The University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA.
J Cardiovasc Pharmacol Ther. 2010 Dec;15(4):373-9. doi: 10.1177/1074248410372926. Epub 2010 Aug 12.
to assess the impact of paroxetine coadministration on the stereoselective pharmacokinetic (PK) properties of carvedilol.
prospective, randomized, 2-phase crossover.
the University of Michigan General Clinical Research Unit and Michigan Clinical Research Unit.
twelve healthy volunteers aged 18 to 45 years, male and female, receiving no treatment with prescription or nonprescription medications.
participants received single dose oral carvedilol (12.5 mg) with and without coadministration of immediate-release paroxetine (10 mg orally twice daily), in random order. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, and 24 hours post-carvedilol dose for determination of R and S carvedilol plasma enantiomer concentrations by high pressure liquid chromatography.
pharmacokinetic (PK) parameters were calculated for each enantiomer by noncompartmental methods and compared between study phases by analysis of variance (ANOVA) controlling for study phase order and subject, with Tukey's studentized range test post hoc. Area under the concentration-time curve (AUC) increased significantly with paroxetine coadministration, approximately 2.5-fold and 1.9-fold for the R and S enantiomers, respectively. R/S AUC ratio increased significantly, from approximately 2.3 to 3.0. Individual increases in enantiomeric AUCs with paroxetine coadministration ranged from 0% to 571% and changes in R/S ratio ranged from -8% to 108%. Heart rate, P-R interval, and blood pressure were monitored and no clinically significant changes in carvedilol effects were noted.
this study demonstrated a PK drug-drug interaction between paroxetine and carvedilol, with considerable interparticipant variability in carvedilol PK parameters and magnitude of drug interaction. Stereoselectivity of carvedilol metabolism is preserved with paroxetine coadministration, and R/S AUC ratio generally widens. Although this drug interaction could potentially increase adrenergic antagonism and have significant clinical effects in patients, these effects were not seen in our healthy volunteer participants.
评估帕罗西汀合用对卡维地洛立体选择性药代动力学（PK）特性的影响。
前瞻性、随机、2 期交叉。
密歇根大学普通临床研究单位和密歇根临床研究单位。
12 名年龄在 18 至 45 岁之间的健康志愿者，男女均无处方或非处方药物治疗。
参与者接受单次口服卡维地洛（12.5 毫克），并随机接受或不接受即时释放帕罗西汀（10 毫克口服，每日 2 次）的合并治疗。在卡维地洛给药后 0、0.25、0.5、0.75、1、1.5、2、4、6、8、10、12 和 24 小时采集血样，通过高压液相色谱法测定 R 和 S 卡维地洛血浆对映体浓度。
通过非房室方法计算每个对映体的药代动力学（PK）参数，并通过方差分析（ANOVA）进行比较，同时控制研究阶段顺序和个体，并用 Tukey 的学生化范围检验进行事后检验。与帕罗西汀合用后，R 和 S 对映体的 AUC 均显著增加，分别约为 2.5 倍和 1.9 倍。R/S AUC 比值显著增加，从约 2.3 增加到 3.0。帕罗西汀合用后，个体对映体 AUC 的增加范围为 0%至 571%，R/S 比值的变化范围为-8%至 108%。监测心率、P-R 间隔和血压，未发现卡维地洛作用的临床显著变化。
这项研究表明帕罗西汀和卡维地洛之间存在 PK 药物相互作用，卡维地洛 PK 参数和药物相互作用的幅度存在相当大的个体间变异性。与帕罗西汀合用后，卡维地洛代谢的立体选择性得以保留，R/S AUC 比值通常会变宽。尽管这种药物相互作用可能会增加肾上腺素拮抗剂的作用，并对患者产生显著的临床影响，但在我们的健康志愿者参与者中并未观察到这些影响。
