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Quantitative and qualitative analysis of the novel antitumor 1,3,4-oxadiazole derivative (GLB) and its metabolites using HPLC-UV and UPLC-QTOF-MS.

Li P, Wang X, Li J, Meng ZY, Li SC, Li ZJ, Lu YY, Ren H, Lou YQ, Lu C, Dou GF, Zhang GL - Sci Rep (2015)

Bottom Line: Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative.The lower limit of quantification was 10 ng/mL.Our results indicated that the di-hydroxylation (M1) and hydroxylation (M2) of GLB are the major metabolites.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, PR. China.

ABSTRACT
Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative. This research first reported a simple, specific, sensitive and stable high performance liquid chromatography-ultraviolet detector (HPLC-UV) method for the quantitative determination of GLB in plasma. In this method, the chromatographic separation was achieved with a reversed phase C18 column. The calibration curve for GLB was linear at 300 nm. The lower limit of quantification was 10 ng/mL. The precision, accuracy and stability of the method were validated adequately. This method was successfully applied to the pharmacokinetic study in rats for detection of GLB after oral administration. Moreover, the structures of parent compound GLB and its two major metabolites M1 and M2 were identified in plasma using an ultra performance liquid chromatography-electrospray ionization-quadrupole-time of flight- mass spectrometry (UPLC-ESI-QTOF-MS) method. Our results indicated that the di-hydroxylation (M1) and hydroxylation (M2) of GLB are the major metabolites. In conclusion, the present study provided valuable information on an analytical method for the determination of GLB and its metabolites in rats, can be used to support further developing of this antitumor agent.

No MeSH data available.


Related in: MedlinePlus

Representative UPLC chromatograms and tandem ESI-QTOF-MS mass spectrograms of(A): blank rat plasma; (B): GLB (3.50 min and m/z 497.09), metabolite M1 (2.56 min and m/z 529.08) and M2 (2.86 min and m/z 513.09) in a rat plasma sample at 6 h after oral administration GLB (100 mg/kg); (C): mass spectrograms of the parent compound GLB; (D): metabolites M1 and (E): metabolites M2 in positive scan mode using electrospray ionization (ESI) and in-source collisionally induced dissociation detected by UPLC-QTOF-MS/MS in a rat plasma sample at 6 h after a single oral administration of GLB (100 mg/kg).
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f3: Representative UPLC chromatograms and tandem ESI-QTOF-MS mass spectrograms of(A): blank rat plasma; (B): GLB (3.50 min and m/z 497.09), metabolite M1 (2.56 min and m/z 529.08) and M2 (2.86 min and m/z 513.09) in a rat plasma sample at 6 h after oral administration GLB (100 mg/kg); (C): mass spectrograms of the parent compound GLB; (D): metabolites M1 and (E): metabolites M2 in positive scan mode using electrospray ionization (ESI) and in-source collisionally induced dissociation detected by UPLC-QTOF-MS/MS in a rat plasma sample at 6 h after a single oral administration of GLB (100 mg/kg).

Mentions: Because of two unknown chromatographic peaks were detected by HPLC after oral dose GLB in rat plasma, their structures were further identified and the metabolic pathways were investigated using UPLC-MS method. As showed in Table 4, the data of GLB and its major two metabolites from the UPLC ESI-QTOF-MS/MS were compared. Based on the chromatographic retention times and mass spectral patterns (m/z and mass errors) between the parent drug and their product ions, the structures of metabolites of GLB could be estimated, in spite of lacking standards of metabolites. As shown in Fig. 3A,3B, the parent compound GLB profiles at the UPLC elution and mass spectrums were retention time 3.50 min and the molecular ion m/z 497, respectively. Metabolites M1 and M2 were detected at shorter retention times (2.56 and 2.86 min, respectively), and heavier molecular ions as m/z 529 (497 + 32 Da) and 513 (497 + 16 Da), respectively.


Quantitative and qualitative analysis of the novel antitumor 1,3,4-oxadiazole derivative (GLB) and its metabolites using HPLC-UV and UPLC-QTOF-MS.

Li P, Wang X, Li J, Meng ZY, Li SC, Li ZJ, Lu YY, Ren H, Lou YQ, Lu C, Dou GF, Zhang GL - Sci Rep (2015)

Representative UPLC chromatograms and tandem ESI-QTOF-MS mass spectrograms of(A): blank rat plasma; (B): GLB (3.50 min and m/z 497.09), metabolite M1 (2.56 min and m/z 529.08) and M2 (2.86 min and m/z 513.09) in a rat plasma sample at 6 h after oral administration GLB (100 mg/kg); (C): mass spectrograms of the parent compound GLB; (D): metabolites M1 and (E): metabolites M2 in positive scan mode using electrospray ionization (ESI) and in-source collisionally induced dissociation detected by UPLC-QTOF-MS/MS in a rat plasma sample at 6 h after a single oral administration of GLB (100 mg/kg).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493701&req=5

f3: Representative UPLC chromatograms and tandem ESI-QTOF-MS mass spectrograms of(A): blank rat plasma; (B): GLB (3.50 min and m/z 497.09), metabolite M1 (2.56 min and m/z 529.08) and M2 (2.86 min and m/z 513.09) in a rat plasma sample at 6 h after oral administration GLB (100 mg/kg); (C): mass spectrograms of the parent compound GLB; (D): metabolites M1 and (E): metabolites M2 in positive scan mode using electrospray ionization (ESI) and in-source collisionally induced dissociation detected by UPLC-QTOF-MS/MS in a rat plasma sample at 6 h after a single oral administration of GLB (100 mg/kg).
Mentions: Because of two unknown chromatographic peaks were detected by HPLC after oral dose GLB in rat plasma, their structures were further identified and the metabolic pathways were investigated using UPLC-MS method. As showed in Table 4, the data of GLB and its major two metabolites from the UPLC ESI-QTOF-MS/MS were compared. Based on the chromatographic retention times and mass spectral patterns (m/z and mass errors) between the parent drug and their product ions, the structures of metabolites of GLB could be estimated, in spite of lacking standards of metabolites. As shown in Fig. 3A,3B, the parent compound GLB profiles at the UPLC elution and mass spectrums were retention time 3.50 min and the molecular ion m/z 497, respectively. Metabolites M1 and M2 were detected at shorter retention times (2.56 and 2.86 min, respectively), and heavier molecular ions as m/z 529 (497 + 32 Da) and 513 (497 + 16 Da), respectively.

Bottom Line: Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative.The lower limit of quantification was 10 ng/mL.Our results indicated that the di-hydroxylation (M1) and hydroxylation (M2) of GLB are the major metabolites.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, PR. China.

ABSTRACT
Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative. This research first reported a simple, specific, sensitive and stable high performance liquid chromatography-ultraviolet detector (HPLC-UV) method for the quantitative determination of GLB in plasma. In this method, the chromatographic separation was achieved with a reversed phase C18 column. The calibration curve for GLB was linear at 300 nm. The lower limit of quantification was 10 ng/mL. The precision, accuracy and stability of the method were validated adequately. This method was successfully applied to the pharmacokinetic study in rats for detection of GLB after oral administration. Moreover, the structures of parent compound GLB and its two major metabolites M1 and M2 were identified in plasma using an ultra performance liquid chromatography-electrospray ionization-quadrupole-time of flight- mass spectrometry (UPLC-ESI-QTOF-MS) method. Our results indicated that the di-hydroxylation (M1) and hydroxylation (M2) of GLB are the major metabolites. In conclusion, the present study provided valuable information on an analytical method for the determination of GLB and its metabolites in rats, can be used to support further developing of this antitumor agent.

No MeSH data available.


Related in: MedlinePlus