Abstract
The metabolic profile of dicentrine, a selective α1-adrenoceptor antagonist with potent antiarrhythmic and antihypertensive activities, in miniature pig urine via oral administration was investigated for the first time. The urine, collected after a single oral administration of dicentrine, was pretreated using solvent extraction and column chromatographic methods to identify the metabolites containing fractions. Twenty-four metabolites (MI-1–9 and MII-1-15), of which 21 compounds are new, were identified by mass spectrometry and high-performance liquid chromatography-diode array detector solid-phase extraction-NMR techniques. Of these, 14 metabolites (MI-5, MII-1 and 2, and MII-5-15) were further isolated for structure confirmation. The phase I metabolic transformations of dicentrine were found to be N-demethylation, N-oxidation, O-demethylation (9,10-OMe), O,O-demethylenation (1-OCH2O-2), and hydroxylation at the benzylic (C-4) and the aromatic (C-3) positions, whereas those for the phase II were O-glucuronidation and O-glucosylation of the phenolic group of the phase I metabolites.
Footnotes
This study was supported by the National Science Council, Republic of China [Grants NSC96-2323-B-002-001, NSC97-2323-B-002-001].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.033795.
↵
The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
-
ABBREVIATIONS:
- MS/MS
- tandem mass spectrometry
- HPLC
- high-performance liquid chromatography
- SPE
- solid-phase extraction
- HRESIMS
- high-resolution electrospray ionization mass spectrometry
- MeOH
- methanol
- MS
- mass spectrometry
- 2D
- two dimensional
- HMQC
- heteronuclear multiple quantum correlation
- HSQC
- heteronuclear single quantum correlation
- HMBC
- heteronuclear multiple bond coherence
- NOE
- nuclear Overhauser effect
- NOESY
- nuclear Overhauser effect spectroscopy
- DAD
- diode array detector
- RP
- reverse-phase
- TFA
- trifluoroacetic acid
- ESI
- electrospray ionization
- 1D
- one-dimensional
- GlcUA
- glucuronyl.
- Received April 4, 2010.
- Accepted July 9, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|