The metabolism and excretion of 2‐methylaminoethoxycarbonyl‐4,4′‐dimethoxy‐5,6,5′,6′‐dimethylenedioxybiphenyl‐2′‐carboxylic acid (DDB‐S) in rats and human

Abstract

The metabolism and excretion of 2-methylaminoethoxycarbonyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2'-carboxylic acid (DDB-S) were investigated in both rats and humans using liquid chromatography/electrospray ion trap mass spectrometry (LC/ESI-MS/MS). In rats, DDB-S was rapidly eliminated from the body after a single 50 mg/kg intravenous injection, with urine being a major excretion route. DDB-S was metabolically stable; approximately 96% of the administered dose was recovered in the form of the parent compound. Nevertheless, 12 metabolites were detected in the urine and feces collected from DDB-S-treated rats. The structural characterizations of the metabolites were elucidated from the MS(n) spectral analysis. Because DDB-S has a pseudo-symmetrical methylenedioxy biphenyl structure, regioselective deuterium-substituted DDB-S (d(5)-DDB-S) was used to assign the metabolic modification. The major metabolic pathways of DDB-S were identified as demethylenation of the methylenedioxy moiety, O-demethylation of the methoxy moiety and glucuronidation. In addition, N-demethylation of the methylaminoethyl group was also detected as a minor reaction.

High-performance liquid chromatography–tandem mass spectrometry in the identification and determination of phase I and phase II drug metabolites

“…In general, low-resolution mass analyzers (e.g., quadrupoles and ion traps) have resolution in the low-thousands range, while high-resolution analyzers should provide a minimum resolution of 15,000 for time of flight (TOF) based analyzers [ 42 , 71 , 101 ] or over 50,000 for Fourier transform mass analyzers [ 102 – 104 ]. The advantage of ion traps (both spherical and linear) is the possibility of MS n scan, which is useful for studying fragmentation paths [ 49 , 105 – 108 ], as illustrated for the example of the fragmentation pattern determined on the basis of MS n spectra (Fig. 3 ).…”

“…5 MS 2 and MS 3 spectra measured with an ion-trap analyzer for a nonlabeled and b d 5 -labeled drug 2-methylaminoethoxycarbonyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2′-carboxylic acid (DDB-S). (Reprinted with permission from [ 105 ]) …”

“…The only remarkable difference is found in their mass spectra, because the m / z values are shifted by the corresponding mass increment, which enables the parallel peak area integration of nonlabeled target drug (or metabolite) and labeled internal standard [ 74 , 133 , 167 – 169 ]. Another valuable application of deuterated analogs is the verification of proposed fragmentation pathways [ 105 ].…”

Elucidation of the in vitro metabolic profile of stable isotope labeled BAL19403 by accurate mass capillary liquid chromatography/quadrupole time‐of‐flight mass spectrometry and isotope exchange

“…An elegant alternative is the use of stable isotope labeled drug analogues. Mixtures of labeled and unlabeled drug yield a characteristic isotopic pattern during MS analysis, which can be used to help identify metabolites 9–12. This approach, which is particularly advantageous in the case that unexpected or atypical biotransformations occur, was chosen for the elucidation of the metabolic pattern of BAL19403 in conjunction with structural elucidation of the observed metabolites.…”