Metabolism of Dicentrine: Identification of the Phase I and Phase II Metabolites in Miniature Pig Urine

Abstract

ABSTRACT:The metabolic profile of dicentrine, a selective ␣ 1 -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-OCH 2 O-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.

Metabolism of (2S)-Pterosin A: Identification of the Phase I and Phase II Metabolites in Rat Urine

“…pounds did show hydroxylation on 1-indanone substructure in rats microsomes (Coombs et al, 1985;Boyd et al, 1993) and in human (Brunel et al, 1995). Our study reveals the amounts of 3␣-hydroxylated metabolites to be much more than those of 3␤-hydroxylated ones, similar to what was observed in dicentrine metabolites (Lai et al, 2010) and implying the regioselectivity of hydroxylation at C-3. The regioselectivity of benzylic hydroxylation also occurred in semagacestat metabolites, which were primarily formed by CYP3A4 and CYP3A5 (Yi et al, 2010).…”

“…Prominent among these is the technique of HPLC-SPE-NMR, for which a SPE cartridge is used to trap multiple injections of a metabolite to enable sufficient accumulation for NMR measurement and thereby eliminating the eluent effect on 1 H NMR signals. Various studies successfully applied such a technique to identify the metabolites of drugs or bioactive compounds (Burton et al, 1997;Spraul et al, 2003;Godejohann et al, 2004;Sandvoss et al, 2005;Lai et al, 2010) and the constituents in complex natural products (Wang and Lee, 2005;Lam et al, 2007;Lee et al, 2007). In the present study, HPLC-SPE-TT-NMR, which equipped a liquid handler between SPE and NMR to transfer compound from SPE to a 2-mm NMR tube for NMR measurement, and HPLC-HRESIMS were applied to characterize the metabolites of (2S)-pterosin A (1) in rat urine, collected in 24 h after intragastrical oral administration (Brant and Remon, 1991).…”

Identification of the metabolites of TCM prescription Sinisan, found in miniature pig urine via intragastric administration

“…Liquiritigenin (38) has been shown to be a substratedependent inhibitor of UGT isoforms [26] and thus might influence the metabolism of naringenin in liver. No sulfate conjugates were detected in this study, consistent with the metabolic study of dicentrine [10] in pig, but the result is different from that of using rat as experimental animal.…”

“…Seven of the nine endogenous metabolites were identified as p-hydroxyhippuric acid (1), m-hydroxyhippuric acid (2), (4-hydroxyphenyl)-acetic acid (7), hippuric acid (10), N-(indole-2-carbonyl)-methylglycine (20) (Table S2; Supplemental data) [16], (E)-cinnamoylglycine (28), and nonanedioic acid (29), respectively, by comparison of their UV, 1 H NMR spectroscopic data (Table S3; Supplemental data), obtained from HPLC-DAD-SPE-TT-NMR, and MS data, obtained from HPLC-MS (Table 1) with those reported in the literatures (Refs. 1-3 and 11; Supplemental data).…”

In vitro and in vivo identification of metabolites of magnoflorine by LC LTQ‐Orbitrap MS and its potential pharmacokinetic interaction in Coptidis Rhizoma decoction in rat

“…). These two types of isoquinoline alkaloids have different structures, so their pharmacological activities (Cao et al ., ; Zhao and Zhao, ) and biotransformation (Chen et al ., ; Lai et al ., ) also show some differences. A great deal of research on protoberberine alkaloids had been carried out recently, especially on berberine.…”