Kapil R P, Emm T A, Mousa S A, Padovani P K, Quon C Y, Lam G N
Drug Metabolism and Pharmacokinetics Section, Stine-Haskell Research Center, DuPont Merck Pharmaceutical Company, Newark, DE 19714, USA.
Thromb Res. 1997 May 1;86(3):221-32. doi: 10.1016/s0049-3848(97)00065-0.
The pharmacokinetic-pharmacodynamic (PK/PD) relationship of a novel platelet glycoprotein IIb/IIIa receptor antagonist, XU063, was evaluated as a function of biological matrix in beagle dogs. The disposition of 14C-radioactivity in various blood or plasma matrices and kinetics of inhibition of adenosine diphosphate (ADP) induced platelet aggregation were determined in beagle dogs following an intravenous infusion of 14C-XU063 at 2 micrograms/kg for 45 min. The 14C-radioactivity was maximum in platelet poor plasma (PPP) harvested from blood collected in EDTA and lowest in PPP harvested from blood collected in citrated vacutainers over the entire concentration versus time profile during and post infusion. The 14C-radioactivity values in blood and platelet rich plasma (PRP) were comparable and were between EDTA PPP and citrated PPP values. The resultant estimates of the PK and PD parameters of 14C-XU063 varied widely depending on the type of matrix used. The systemic clearance values for 14C-XU063 were 1 and 10 mL/min/kg for EDTA and citrated PPP, respectively. The values for the volume of distribution at steady-state were 0.2 and 1.3 L/kg, for EDTA and citrated PPP, respectively. The terminal elimination half-life appeared independent of the matrix with a median value of 2 h. The estimated ex vivo IC50 values of XU063 ranged from 0.4 ng/mL (citrated PPP, platelet free drug) to 7 ng/mL (EDTA PPP, total drug). These results demonstrated the dependence of PK and PD parameters of antiplatelet agent XU063 on the type of biological matrix used to determine concentrations of XU063. The pros and cons of various blood sample collection methods for the evaluation of PK/PD relationship of potential antiplatelet agents are presented.
在比格犬中，评估了新型血小板糖蛋白IIb/IIIa受体拮抗剂XU063的药代动力学-药效学（PK/PD）关系与生物基质的函数关系。在比格犬静脉输注2μg/kg的14C-XU063 45分钟后，测定了14C放射性在各种血液或血浆基质中的分布以及对二磷酸腺苷（ADP）诱导的血小板聚集的抑制动力学。在输注期间和输注后整个浓度-时间曲线中，从EDTA抗凝血液中采集的血小板贫乏血浆（PPP）中的14C放射性最高，而从枸橼酸盐真空采血管采集的血液中收获的PPP中的14C放射性最低。血液和富血小板血浆（PRP）中的14C放射性值相当，介于EDTA PPP和枸橼酸盐PPP值之间。14C-XU063的PK和PD参数的最终估计值因所用基质类型而异。14C-XU063在EDTA和枸橼酸盐PPP中的全身清除率值分别为1和10 mL/min/kg。稳态分布容积值在EDTA和枸橼酸盐PPP中分别为0.2和1.3 L/kg。终末消除半衰期似乎与基质无关，中位数为2小时。XU063的体外IC50估计值范围为0.4 ng/mL（枸橼酸盐PPP，无血小板药物）至7 ng/mL（EDTA PPP，总药物）。这些结果表明抗血小板药物XU063的PK和PD参数取决于用于测定XU063浓度的生物基质类型。本文介绍了各种血液样本采集方法在评估潜在抗血小板药物PK/PD关系方面的优缺点。
