摘要
Pharmacokinetics of cyadox （CYX） and its major metabolites in healthy swine was investigated in this paper. 1,4- Bisdesoxycyadox （BDCYX）, cyadox-1-monoxide （CYX-1-O） and quinoxaline-2-carboxylic acid （QCA）, three main metabolites of cyadox, were synthesized by College of Science, China Agricultural University. Cyadox （CYX） was administered to 8 healthy cross-bread swine intravenously （i.v.） and orally （p.o.） at a dosage of 1 mg kg^-1 body weight and 40 mg kg-1 body weight respectively in a randomized crossover design test with 2-wk washout period. A sensitive high-performance liquid chromatography-tandem mass spectrometry （LC-ESI-MS/MS） method was developed for the determination of cyadox and its major metabolites in plasma. CYX and its major metabolites BDCYX, and CYX-1-O can be detected after intravenous administration of cyadox while CYX and its metabolites BDCYX, CYX-1-O and QCA can be detected after oral administration of CYX. Plasma concentration vs. time profiles of CYX and its major metabolites were analyzed by non-compartmental pharmacokinetic method. Following i.v. administration, the areas under the plasma concentration-time curve （AUC0-∞） were （0.38±0.03） lag mL-I h （CYX）, （0.018±0.002） lag mL-1 h （BDCYX） and （0.17±0.02） lag mL^-1 h （CYX- 1-O）, respectively. The terminal elimination half-lives （t1/2kz） were determined to be （0.93±0.07） h （CYX）, （1.45±0.04） h （BDCYX）, and （0.92±0.04） h （CYX-1-O）, respectively. Steady-state distribution volume （Vss） of （2.14±0.11） L kg^-1 and total body clearance （CL） of （2.84±0.19） L h^-1 kg^-1 were determined for CYX after i.v. dosing. The bioavailability （F） of CYX was 2.85% for oral administration. After single i.v. administration, peak plasma concentrations （Cmax） of （1.08±0.06） lag mL^-1 （CYX）, （0.0068~ 0.0004） lag mL-1 （BDCYX） and （0.25~0.03） gg mL-~ （CYX-I-O） were observed at Tmax of 0.033 h （CYX）, 1 h （BDCYX） and 0.033 h （CYX-1-O）, respectively. The main pharmacokinetic parameters after p.o. administration were as follows： AUC0.= were （0.42~0.04） lag mL^-1 h （CYX）, （1.38±0.14） μg mL-1 h （BDCYX）, （0.59±0.02） lag mL-1 h （CYX-1-O） and （1.48＋0.09） lag mL-＇ h （QCA）, respectively, t1/2λz were （4.77±0.33） h （CYX）, （5.77±0.56） h （BDCYX）, （4.12＋0.28） h （CYX-1-O）, and （8.51＋0.39） h （QCA）, respectively. After p.o. administration, CmaxS of （0.033±0.002） μg mL^-1 （CYX）, （0.22±0.03） mg mL^-1 （BDCYX）, （0.089±0.005） μg mL^-1 （CYX-1-O）, and （0.17± 0.01） mg mL^-1 （QCA） were observed at Tmax of（7.38±0.33） h （CYX）, （7.25±0.31） h （BDCYX）, （7.38±0.33） h （CYX-1-O）, and （7.25±0.31） h （QCA）, respectively. The results showed that CYX was slowly absorbed after oral administration and most of CYX was transformed to its metabolites in swine. The area under plasma concentration-time curve （AUC0-∞）of metabolites were higher than that of CYX after p.o. administration, and the elimination half-lives （t1/2λz） of QCA were longer than those of CYX, CYX-1-O, and BDCYX after oral administration.
Pharmacokinetics of cyadox （CYX） and its major metabolites in healthy swine was investigated in this paper. 1,4- Bisdesoxycyadox （BDCYX）, cyadox-1-monoxide （CYX-1-O） and quinoxaline-2-carboxylic acid （QCA）, three main metabolites of cyadox, were synthesized by College of Science, China Agricultural University. Cyadox （CYX） was administered to 8 healthy cross-bread swine intravenously （i.v.） and orally （p.o.） at a dosage of 1 mg kg^-1 body weight and 40 mg kg-1 body weight respectively in a randomized crossover design test with 2-wk washout period. A sensitive high-performance liquid chromatography-tandem mass spectrometry （LC-ESI-MS/MS） method was developed for the determination of cyadox and its major metabolites in plasma. CYX and its major metabolites BDCYX, and CYX-1-O can be detected after intravenous administration of cyadox while CYX and its metabolites BDCYX, CYX-1-O and QCA can be detected after oral administration of CYX. Plasma concentration vs. time profiles of CYX and its major metabolites were analyzed by non-compartmental pharmacokinetic method. Following i.v. administration, the areas under the plasma concentration-time curve （AUC0-∞） were （0.38±0.03） lag mL-I h （CYX）, （0.018±0.002） lag mL-1 h （BDCYX） and （0.17±0.02） lag mL^-1 h （CYX- 1-O）, respectively. The terminal elimination half-lives （t1/2kz） were determined to be （0.93±0.07） h （CYX）, （1.45±0.04） h （BDCYX）, and （0.92±0.04） h （CYX-1-O）, respectively. Steady-state distribution volume （Vss） of （2.14±0.11） L kg^-1 and total body clearance （CL） of （2.84±0.19） L h^-1 kg^-1 were determined for CYX after i.v. dosing. The bioavailability （F） of CYX was 2.85% for oral administration. After single i.v. administration, peak plasma concentrations （Cmax） of （1.08±0.06） lag mL^-1 （CYX）, （0.0068~ 0.0004） lag mL-1 （BDCYX） and （0.25~0.03） gg mL-~ （CYX-I-O） were observed at Tmax of 0.033 h （CYX）, 1 h （BDCYX） and 0.033 h （CYX-1-O）, respectively. The main pharmacokinetic parameters after p.o. administration were as follows： AUC0.= were （0.42~0.04） lag mL^-1 h （CYX）, （1.38±0.14） μg mL-1 h （BDCYX）, （0.59±0.02） lag mL-1 h （CYX-1-O） and （1.48＋0.09） lag mL-＇ h （QCA）, respectively, t1/2λz were （4.77±0.33） h （CYX）, （5.77±0.56） h （BDCYX）, （4.12＋0.28） h （CYX-1-O）, and （8.51＋0.39） h （QCA）, respectively. After p.o. administration, CmaxS of （0.033±0.002） μg mL^-1 （CYX）, （0.22±0.03） mg mL^-1 （BDCYX）, （0.089±0.005） μg mL^-1 （CYX-1-O）, and （0.17± 0.01） mg mL^-1 （QCA） were observed at Tmax of（7.38±0.33） h （CYX）, （7.25±0.31） h （BDCYX）, （7.38±0.33） h （CYX-1-O）, and （7.25±0.31） h （QCA）, respectively. The results showed that CYX was slowly absorbed after oral administration and most of CYX was transformed to its metabolites in swine. The area under plasma concentration-time curve （AUC0-∞）of metabolites were higher than that of CYX after p.o. administration, and the elimination half-lives （t1/2λz） of QCA were longer than those of CYX, CYX-1-O, and BDCYX after oral administration.
基金
supported by the National Basic Research Program of China (2009CB118805)
the Key Technologies R&D Program of China during the 11th-Five Year Plan period (2009BADB7B05-03)
