title: Nonlinear pharmacokinetic properties of mildronate capsules: a randomized, open-label, single- and multiple-dose study in healthy volunteers.
abstract: Mildronate has been used as antianginal drug in parts of Europe for many years, but its pharmacokinetic (PK) properties in humans remain unclear. This study was designed to assess and compare the PK properties of mildronate capsules after single escalating oral dose and multiple doses in healthy Chinese volunteers. Volunteers were randomly assigned to receive a single dose of 250, 500, 1000, 1250 or 1500 mg of mildronate capsules. Those who received the 500-mg dose continued on the multiple-dose phase and received 500 mg three times a day for 13 days. Plasma drug concentrations were analysed by ultraperformance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Tolerability was assessed throughout the study. A total of 40 Chinese volunteers were enrolled in the study. No period or sequence effect was observed. Area under the concentration and C(max) were increased proportionally with the dose levels, whereas t(1/2) and V(d)/f were dependent on the dose. Nonlinear PK properties were found at doses of 250-1500 mg. There was an accumulation after multiple-dose administration. No serious adverse events (AEs) were reported in the PK study. The formulation was well tolerated.
authors.affiliation: Clinical Pharmacy Research Institute, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Li-Jing
authors.initials: LJ
authors.lastname: Cai
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Qi-Zhi
authors.initials: QZ
authors.lastname: Zhang
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Peng
mesh_terms: D000328:Adult; D002138:Calibration; D002214:Capsules; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002681:China; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D057230:Limit of Detection; D008297:Male; D008657:Metabolic Clearance Rate; D008763:Methylhydrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D055815:Young Adult; D050563:gamma-Butyrobetaine Dioxygenase / Q000037:antagonists & inhibitors*
chemical_list: D002214:Capsules; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D008763:Methylhydrazines; C050147:3-(2,2,2-trimethylhydrazine)propionate; D050563:gamma-Butyrobetaine Dioxygenase