Journal of Steroid Biochemistry and Molecular Biology, 58, 611-617.
Aragones, M. I. H. ; Purohit, A. ; Parish, D. ; Sahm, U. G. ; Pouton, C. W. ; Potter, B. V. L. ; Reed, M. J. / Pharmacokinetics of oestrone-3-O-sulphamate : Journal of Steroid Biochemistry and Molecular Biology. In: Journal of Steroid Biochemistry and Molecular Biology. 1996 ; Vol. 58. pp. 611-617.
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Pharmacokinetics of oestrone-3-O-sulphamate : Journal of Steroid Biochemistry and Molecular Biology. / Aragones, M. I. H.; Purohit, A.; Parish, D.; Sahm, U. G.; Pouton, C. W.; Potter, B. V. L.; Reed, M. J.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 58, 1996, p. 611-617.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pharmacokinetics of oestrone-3-O-sulphamate

T2 - Journal of Steroid Biochemistry and Molecular Biology

AU - Aragones, M. I. H.

AU - Purohit, A.

AU - Parish, D.

AU - Sahm, U. G.

AU - Pouton, C. W.

AU - Potter, B. V. L.

AU - Reed, M. J.

N1 - M1 - 5-6 Hidalgo Aragones, M I Purohit, A Parish, D Sahm, U G Pouton, C W Potter, B V Reed, M J eng Research Support, Non-U.S. Gov't ENGLAND 1996/08/01 J Steroid Biochem Mol Biol. 1996 Aug;58(5-6):611-7.

PY - 1996

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N2 - 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 Ih 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. Copyright (C) 1996 Elsevier Science Ltd.

AB - 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 Ih 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. Copyright (C) 1996 Elsevier Science Ltd.

KW - Animals Enzyme Inhibitors/administration & dosage/pharmacokinetics Estrone/administration & dosage/analogs & derivatives/pharmacokinetics Female Rats Rats, Wistar Sulfatases/antagonists & inhibitors

M3 - Article

VL - 58

SP - 611

EP - 617

JO - Journal of Steroid Biochemistry and Molecular Biology

JF - Journal of Steroid Biochemistry and Molecular Biology

SN - 0960-0760

ER -