A prodrug approach to increasing the oral potency of a phenolic drug. 1. Synthesis, characterization, and stability of an O-(imidomethyl) derivative of 17β-estradiol

Patel J.U., Prankerd R.J. and Sloan K.B. (1994) A prodrug approach to increasing the oral potency of a phenolic drug. 1. Synthesis, characterization, and stability of an O-(imidomethyl) derivative of 17β-estradiol. Journal of Pharmaceutical Sciences, 83 10: 1477-1481. doi:10.1002/jps.2600831022


Author Patel J.U.
Prankerd R.J.
Sloan K.B.
Title A prodrug approach to increasing the oral potency of a phenolic drug. 1. Synthesis, characterization, and stability of an O-(imidomethyl) derivative of 17β-estradiol
Journal name Journal of Pharmaceutical Sciences   Check publisher's open access policy
ISSN 0022-3549
Publication date 1994-01-01
Sub-type Article (original research)
DOI 10.1002/jps.2600831022
Open Access Status Not yet assessed
Volume 83
Issue 10
Start page 1477
End page 1481
Total pages 5
Language eng
Subject 3002 Drug Discovery
1605 Policy and Administration
1600 Chemistry
1313 Molecular Medicine
3004 Pharmacology
3003 Pharmaceutical Science
Abstract An O‐(saccharinylmethyl) prodrug was synthesized to improve the poor oral potency of the phenolic drug 17β‐estradiol. This O‐(imidomethyl) type of prodrug was designed to undergo chemical hydrolysis and to be a poor substrate for enzymatic hydrolysis. At 37 °C, it was found to exhibit half‐lives of about 13 min in 50% methanol:pH 7.0 (v/v) phosphate buffer, about 3 min in rat plasma, about 15 min in human plasma, and about 50 min in 20% rat liver homogenate. Introduction of the enzyme poison tetraethyl pyrophosphate or the protein denaturant sodium fluoride into rat plasma had no significant effect on the half‐life. Thus, the observed increased rate of hydrolysis in biological media is not due to enzymatic catalysis but to a nonspecific solventlike effect. The fact that the rate of hydrolysis in the methanol:buffer exhibited a first‐order dependence on the hydroxide ion concentration and that the rate of hydrolysis increased with increasing methanol concentrations up to 70% supported an S2 mechanism of hydrolysis for the prodrug. These results suggest that an O‐(imidomethyl) type prodrug is insensitive to enzymatic catalysis of hydrolysis yet may hydrolyze quickly enough to release 17β‐estradiol faster than 17β‐estradiol is conjugated and excreted. Copyright
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: Scopus Import - Archived
 
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