The present study was carried out to investigate the pharmacokinetics of mequindox （MEQ）, a new synthetic quinoxaline 1,4-dioxide derivative and its two main metabolites M1 [2-isoethanol mequinoox], M2 [2-isoethanol...The present study was carried out to investigate the pharmacokinetics of mequindox （MEQ）, a new synthetic quinoxaline 1,4-dioxide derivative and its two main metabolites M1 [2-isoethanol mequinoox], M2 [2-isoethanol 1-desoxymequindox] in healthy swine. MEQ （10 mg kg-1 body weight） was administered to nine healthy cross-bread swine via oral, intramuscular, and intravenous routes in a randomized 3x3 crossover design with a 1-wk washout period. A sensitive high-performance liquid chromatography （HPLC） method was used for the determination of plasma concentrations of MEQ and its metabolites M1 and M2. Plasma concentration versus time profiles of MEQ and its metabolites, M1 and M2, were analyzed by noncompartmental analysis using WinNonlin 5.2 software. The mean maximum concentrations （Cmax） of M1 and M2 after intravenous administration of MEQ were （5.27±1.59） lag mL-1 at 1.78 h and （1.01±0.29） μg mL-1 at 0.92 h, respectively. The mean maximum concentrations （Cmax） ofMEQ, M1, and M2 were found to be （6.96±3.23）, （6.61±1.56）, and （0.78 ±0.25） lag mL-1 respectively at 0.15, 1.61, and 1.30 h after intramuscular administration of MEQ, respectively and （0.75±0.45）, （6.90±1.52）, and （0.62±0.21） lag mL-1, respectively at 0.40, 1.57, and 2.00 h, respectively after oral administration of MEQ. The apparent elimination half-lives （b2） ofMEQ, M1, and M2 were （0.84±0.35）, （7.57±3.93）, and （9.56±6.00） h, respectively after intravenous administration of MEQ; （0.50±0.25）, （6.30±3.00）, and （5.94±2.54） h, respectively after intramuscular administration of MEQ; and （1.64± 1.17）, （5.59±1.93）, and （16.25±10.27） h, respectively after oral administration of MEQ. The mean areas under the plasma concentration-time curve （AUC0-∝） of MEQ, M1, and M2 were （4.88±1.54）, （36.93±17.50）, and （5.16±94） μg h mL-1, respectively after intravenous administration of MEQ; （4.18±0.76）, （48.25±20.82）, and （4.88±2.21） μg h mL-1 , respectively after intramuscular administration of MEQ; and （1.01±0.40）, （48.83±20.71）, and （5.54±2.23） μg h mL-1, respectively after oral administration of MEQ. MEQ was rapidly absorbed and metabolized in swine after oral, intramuscular, and intravenous administration. Further studies are required to investigate the double-peak phenomenon observed in the plasma concentration-time profile after oral administration and the pharmacokinetics of other metabolites of MEQ.展开更多
Mequindox （MEQ）, 3-methyl-2-quinoxalinacetyl-l,4-dioxide, is widely used in Chinese veterinary medicine as an antimicrobial agent and feed additive. Its toxicity has been reported to be closely related to its metabo...Mequindox （MEQ）, 3-methyl-2-quinoxalinacetyl-l,4-dioxide, is widely used in Chinese veterinary medicine as an antimicrobial agent and feed additive. Its toxicity has been reported to be closely related to its metabolism. To understand the pathways underlying MEQ＇s metabolism more clearly, we studied its metabolism in isolated rat liver cells by using liquid chromatography coupled with electrospray ionization hybrid linear trap quadrupole orbitrap （LC-LTQ-Orbitrap） mass spectrometry. The structures of MEQ metabolites and their product ions were readily and reliably characterized on the basis of accurate MS2 spectra and known structure of MEQ. Eleven metabolites were detected in isolated rat liver cells, two of which were detected for the first time in vitro. The major metabolic pathways reported previously for in vitro metabolism of MEQ in rat microsomes were confirmed in this study, including N O group reduction, carbonyl reduction, and methyl monohydroxylation. In addition, we fotmd that acetyl hydroxylation was an important pathway of MEQ metabolism. The results also demonstrate that cellular systems more closely simulate in vivo conditions than do other in vitro systems such as microsomes. Taken together, these data contribute to our understanding of the in vivo metabolism of MEQ.展开更多
基金supported by the National Basic Research Program of China (973 Program,2009CB118805)the National Key Technology Research and Development Program of China during the 10th Five-Year Plan Period (2009BADB7B05-03)
文摘The present study was carried out to investigate the pharmacokinetics of mequindox （MEQ）, a new synthetic quinoxaline 1,4-dioxide derivative and its two main metabolites M1 [2-isoethanol mequinoox], M2 [2-isoethanol 1-desoxymequindox] in healthy swine. MEQ （10 mg kg-1 body weight） was administered to nine healthy cross-bread swine via oral, intramuscular, and intravenous routes in a randomized 3x3 crossover design with a 1-wk washout period. A sensitive high-performance liquid chromatography （HPLC） method was used for the determination of plasma concentrations of MEQ and its metabolites M1 and M2. Plasma concentration versus time profiles of MEQ and its metabolites, M1 and M2, were analyzed by noncompartmental analysis using WinNonlin 5.2 software. The mean maximum concentrations （Cmax） of M1 and M2 after intravenous administration of MEQ were （5.27±1.59） lag mL-1 at 1.78 h and （1.01±0.29） μg mL-1 at 0.92 h, respectively. The mean maximum concentrations （Cmax） ofMEQ, M1, and M2 were found to be （6.96±3.23）, （6.61±1.56）, and （0.78 ±0.25） lag mL-1 respectively at 0.15, 1.61, and 1.30 h after intramuscular administration of MEQ, respectively and （0.75±0.45）, （6.90±1.52）, and （0.62±0.21） lag mL-1, respectively at 0.40, 1.57, and 2.00 h, respectively after oral administration of MEQ. The apparent elimination half-lives （b2） ofMEQ, M1, and M2 were （0.84±0.35）, （7.57±3.93）, and （9.56±6.00） h, respectively after intravenous administration of MEQ; （0.50±0.25）, （6.30±3.00）, and （5.94±2.54） h, respectively after intramuscular administration of MEQ; and （1.64± 1.17）, （5.59±1.93）, and （16.25±10.27） h, respectively after oral administration of MEQ. The mean areas under the plasma concentration-time curve （AUC0-∝） of MEQ, M1, and M2 were （4.88±1.54）, （36.93±17.50）, and （5.16±94） μg h mL-1, respectively after intravenous administration of MEQ; （4.18±0.76）, （48.25±20.82）, and （4.88±2.21） μg h mL-1 , respectively after intramuscular administration of MEQ; and （1.01±0.40）, （48.83±20.71）, and （5.54±2.23） μg h mL-1, respectively after oral administration of MEQ. MEQ was rapidly absorbed and metabolized in swine after oral, intramuscular, and intravenous administration. Further studies are required to investigate the double-peak phenomenon observed in the plasma concentration-time profile after oral administration and the pharmacokinetics of other metabolites of MEQ.
基金financially supported by the National Basic Research Program of China(2009CB118800)
文摘Mequindox （MEQ）, 3-methyl-2-quinoxalinacetyl-l,4-dioxide, is widely used in Chinese veterinary medicine as an antimicrobial agent and feed additive. Its toxicity has been reported to be closely related to its metabolism. To understand the pathways underlying MEQ＇s metabolism more clearly, we studied its metabolism in isolated rat liver cells by using liquid chromatography coupled with electrospray ionization hybrid linear trap quadrupole orbitrap （LC-LTQ-Orbitrap） mass spectrometry. The structures of MEQ metabolites and their product ions were readily and reliably characterized on the basis of accurate MS2 spectra and known structure of MEQ. Eleven metabolites were detected in isolated rat liver cells, two of which were detected for the first time in vitro. The major metabolic pathways reported previously for in vitro metabolism of MEQ in rat microsomes were confirmed in this study, including N O group reduction, carbonyl reduction, and methyl monohydroxylation. In addition, we fotmd that acetyl hydroxylation was an important pathway of MEQ metabolism. The results also demonstrate that cellular systems more closely simulate in vivo conditions than do other in vitro systems such as microsomes. Taken together, these data contribute to our understanding of the in vivo metabolism of MEQ.
