Abstract:
This study assessed the pharmacokinetics (PKs) and pharmacodynamics (PDs) of two antihypertensive drugs, nifedipine and captopril, by exploring their main (blood pressure [BP]) and secondary effects (heart rate [HR] and QT interval [QT]) in spontaneously hypertensive rats. This study aimed to assess the relationship between PKs and PDs. Using these PD parameters, BP, HR, and QT during coadministration were estimated. The coadministration of nifedipine and captopril resulted in an increase in nifedipine\'s total body clearance (CLtot) and a reduction in its mean residence time (MRT) with an increase in the terminal elimination half-life (t1/2) and volume of distribution at steady state (Vdss) of captopril. However, no significant PK interactions were observed. During monotherapy, BP reduced rapidly following nifedipine infusion. Subsequently, despite the increase in nifedipine plasma concentration, BP recovered, likely because of homeostasis. Similar results were observed with coadministration. Subsequently, BP demonstrated a sustained reduction that was greater than or equal to the additive effect estimated from each PK. Captopril exhibited a minimal effect on HR, except for a transient increase observed immediately after starting infusion, consistent with observations during coadministration. Subsequently, the HR reduction was nearly equal to that calculated from the nifedipine PK. QT prolongation was more rapid with captopril than with nifedipine. Although QT prolongation during the initial 60 min of coadministration was approximately the sum of both effects, the recovery period to baseline QT was faster than that in the simulation.
摘要:
这项研究评估了两种抗高血压药物的药代动力学(PKs)和药效学(PDs),硝苯地平和卡托普利,通过探索其在自发性高血压大鼠中的主要作用(血压[BP])和次要作用(心率[HR]和QT间期[QT])。本研究旨在评估PKs和PDs之间的关系。使用这些PD参数,BP,HR,估计联合用药期间的QT。硝苯地平和卡托普利的共同给药导致硝苯地平的总体内清除率(CLtot)增加,平均停留时间(MRT)减少,终末消除半衰期(t1/2)和卡托普利稳态分布体积(Vdss)增加。然而,没有观察到显著的PK相互作用。在单药治疗期间,输注硝苯地平后,BP迅速降低。随后,尽管硝苯地平血浆浓度增加,BP恢复,可能是因为稳态。在共同施用的情况下观察到类似的结果。随后,BP表现出大于或等于从每个PK估计的累加效应的持续降低。卡托普利对HR的影响很小,除了在开始输注后立即观察到的瞬时增加,与共同管理期间的观察结果一致。随后,HR降低与硝苯地平PK计算的几乎相等.卡托普利的QT延长比硝苯地平更快。尽管共同给药的最初60分钟内的QT延长大约是两种作用的总和,到基线QT的恢复期比模拟中的更快。