Pharmacokinetics, Pharmacodynamics, and Tolerability of Single and Multiple Doses of Trandolapril, an Effective Angiotensin-Converting Enzyme Inhibitor, in Healthy Chinese Subjects
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- 作者：Xiaojiao Li ; Chang Liu ; Min Wu ; Hong Zhang…
- 刊名：European Journal of Drug Metabolism and Pharmacokinetics
- 出版年：2016
- 出版时间：August 2016
- 年：2016
- 卷：41
- 期：4
- 页码：373-384
- 全文大小：2,072 KB
- 刊物主题：Pharmacology/Toxicology; Pharmacy; Human Physiology; Pharmaceutical Sciences/Technology; Medical Biochemistry;
- 出版者：Springer Paris
- ISSN：2107-0180
- 卷排序：41
文摘
Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1–2–4 mg, 2–4–1 mg, and 4–1–2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC–MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (Cmax, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0–∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than Tmax. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.Xiaojiao Li and Chang Liu have contributed equally to this work.