五酯软胶囊和甲磺酸伊马替尼片联合给药后对大鼠体内伊马替尼药动学的影响
|
摘要
目的:研究五酯软胶囊和甲磺酸伊马替尼片联合给药后对大鼠体内伊马替尼药动学的影响。方法:将大鼠分为单次给药组和连续给药组。单次给药组大鼠分为伊马替尼1组(灌胃空白大豆油+伊马替尼混悬液10 mg/kg),五酯软胶囊低、中、高剂量+伊马替尼组(灌胃五酯软胶囊溶液134、268、536 mg/kg+伊马替尼混悬液10 mg/kg),每组6只,各组大鼠灌胃空白大豆油/五酯软胶囊溶液30 min后再灌胃伊马替尼混悬液。连续给药组大鼠分为伊马替尼2组(灌胃空白大豆油+灌胃伊马替尼混悬液10 mg/kg),五酯软胶囊低剂量+伊马替尼组(灌胃五酯软胶囊溶液134 mg/kg+伊马替尼混悬液10 mg/kg),每组6只,各组大鼠连续灌胃空白大豆油/五酯软胶囊溶液14 d,每天1次,末次给药30 min后,再灌胃伊马替尼混悬液。各组大鼠分别于伊马替尼给药前和末次给药后0.5、1、2、2.5、3、4、5、6、8、12、24、36 h取血100μL,采用高效液相色谱-串联质谱(HPLC-MS/MS)法测定大鼠血浆中伊马替尼的血药浓度,绘制药-时曲线,并用DAS 2.0软件拟合药动学参数。结果:单次给药后,与伊马替尼1组比较,五酯软胶囊低、中、高剂量+伊马替尼组大鼠c_(max)、t_(1/2)、AUC_(0-36 h)、AUMC_(0-36 h)均显著增加(P<0.05或P<0.01);连续给药后,与伊马替尼2组比较,伊马替尼+五酯软胶囊低剂量组大鼠c_(max)、t_(1/2)、AUMC_(0-36 h)均显著增加(P<0.05或P<0.01)。结论:五酯软胶囊单次给药和连续给药均对伊马替尼的药动学有影响,可增加伊马替尼血药浓度,并延长其半衰期。
OBJECTIVE:To study the effects of Wuzhi soft capsule and imatinib mesylate tablet on the pharmacokinetics of imatinib in rats. METHODS:The rats were divided into single administration group and consecutive administration group. The single administration group was divided into imatinib group one(ig administration of blank soybean oil + imatinib suspension 10 mg/kg),low-dose,medium-dose and high-dose of Wuzhi soft capsule + imatinib group(ig administration of Wuzhi soft capsule solution 134,268,536 mg/kg + imatinib suspension 10 mg/kg),with 6 rats in each group. Each group was given imatinib suspension intragastrically 30 min after intragastric administration of blank soybean oil/Wuzhi soft capsule solution. The consecutive administration group was divided into imatinib group two(ig administration of blank soybean oil+imatinib suspension 10 mg/kg),Wuzhi soft capsule low-dose+imatinib group(ig administration of Wuzhi soft capsule solution 134 mg/kg+imatinib suspension 10 mg/kg),with 6 rats in each group. Each group was given blank soybean oil/Wuzhi soft capsule solution intragastrically for consecutive 14 d,once a day;30 min after last administration,ig imatinib suspension. About 100 μL blood was collected before imatinib,0.5,1,2,2.5,3,4,5,6,8,12,24 and 36 h after medication. The plasma concentration of imatinib was determined by HPLC-MS/MS. The pharmacokinetic parameters were fitted by using DAS 2.0 software. RESULTS:After single administration,compared with imatinib group one,c_(max),t_(1/2),AUC_(0-36 h) and AUMC_(0-36 h) in low-dose,medium-dose and high-dose of Wuzhi soft capsule + imatinib group were increased significantly(P<0.05 or P<0.01). After consecutive administration,compared with imatinib group two,c_(max),t_(1/2) and AUMC_(0-36 h) of imatinib+low-dose of Wuzhi soft capsule group were increased significantly(P<0.05 or P<0.01). CONCLUSIONS:Single administration and consecutive administration of Wuzhi soft capsule influence the pharmacokinetics of imatinib, increase plasma concentration of imatinib and prolong half-time.
OBJECTIVE:To study the effects of Wuzhi soft capsule and imatinib mesylate tablet on the pharmacokinetics of imatinib in rats. METHODS:The rats were divided into single administration group and consecutive administration group. The single administration group was divided into imatinib group one(ig administration of blank soybean oil + imatinib suspension 10 mg/kg),low-dose,medium-dose and high-dose of Wuzhi soft capsule + imatinib group(ig administration of Wuzhi soft capsule solution 134,268,536 mg/kg + imatinib suspension 10 mg/kg),with 6 rats in each group. Each group was given imatinib suspension intragastrically 30 min after intragastric administration of blank soybean oil/Wuzhi soft capsule solution. The consecutive administration group was divided into imatinib group two(ig administration of blank soybean oil+imatinib suspension 10 mg/kg),Wuzhi soft capsule low-dose+imatinib group(ig administration of Wuzhi soft capsule solution 134 mg/kg+imatinib suspension 10 mg/kg),with 6 rats in each group. Each group was given blank soybean oil/Wuzhi soft capsule solution intragastrically for consecutive 14 d,once a day;30 min after last administration,ig imatinib suspension. About 100 μL blood was collected before imatinib,0.5,1,2,2.5,3,4,5,6,8,12,24 and 36 h after medication. The plasma concentration of imatinib was determined by HPLC-MS/MS. The pharmacokinetic parameters were fitted by using DAS 2.0 software. RESULTS:After single administration,compared with imatinib group one,c_(max),t_(1/2),AUC_(0-36 h) and AUMC_(0-36 h) in low-dose,medium-dose and high-dose of Wuzhi soft capsule + imatinib group were increased significantly(P<0.05 or P<0.01). After consecutive administration,compared with imatinib group two,c_(max),t_(1/2) and AUMC_(0-36 h) of imatinib+low-dose of Wuzhi soft capsule group were increased significantly(P<0.05 or P<0.01). CONCLUSIONS:Single administration and consecutive administration of Wuzhi soft capsule influence the pharmacokinetics of imatinib, increase plasma concentration of imatinib and prolong half-time.
引文
[1]HERVIOU P,THIVAT E,RICHARD D,et al.Therapeutic drug monitoring and tyrosine kinase inhibitors[J].Oncol Lett,2016,12(2):1223-1232.
[2]DEMETRI GD,WANG Y,WEHRLE E,et al.Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors[J].J Clin Oncol,2009,27(19):3141-3147.
[3]宋玲玲,国华智,王玲.慢性粒细胞白血病患者血清α1-酸性糖蛋白、伊马替尼浓度与疗效关系[J].齐齐哈尔医学院学报,2016,37(12):1527-1528.
[4]徐泽宽,徐皓.甲磺酸伊马替尼血药浓度监测对指导胃肠间质瘤治疗及评估预后临床意义[J].中国实用外科杂志,2015,35(4):387-390.
[5]GOTTA V,WIDMER N,DECOSTERD LA,et al.Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization:results from a randomized controlled trial[J].Cancer Chemother and Pharmacol,2014,74(6):1307-1319.
[6]TAI T,HUANG X,SU Y,et al.Glycyrrhizin accelerates the metabolism of triptolide through induction of CYP3Ain rats[J].J Ethnopharmacol,2014,152(2):358-363.
[7]TU JH,HE YJ,CHEN Y,et al.Effect of glycyrrhizin on the activity of CYP3A enzyme in humans[J].Eur J Clin Pharmacol,2010,66(8):805-810.
[8]ZHAO J,SUN T,WU JJ,et al.Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G,two lignan analogs derived from Schisandra chinensis[J].Fitoterapia,2017.DOI:10.1016/j.fitote.2017.03.010.
[9]国家药典委员会.中华人民共和国药典:四部[S].2015年版.北京:中国医药科技出版社,2015:363.
[10]GSCHWIND HP,PFAAR U,WALDMEIER F,et al.Metabolism and disposition of imatinib mesylate in healthy volunteers[J].Drug Metab Dispos,2005,33(10):1503-1512.
[11]DOHSE M,SCHARENBERG C,SHUKLA S,et al.Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib,nilotinib and dasatinib[J].Drug Metab Dispos,2010,38(8):1371-1380.
[12]LUO X,LI T,YU Z,et al.The impact of azole antifungal drugs on imatinib metabolism in human liver microsomes[J].Xenobiotica,2018.DOI:10.1080/00498254.2018.1473662.
[13]OOSTENDORP RL,BUCKLE T,BEIJNEN JH,et al.The effect of P-gp(Mdr1a/1b),BCRP(Bcrp1)and P-gp/BCRP inhibitors on the in vivo absorption,distribution,metabolism and excretion of imatinib[J].Invest New Drugs,2009,27(1):31-40.
[14]LIU X,XU T,LI W,et al.The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats[J].Biomed Res Int,2013.DOI:10.1155/2013/789184.
[15]WANG Z,WANG L,XIA M,et al.Pharmacokinetics interaction between imatinib and genistein in rats[J].Biomed Res Int,2015.DOI:10.1155/2015/368976.
[16]SMITH P,BULLOCK JM,BOOKER BM,et al.The influence of St John’s wort on the pharmacokinetics and protein binding of imatinib mesylate[J].Pharmacotherapy,2004,24(11):1508-1514.
[17]FRYE RF,FITZGERALD SM,LAGATTUTA TF,et al.Effect of St John’s wort on imatinib mesylate pharmacokinetics[J].Clin Pharmacol Ther,2004,76(4):323-329.
[18]PENG B,DUTREIX C,MEHRING G,et al.Absolute bioavailability of imatinib(Glivec)orally versus intravenous infusion[J].J Clin Pharmacol,2004,44(2):158-162.
[2]DEMETRI GD,WANG Y,WEHRLE E,et al.Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors[J].J Clin Oncol,2009,27(19):3141-3147.
[3]宋玲玲,国华智,王玲.慢性粒细胞白血病患者血清α1-酸性糖蛋白、伊马替尼浓度与疗效关系[J].齐齐哈尔医学院学报,2016,37(12):1527-1528.
[4]徐泽宽,徐皓.甲磺酸伊马替尼血药浓度监测对指导胃肠间质瘤治疗及评估预后临床意义[J].中国实用外科杂志,2015,35(4):387-390.
[5]GOTTA V,WIDMER N,DECOSTERD LA,et al.Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization:results from a randomized controlled trial[J].Cancer Chemother and Pharmacol,2014,74(6):1307-1319.
[6]TAI T,HUANG X,SU Y,et al.Glycyrrhizin accelerates the metabolism of triptolide through induction of CYP3Ain rats[J].J Ethnopharmacol,2014,152(2):358-363.
[7]TU JH,HE YJ,CHEN Y,et al.Effect of glycyrrhizin on the activity of CYP3A enzyme in humans[J].Eur J Clin Pharmacol,2010,66(8):805-810.
[8]ZHAO J,SUN T,WU JJ,et al.Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G,two lignan analogs derived from Schisandra chinensis[J].Fitoterapia,2017.DOI:10.1016/j.fitote.2017.03.010.
[9]国家药典委员会.中华人民共和国药典:四部[S].2015年版.北京:中国医药科技出版社,2015:363.
[10]GSCHWIND HP,PFAAR U,WALDMEIER F,et al.Metabolism and disposition of imatinib mesylate in healthy volunteers[J].Drug Metab Dispos,2005,33(10):1503-1512.
[11]DOHSE M,SCHARENBERG C,SHUKLA S,et al.Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib,nilotinib and dasatinib[J].Drug Metab Dispos,2010,38(8):1371-1380.
[12]LUO X,LI T,YU Z,et al.The impact of azole antifungal drugs on imatinib metabolism in human liver microsomes[J].Xenobiotica,2018.DOI:10.1080/00498254.2018.1473662.
[13]OOSTENDORP RL,BUCKLE T,BEIJNEN JH,et al.The effect of P-gp(Mdr1a/1b),BCRP(Bcrp1)and P-gp/BCRP inhibitors on the in vivo absorption,distribution,metabolism and excretion of imatinib[J].Invest New Drugs,2009,27(1):31-40.
[14]LIU X,XU T,LI W,et al.The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats[J].Biomed Res Int,2013.DOI:10.1155/2013/789184.
[15]WANG Z,WANG L,XIA M,et al.Pharmacokinetics interaction between imatinib and genistein in rats[J].Biomed Res Int,2015.DOI:10.1155/2015/368976.
[16]SMITH P,BULLOCK JM,BOOKER BM,et al.The influence of St John’s wort on the pharmacokinetics and protein binding of imatinib mesylate[J].Pharmacotherapy,2004,24(11):1508-1514.
[17]FRYE RF,FITZGERALD SM,LAGATTUTA TF,et al.Effect of St John’s wort on imatinib mesylate pharmacokinetics[J].Clin Pharmacol Ther,2004,76(4):323-329.
[18]PENG B,DUTREIX C,MEHRING G,et al.Absolute bioavailability of imatinib(Glivec)orally versus intravenous infusion[J].J Clin Pharmacol,2004,44(2):158-162.