乐卡地平与多索茶碱在大鼠体内药动学相互影响

Study on the Pharmacokinetic Interaction between Lercanidipine and Doxofylline in Rats

目的探讨乐卡地平与多索茶碱联合应用在大鼠体内药动学相互影响特征。方法大鼠随机分为3组,分别灌胃给药乐卡地平、多索茶碱、乐卡地平+多索茶碱,经眼眶取血后离心得血浆。建立HPLC法同时测定乐卡地平与多索茶碱浓度,描绘血药浓度-时间曲线,采用DAS 3.2软件对药动学参数进行分析。结果乐卡地平单用与联用主要药动学参数如下,AUC_(0-∞):(2389.80±579.60)和(1402.64±166.18)μg/(h·mL);MRT_(0-∞):(5.91±0.95)和(4.97±0.31)h;t 1/2:(2.78±0.76)和(2.10±0.78)h;T_(max):(3.00±1.10)和(3.33±1.03)h;CL:(6.60±1.66)和(10.82±1.26)L/(h·kg);C_(max):(388.44±70.64)和(259.20±51.16)ng·mL^(-1);多索茶碱单用与联用主要药动学参数如下,AUC_(0-∞):(41.30±2.26)和(17.71±2.40)mg/(h·mL);MRT_(0-∞):(2.09±0.16)和(2.34±0.34)h;t 1/2:(1.51±0.28)和(1.44±0.33)h;T_(max):(0.50±0.00)和(0.50±0.00)h;CL:(1.21±0.07)和(2.86±0.34)L/(h·kg);C_(max):(15.46±0.84)和(9.18±0.68)mg·mL^(-1),结论与单用相比,联用后乐卡地平的AUC_(0-∞)、C_(max)、K值等显著降低,CL显著增大(P<0.01);多索茶碱的AUC_(0-∞)、C_(max)等显著降低,CL等显著增加(P<0.01)。二种药物联用导致吸收延缓,消除加快,因此不建议二者联用。

OBJECTIVE To investigate the pharmacokinetic interaction of the lercanidipinecombinewith doxofylline in rats.METHODS Rats wererandomly divided into three groups,which were administrated with lercanidipine,doxofylline,lecardipine+doxofylline,respectively.Blood was collected from orbitat different time points,and plasma was obtained by centrifugation.A HPLC method was established for simultaneous determination of lercanidipine and doxofyllineconcentrations,the average blood concentration-time curve was drawn and the pharmacokinetic parameters were analyzed by DAS 3.2 software.RESULTS The main pharmacokinetic parameters of lercanidipinein alone and in combination were as follows:AUC_(0-∞):(2389.80±579.60)and(1402.64±166.18)μg/(h·mL);MRT_(0-∞):(5.91±0.95)and(4.97±0.31)h;t 1/2:(2.78±0.76)and(2.10±0.78)h;T_(max):(3.00±1.10)and(3.33±1.03)h;CL:(6.60±1.66)and(10.82±1.26)L/(h·kg);C_(max):(388.44±70.64)and(259.20±51.16)ng·mL^(-1).The pharmacokinetic parameters of doxofylline alone and in combination were as follows:AUC_(0-∞):(41.30±2.26)and(17.71±2.40)mg/(h·mL);MRT_(0-∞):(2.09±0.16)and(2.34±0.34)h;t 1/2:(1.51±0.28)and(1.44±0.33)h;T_(max):(0.50±0.00)and(0.50±0.00)h;CL:(1.21±0.07)and(2.86±0.34)L/(h·kg);C_(max):(15.46±0.84)and(9.18±0.68)mg·mL^(-1).CONCLUSION Compared with single use,the AUC_(0-∞),C_(max)and K valuesof lercanidipinewere significantly decreased and CL was significantly increased after combination(P<0.01).The AUC_(0-∞)、C_(max)of doxofyllinewere significantly decreased,while CL was significantly increased(P<0.01).The combination of the two drugs leads to delayed absorption and accelerated elimination,so the combination of the two drugs is not recommended.