A simple and sensitive LC–ESI-MS (ion trap) method for the determination of bupropion and its major metabolite, hydroxybupropion in rat plasma and brain microdialysates

Yeniceli, Duygu; Şener, Erol; Korkmaz, Orhan Tansel; Doğrukol-Ak, Dilek; Tunçel, Neşe

doi:10.1016/j.talanta.2010.11.063

Cited by 31 publications

(33 citation statements)

References 29 publications

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“…3C (b) was considered to be generated by neutral loss of water from the bupropion metabolite. The latter metabolite has been known to be generated in other species such as humans and rats, and the obtained spectral data were consistent with the previous report (Yeniceli et al, 2011), suggesting that the same metabolite is also generated in monkeys.…”

Section: Cyp2c76 Metabolism Of 89 Compoundssupporting

confidence: 91%

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Evaluation of 89 Compounds for Identification of Substrates for Cynomolgus Monkey CYP2C76, a New Bupropion/Nifedipine Oxidase

et al. 2014

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Cynomolgus monkeys are widely used in preclinical studies during drug development because of their evolutionary closeness to humans, including their cytochrome P450s (P450s). Most cynomolgus monkey P450s are almost identical ( ‡90%) to human P450s; however, CYP2C76 has low sequence identity (approximately 80%) to any human CYP2Cs. Although CYP2C76 has no ortholog in humans and is partly responsible for species differences in drug metabolism between cynomolgus monkeys and humans, a broad evaluation of potential substrates for CYP2C76 has not yet been conducted. In this study, a screening of 89 marketed compounds, including human CYP2C and non-CYP2C substrates or inhibitors, was conducted to find potential CYP2C76 substrates. Among the compounds screened, 19 chemicals were identified as substrates for CYP2C76, including substrates for human CYP1A2 (7-ethoxyresorufin), CYP2B6 (bupropion), CYP2D6 (dextromethorphan), and CYP3A4/5 (dextromethorphan and nifedipine), and inhibitors for CYP2B6 (sertraline, clopidogrel, and ticlopidine), CYP2C8 (quercetin), CYP2C19 (ticlopidine and nootkatone), and CYP3A4/5 (troleandomycin). CYP2C76 metabolized a wide variety of the compounds with diverse structures. Among them, bupropion and nifedipine showed high selectivity to CYP2C76. As for nifedipine, CYP2C76 formed methylhydroxylated nifedipine, which was not produced by monkey CYP2C9, CYP2C19, or CYP3A4, as identified by mass spectrometry and estimated by a molecular docking simulation. This unique oxidative metabolite formation of nifedipine could be one of the selective marker reactions of CYP2C76 among the major CYP2Cs and CYP3As tested. These results suggest that monkey CYP2C76 contributes to bupropion hydroxylation and formation of different nifedipine oxidative metabolites as a result of its relatively large substrate cavity.

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Section: Cyp2c76 Metabolism Of 89 Compoundssupporting

confidence: 91%

“…4B), indicating this position to be a better metabolic site of CYP2C76. These simulation results were consistent with the known structure of bupropion metabolites reported previously (Yeniceli et al, 2011). The estimated structures of nifedipine and bupropion metabolites are shown in Fig.…”

Section: Cyp2c76 Metabolism Of 89 Compoundssupporting

confidence: 91%

Evaluation of 89 Compounds for Identification of Substrates for Cynomolgus Monkey CYP2C76, a New Bupropion/Nifedipine Oxidase

et al. 2014

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“…6β-hydroxytestosterone, 4-hydroxytolbutamide, 6-hydroxychlorzoxazone and acetaminophen were determined by previously published HPLC methods Guo et al, 2014) with slight modification. Dextrorphan and hydroxybupropion were determined by previously published LC-MS/MS method (He et al, 2007;Yeniceli et al, 2011) with slight modification. All of the analytical methods employed in the present work were validated according to accepted guidelines (Taverniers et al, 2004) (results not shown).…”

Section: Determination Of Cyp Activities In Rlm and Hlmmentioning

confidence: 99%

Effects of arecoline on hepatic cytochrome P450 activity and oxidative stress

et al. 2014

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-Betel-quid use is associated with the risk of liver cirrhosis and hepatocellular carcinoma. The aim of the present work was to evaluate the impact of arecoline on human hepatic cytochrome P450 (CYP) enzymes in vitro and rat hepatic CYP enzymes, as well as the hepatic oxidative stress and liver injury of rats in vivo. The in vitro results indicated that arecoline hydrobromide (AH) has no significant effect on the activities of CYP2B, 2C9, 3A4, 1A2, 2E1 and 2D6 in human liver microsome (HLM). However, oral administration of AH at 4 and 20 mg/kg/d for seven consecutive days significantly increased the activities of rat hepatic CYP2B, 2E1, 2D, 3A, 2C and 1A2. In addition, AH at 100 mg/kg/d significantly increased the levels of ALT, AST and MDA, decreased the levels of SOD, CAT, GSH-Px and GSH, in rat liver. The in vivo induction of AH on rat hepatic CYP isoforms suggested that the high risk of metabolic interaction should be existed when the substrate drugs of the six kinds of CYP isoforms was administered in betel-quid use human. Furthermore, the in vivo results also suggested that AH-induced hepatoxicity should be associated with the induction of AH on rat hepatic CYP2E1 and 2B.

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“…Reported C max based on Bupropion hydrochloride 100 mg tablets for BPR, HBPR and THBPR are 136.2 ng/ml, 269.0 ng/ml and 88.8 ng/ml, respectively. Literature reveals that HPLC methods for plasma, [1][2][3][4] stability method for plasma, 5 metabolite characterization, [6][7] LC-MS methods for human plasma [8][9][10][11][12][13] and rat plasma, 14 pharmacokinetics analysis in human or rat plasma [15][16][17][18][19][20][21][22][23][24] for bupropion and/its metabolite(s) and LC-MS methods for bupropion with combination [25][26][27] are reported. It is noted that reported HPLC methods are not sensitive for the quantification in terminal plasma concentration of bupropion and/or metabolites.…”

Section: Introductionmentioning

confidence: 99%

“…The reported methods 13,15,19,21,22,24 are used for quantification of Bupropion only. While the reported methods 4,11,14,17,18 are used for quantitation of Bupropion and hydroxyl bupropion from plasma samples and hence are not in accordance to Office of Generic Drug guidance for Bupropion BE study requirement. However, reported LC-MS methods, [8][9] are used for estimation of bupropion with other three metabolites for plasma, neither used isotope labelled standards as internal standards nor performed incurred sample reanalysis which are current European regulatory requirement.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Quantitative Determination of Bupropion and its Metabolites by High Performance Liquid Chromatography Tandem Mass Spectrometry Detection: Application to Bioequivalence Study

Shahi¹,

Patel²,

Shah³

et al. 2018

IJPER

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Objective: A rapid, selective, sensitive, precise and accurate liquid chromatography in tandem with electro-spray ionization mass spectrometry method has been developed and validated for the simultaneous quantification of bupropion (BPR), hydroxyl bupropion (HBPR), erythrohydrobupropion (EHBPR) and threohydrobupropion (THBPR) in human plasma using only 100µL of human plasma sample. Methodology: Multi reaction monitoring detection was performed by electrospray ionization in the positive ion mode, conferring an additional selectivity to the method. The solid phase extraction technique was used for sample preparation. Chromatographic separation of drug and metabolites with better peak shape and resolution was achieved by using an Acquity BEH phenyl column with an isocratic elution of 42 % methanol and 58 % ammonia (0.06%, v/v) aqueous solution at a flow rate of 0.5 ml/min. Methanol was chosen because it enabled good resolution between THBPR and EHBPR as well as good peak symmetry of all the four analytes. Detection was carried out by mass spectrometry using positive electro-spray ionization mode, and the compounds were monitored using multiple reactions monitoring method. Deuterium-labeled isotopes of the compounds were used as internal standards. Results and Conclusion: No significant matrix effect was observed in the presented method. The assay method was validated over the concentration range of 1.75-500 ng/ml for BPR; 5-1000 ng/ml for HBPR; 0.5-100 ng/ml for EHBPR; and 2-500 ng/ml for THBPR as per FDA guideline and validated method was successfully applied for estimation of drug and metabolite concentration in the healthy adult volunteers, bioequivalence and pharmacokinetic study of Bupropion hydrochloride 300 mg extended release tablets under fasting condition.

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A simple and sensitive LC–ESI-MS (ion trap) method for the determination of bupropion and its major metabolite, hydroxybupropion in rat plasma and brain microdialysates

Cited by 31 publications

References 29 publications

Evaluation of 89 Compounds for Identification of Substrates for Cynomolgus Monkey CYP2C76, a New Bupropion/Nifedipine Oxidase

Evaluation of 89 Compounds for Identification of Substrates for Cynomolgus Monkey CYP2C76, a New Bupropion/Nifedipine Oxidase

Effects of arecoline on hepatic cytochrome P450 activity and oxidative stress

Simultaneous Quantitative Determination of Bupropion and its Metabolites by High Performance Liquid Chromatography Tandem Mass Spectrometry Detection: Application to Bioequivalence Study

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