卡马西平、拉莫三嗪和司替戊醇对丙戊酸及其代谢物血浆浓度的影响

Effects of carbamazepine,lamotrigine and stiripentol on the plasma concentrations of valproic acid and its metabolites

目的研究卡马西平、拉莫三嗪和司替戊醇对丙戊酸及其代谢物血浆浓度的影响。方法24只SD雄性大鼠随机分成4组,每组6只。第1组灌胃给予200 mg·kg^(-1)丙戊酸,第2组灌胃给予200 mg·kg^(-1)丙戊酸+50 mg·kg^(-1)卡马西平,第3组灌胃给予200 mg·kg^(-1)丙戊酸+10 mg·kg^(-1)拉莫三嗪,第4组灌胃给予200 mg·kg^(-1)丙戊酸+300 mg·kg^(-1)司替戊醇,用HPLC-MS/MS法来测定大鼠血浆中丙戊酸及其代谢物2-丙基-2-戊烯酸(2-ene-VPA)、2-丙基-4-戊烯酸(4-ene-VPA)和丙戊酸-O-葡糖醛酸(VPA-G)的浓度。结果第1,2,3,4组中丙戊酸的主要药代动力学参数:C_(max)分别为(27.27±8.10),(16.95±4.65),(28.25±7.34)和(52.26±24.50)μg·mL^(-1),t_(max)分别为(0.31±0.16),(0.18±0.09),(0.18±0.09)和(0.29±0.10)h,AUC_(0~24 h)分别为(59.31±10.08),(58.18±14.48),(67.15±8.23)和(100.76±22.08)μg·mL^(-1)·h;这4组中2-ene-VPA的主要药代动力学参数:C_(max)(峰面积)分别为1.02×10^(7)±1.58×10^(6),9.99×10^(6)±1.64×10^(6),1.28×10^(7)±2.30×10^(6)和2.05×10^(7)±3.90×10^(6),t_(max)分别为(1.67±0.52),(1.00±0.01),(1.00±0.01)和(1.17±0.41)h,AUC_(0~24 h)(峰面积)分别为8.26×10^(7)±1.77×10^(7),9.96×10^(7)±2.25×10^(7),1.16×10^(8)±2.64×10^(7)和1.28×10^(8)±6.59×10^(7);这4组中4-ene-VPA的主要药代动力学参数:C_(max)(峰面积)分别为2.35×10^(6)±4.02×105,1.60×10^(6)±3.19×105,1.88×10^(6)±4.55×105和3.84×10^(6)±1.20×10^(6),t_(max)分别为(0.90±0.22),(1.00±0.01),(0.80±0.27)和(1.00±0.01)h,AUC_(0~24 h)(峰面积)分别为1.40×10^(7)±2.81×10^(6),2.02×10^(7)±2.58×10^(6),2.22×10^(7)±2.59×10^(6)和1.96×10^(7)±1.38×10^(6);这4组中VPA-G的主要药代动力学参数:C_(max)(峰面积)分别为1.57×10^(8)±1.96×10^(7),5.15×10^(7)±1.94×10^(7),1.19×10^(8)±3.27×10^(7)和3.02×10^(8)±1.23×10^(8),t_(max)分别为(0.90±0.22),(0.50±0.01),(0.50±0.01)和(0.92±0.20)h,AUC_(0~24 h)(峰面积)分别为3.76×10^(8)±5.58×10^(7),2.40×10^(8)±4.58×10^(7),2.92×10^(8)±1.94×10^(7)和5.61×10^(8)±1.37×10^(8)。结论卡马西平和司替戊醇会影响丙戊酸及其代谢物的血浆浓度。

ObjectiveTo study the effects of carbamazepine,lamotrigine and stiripentol on the plasma concentration of valproic acid and its metabolites.Methods Twenty four male SD rats were randomly divided into four groups,with six rats in each group.The first group was given valproic acid(200 mg·kg^(-1))by gavage,the second group was given valproic acid(200 mg·kg^(-1))+carbamazepine(50 mg·kg^(-1))by gavage,the third group was given valproic acid(200 mg·kg^(-1))+lamotrigine(10 mg·kg^(-1))by gavage,and the fourth group was given valproic acid(200mg·kg^(-1))+stiripentol(300 mg·kg^(-1))by gavage.A HPLC-MS/MS method was established to determine the concentrations of valproic acid and its metabolites 2-propyl-2-pentenoic acid(2-ene-VPA),2-propyl-4-pentenoic acid(4-ene-VPA)and valproic acid-O-glucuronic acid(VPA-G)in rat plasma.Results The main pharmacokinetic parameters of valproic acid in group 1,2,3 and 4:C_(max)were(27.27±8.10),(16.95±4.65),(28.25±7.34)and(52.26±24.50)μg·m L-1;t_(max)were(0.31±0.16),(0.18±0.09),(0.18±0.09)and(0.29±0.10)h;AUC_(0~24 h)were(59.31±10.08),(58.18±14.48),(67.15±8.23)and(100.76±22.08)μg·m L-1·h.The main pharmacokinetic parameters of 2-ene-VPA in four groups:C_(max)(peak area)were1.02×10^(7)±1.58×10^(6),9.99×10^(6)±1.64×10^(6),1.28×10^(7)±2.30×10^(6)and 2.05×10^(7)±3.90×10^(6);t_(max)were(1.67±0.52),(1.00±0.01),(1.00±0.01)and(1.17±0.41)h;AUC_(0~24 h)(peak area)were8.26×10^(7)±1.77×10^(7),9.96×10^(7)±2.25×10^(7),1.16×10^(8)±2.64×10^(7)and 1.28×10^(8)±6.59×10^(7).The main pharmacokinetic parameters of 4-ene-VPA in four groups:C_(max)(peak area)were 2.35×10^(6)±4.02×105,1.60×10^(6)±3.19×105,1.88×10^(6)±4.55×105and 3.84×10^(6)±1.20×10^(6);t_(max)were(0.90±0.22),(1.00±0.01),(0.80±0.27)and(1.00±0.01)h;AUC_(0~24 h)(peak area)were 1.40×10^(7)±2.81×10^(6),2.02×10^(7)±2.58×10^(6),2.22×10^(7)±2.59×10^(6)and 1.96×10^(7)±1.38×10^(6).The main pharmacokinetic parameters of VPA-G in four groups:C_(max)(peak area)were 1.57×10^(8)±1.96×10^(7),5.15×10^(7)±1.94×10^(7),1.19×10^(8)±3.27×10^(7)and 3.02×10^(8)±1.23×10^(8);t_(max)were(0.90±0.22),(0.50±0.01),(0.50±0.01)and(0.92±0.20)h;AUC_(0~24 h)(peak area)were 3.76×10^(8)±5.58×10^(7),2.40×10^(8)±4.58×10^(7),2.92×10^(8)±1.94×10^(7)and 5.61×10^(8)±1.37×10^(8).Conclusion The plasma concentrations of valproic acid and its metabolites are affected by carbamazepine and stiripentol.