Jing-Ying Jia1, You-Li Lu2, Xiao-Chuan Li2, Gang-Yi Liu1, Shui-Jun Li3, Yun Liu1, Yan-Mei Liu1, Chen Yu1, Yi-Ping Wang2. 1. Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China. 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. 3. Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Abstract
BACKGROUND:Depside salts from Salvia miltiorrhiza, with active components of lithospermic acid B (LSB), rosmarinic acid (RA), and lithospermic acid (LA), are a multicomponent drug marketed in China for the treatment of coronary heart disease. OBJECTIVES: The aims of this study were to determine the concentrations of LSB, RA, and LA in human plasma and urine, and to compare the pharmacokinetic properties of depside salts from S miltiorrhiza in healthy Chinese volunteers. METHODS: A randomized, open-label, single-dose study was conducted in healthy Chinese volunteers. Participants were randomly assigned to receive a single intravenous infusion of 100 or 200 mg of depside salts from S miltiorrhiza. Blood was collected through a venous cannula prior to study drug administration (0 min) and at 10, 20, 30, 60, 65, 70, 80, and 90 minutes and 2, 3, 4, 6, 8, 12, and 24 hours after study drug administration. Urine samples were taken before study drug administration (0) and at 0 to 12 and 12 to 24 hours after study drug administration. LSB, RA, and LA concentrations in serum and urine were analyzed by an LC-MS/MS method. Tolerability was determined by clinical assessment; vital signs (ie, blood pressure, heart rate, breathing rate, body temperature) monitoring at baseline and at the end of the study, clinical laboratory tests (ie, hematology, blood biochemistry, hepatic function, renal function, urinalysis), 12-lead ECG measurements, and physical examinations at baseline and after completion of the study. RESULTS:Twelve Chinese volunteers (6 males, 6 females; mean [SD] age, 25.2 [3.8] years; mean height, 165.7 [8.9] cm; mean body mass index, 21.6 [2.5] kg/m(2)) were enrolled in the study. Peak plasma concentrations of LSB, RA and LA were observed at 0.3 to 1 hour following the 1-hour intravenous infusion, with respective mean (SD) Cmax of 4925 (1861), 174 (61), and 361 (101) ng/mL for the 100-mg dose and 10,285 (2259), 308 (77), and 674 (85) ng/mL for the 200-mg dose. The AUClast values for LSB, RA, and LA were 4537 (1265), 129 (28), and 1229 (330) ng/mL/h, respectively, for the 100-mg dose and 10,426 (2589), 260 (53), and 2792 (729) ng/mL/h for the 200-mg dose. No significant difference in pharmacokinetic parameters was observed between male and female subjects. Three metabolites were found in the plasma with low concentrations. The urinary excretion recoveries of LSB, RA, and LA were 0.58% (0.42%), 25.21% (20.61%), and 10.02% (7.72%) for the 100-mg dose and 0.38% (0.18%), 20.11% (10.50%), and 6.34% (3.20%) for the 200-mg dose. No adverse events were reported by the subjects or found by the investigators in the analysis of vital signs, 12-lead ECG measurements, physical examinations, or clinical laboratory tests. CONCLUSIONS: Following single intravenous infusion of 100 or 200 mg of depside salts from S miltiorrhiza to healthy Chinese subjects, no statistical differences in pharmacokinetic parameters were observed between males and females. The 2 doses of depside salts from S miltiorrhiza were clinically well tolerated during the study.
RCT Entities:
BACKGROUND:Depside salts from Salvia miltiorrhiza, with active components of lithospermic acid B (LSB), rosmarinic acid (RA), and lithospermic acid (LA), are a multicomponent drug marketed in China for the treatment of coronary heart disease. OBJECTIVES: The aims of this study were to determine the concentrations of LSB, RA, and LA in human plasma and urine, and to compare the pharmacokinetic properties of depside salts from S miltiorrhiza in healthy Chinese volunteers. METHODS: A randomized, open-label, single-dose study was conducted in healthy Chinese volunteers. Participants were randomly assigned to receive a single intravenous infusion of 100 or 200 mg of depside salts from S miltiorrhiza. Blood was collected through a venous cannula prior to study drug administration (0 min) and at 10, 20, 30, 60, 65, 70, 80, and 90 minutes and 2, 3, 4, 6, 8, 12, and 24 hours after study drug administration. Urine samples were taken before study drug administration (0) and at 0 to 12 and 12 to 24 hours after study drug administration. LSB, RA, and LA concentrations in serum and urine were analyzed by an LC-MS/MS method. Tolerability was determined by clinical assessment; vital signs (ie, blood pressure, heart rate, breathing rate, body temperature) monitoring at baseline and at the end of the study, clinical laboratory tests (ie, hematology, blood biochemistry, hepatic function, renal function, urinalysis), 12-lead ECG measurements, and physical examinations at baseline and after completion of the study. RESULTS: Twelve Chinese volunteers (6 males, 6 females; mean [SD] age, 25.2 [3.8] years; mean height, 165.7 [8.9] cm; mean body mass index, 21.6 [2.5] kg/m(2)) were enrolled in the study. Peak plasma concentrations of LSB, RA and LA were observed at 0.3 to 1 hour following the 1-hour intravenous infusion, with respective mean (SD) Cmax of 4925 (1861), 174 (61), and 361 (101) ng/mL for the 100-mg dose and 10,285 (2259), 308 (77), and 674 (85) ng/mL for the 200-mg dose. The AUClast values for LSB, RA, and LA were 4537 (1265), 129 (28), and 1229 (330) ng/mL/h, respectively, for the 100-mg dose and 10,426 (2589), 260 (53), and 2792 (729) ng/mL/h for the 200-mg dose. No significant difference in pharmacokinetic parameters was observed between male and female subjects. Three metabolites were found in the plasma with low concentrations. The urinary excretion recoveries of LSB, RA, and LA were 0.58% (0.42%), 25.21% (20.61%), and 10.02% (7.72%) for the 100-mg dose and 0.38% (0.18%), 20.11% (10.50%), and 6.34% (3.20%) for the 200-mg dose. No adverse events were reported by the subjects or found by the investigators in the analysis of vital signs, 12-lead ECG measurements, physical examinations, or clinical laboratory tests. CONCLUSIONS: Following single intravenous infusion of 100 or 200 mg of depside salts from S miltiorrhiza to healthy Chinese subjects, no statistical differences in pharmacokinetic parameters were observed between males and females. The 2 doses of depside salts from S miltiorrhiza were clinically well tolerated during the study.
Entities:
Keywords:
LC-MS/MS; healthy volunteers; liquid chromatography tandem mass spectrometry; lithospermic acid; lithospermic acid B; pharmacokinetics; rosmarinic acid