Identification of isocephalomannine in the presence of cephalomannine isomers and alkali metal ion adducts in a paclitaxel active pharmaceutical ingredient using electrospray tandem mass spectrometry

Kannan, Vivekanandan; Swamy, Madugundu Guru; Prasad, Sudhanand; Mukherjee, Rama; Burman, Anand C.

doi:10.1002/rcm.2500

Cited by 9 publications

(5 citation statements)

References 17 publications

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“…In the positive-ion mode, the following fragments were observed for the cephalomannine (Table 1): m/z 832.7, [MϩH] ϩ ; m/z 854.9, [MϩNa] ϩ ; m/z 870.7, [MϩK] ϩ ; m/z 509.6, i.e., consecutive loss of C13 side chain and acetic acid; m/z 309.8, i.e., consecutive loss of C2 side chain, acetic acid, and water on m/z 509.6; m/z 264.6, i.e., C13 side chain; and m/z 246.5, i.e., water loss on m/z 264.6. These fragments were in agreement with Vivekanandan et al (2006). Characteristic fragment ions of metabolites were 16 mass units greater than that of cephalomannine, indicating that both metabolites were monohydroxylated (Table 1).…”

Section: Resultssupporting

confidence: 71%

Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

Jiangwei

Ge²,

Liu³

et al. 2007

Drug Metab Dispos

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ABSTRACT:To investigate how taxane's substituents at C3 affect its metabolism, we compared the metabolism of cephalomannine and paclitaxel, a pair of analogs that differ slightly at the C3 position. After cephalomannine was incubated with human liver microsomes in an NADPH-generating system, two monohydroxylated metabolites (M1 and M2) were detected by liquid chromatography/tandem mass spectrometry. C4؆ (M1) and C6␣ (M2) were proposed as the possible hydroxylation sites, and the structure of M1 was confirmed by 1 H NMR. Chemical inhibition studies and assays with recombinant human cytochromes P450 (P450s) indicated that 4؆-hydroxycephalomannine was generated predominantly by CYP3A4 and 6␣-hydroxycephalomannine by CYP2C8. The overall biotransformation rate between paclitaxel and cephalomannine differed slightly (184 vs. 145 pmol/min/mg), but the average ratio of metabolites hydroxylated at the C13 side chain to C6␣ for paclitaxel and cephalomannine varied significantly (15:85 vs. 64:36) in five human liver samples. Compared with paclitaxel, the major hydroxylation site transferred from C6␣ to C4؆, and the main metabolizing P450 changed from CYP2C8 to CYP3A4 for cephalomannine. In the incubation system with rat or minipig liver microsomes, only 4؆-hydroxycephalomannine was detected, and its formation was inhibited by CYP3A inhibitors. Molecular docking by AutoDock suggested that cephalomannine adopted an orientation in favor of 4؆-hydroxylation, whereas paclitaxel adopted an orientation favoring 3-p-hydroxylation. Kinetic studies showed that CYP3A4 catalyzed cephalomannine more efficiently than paclitaxel due to an increased V m . Our results demonstrate that relatively minor modification of taxane at C3 has major consequence on the metabolism.

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Section: Resultssupporting

confidence: 71%

Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

Jiangwei

Ge²,

Liu³

et al. 2007

Drug Metab Dispos

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“…During the past decade, liquid chromatography/mass spectrometry (LC/MS) has been recognized as the most appropriate analytical technique for structural assignment of taxanes in complex samples due to its specificity and structure‐characterization ability 16–24. However, rapid metabolic profiling of yew materials is still a challenge, since there are numerous trace constituents from different classes and many analogues with similar chromatographic behavior, as well as many regio‐ and stereoisomers 25–29. Recently, ultra‐performance liquid chromatography (UPLC), which employs sub‐2 µm stationary phase particles to achieve superior theoretical plates and extremely high resolution in very short analytical times, has attracted the wide attention of pharmaceutical and biochemical analysts 30–34.…”

Section: Methodsmentioning

confidence: 99%

Profiling of yew hair roots from various species using ultra‐performance liquid chromatography/electrospray ionization mass spectrometry

Luan

Zhang

et al. 2008

Rapid Comm Mass Spectrometry

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An efficient and sensitive profiling approach to complex yew samples was developed using ultra-performance liquid chromatography/electrospray ionization mass spectrometry (UPLC/ESI-MS). The UPLC-based method displayed short analytical time and improved peak capability, as well as high sensitivity. The appropriate in-source collision-induced dissociation (CID) energy was employed to produce informative characteristic ions which could be used for stereochemical and sub-structural assignment of yew constituents. The method was successfully applied in the rapid screening of yew hair roots from various species, and 53 constituents including 47 taxoids were detected from partially purified root extract. Notably, C-7 hydroxytaxane stereoisomers could be identified based on their different fragment ions under the optimal profiling conditions. It was also observed that hair roots from different Taxus species exhibited nearly identical chemical distribution, indicating they had similar metabolic frameworks. Additionally, Taxus root resources also display benign medicinal perspective because they have relatively simple chemical profiles and possess high yields of valuable taxanes such as paclitaxel, cephalomannine, 10-deacetylpaclitaxel and 7-xylosyltaxanes.

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“…During the past decade, liquid chromatography/mass spectrometry (LC/MS) has been recognized as the most appropriate analytical technique for qualitative analysis or pharmacokinetic studies of taxane analogues from realistic samples due to its high sensitivity, specificity and structure characterization ability 12–24. Among these reports, electrospray ionization (ESI) was preferred due to its high‐efficiency ionization 18–24. A particular challenge for mass spectrometry is distinguishing and characterizing isomers.…”

Section: Methodsmentioning

confidence: 99%

Stereochemical differentiation of C‐7 hydroxyltaxane isomers by electrospray ionization mass spectrometry

Zhang

et al. 2009

Rapid Comm Mass Spectrometry

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In this study, different electrospray ionization mass spectrometric (ESI-MS) methods were utilized to analyze several pairs of taxane stereoisomers including paclitaxel and 7-epi-paclitaxel. Both ESI-MS and tandem mass spectrometry (MS/MS) techniques provided stereochemically dependent mass spectra in negative-ion mode, and all studied stereoisomers could be easily distinguished based on their characteristic ions or distinct fragmentation patterns. MS/MS experiments for several taxane analogues at various collision energies were performed to elucidate potential dissociation pathways. The gas-phase deprotonation potentials were also calculated to estimate the most thermodynamically favorable deprotonation site using DFT B3LYP/6-31G(d). The results of the theoretical studies agreed well with the fragmentation patterns of paclitaxel and 7-epi-paclitaxel observed from MS/MS experiments. In addition, it was found that liquid chromatography (LC)/ESI-MS was a useful and sensitive technique for assignment of C-7 taxane stereoisomers from realistic samples.

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Identification of isocephalomannine in the presence of cephalomannine isomers and alkali metal ion adducts in a paclitaxel active pharmaceutical ingredient using electrospray tandem mass spectrometry

Cited by 9 publications

References 17 publications

Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

Profiling of yew hair roots from various species using ultra‐performance liquid chromatography/electrospray ionization mass spectrometry

Stereochemical differentiation of C‐7 hydroxyltaxane isomers by electrospray ionization mass spectrometry

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