title: Pharmacokinetics, Pharmacodynamics, and Tolerability of Single and Multiple Doses of Trandolapril, an Effective Angiotensin-Converting Enzyme Inhibitor, in Healthy Chinese Subjects.
abstract: 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 (C max, 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 T max. 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.
authors: Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Xinmin Street, Changchun, 130061, People's Republic of China.
authors: Xiaojiao
authors: X
authors: Li
authors: The First Hospital of Jilin University, Changchun, People's Republic of China.
authors: Chang
authors: C
authors: Liu
authors: Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Xinmin Street, Changchun, 130061, People's Republic of China.
authors: Min
authors: M
authors: Wu
authors: Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Xinmin Street, Changchun, 130061, People's Republic of China.
authors: Hong
authors: H
authors: Zhang
authors: Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Xinmin Street, Changchun, 130061, People's Republic of China.
authors: Yanfu
authors: Y
authors: Sun
authors: College of Life Science, Jilin University, Changchun, Jilin, People's Republic of China.
authors: Longmei
authors: L
authors: Cheng
authors: Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Xinmin Street, Changchun, 130061, People's Republic of China.
authors: Hong
authors: H
authors: Chen
authors: Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Xinmin Street, Changchun, 130061, People's Republic of China.
authors: Chengjiao
authors: C
authors: Liu
authors: Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Xinmin Street, Changchun, 130061, People's Republic of China.
authors: Lizhi
authors: L
authors: Yang
authors: Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Xinmin Street, Changchun, 130061, People's Republic of China.
authors: Qi
authors: Q
authors: Zhang
authors: Jilin University, Changchun, People's Republic of China.
authors: Yuchen
authors: Y
authors: Cao
authors: College of Life Science, Jilin University, Changchun, Jilin, People's Republic of China.
authors: Jingkai
authors: J
authors: Gu
authors: Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Xinmin Street, Changchun, 130061, People's Republic of China. dingyanhua2003@126.com.
authors: Yanhua
authors: Y
authors: Ding
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D044466:Asian People; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D011355:Prodrugs; C052035:trandolapril; C061095:trandolaprilat