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
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.
